Autism & Genetics

Internet Resources

We report the identification of six patients with 3q29 microdeletion syndrome. The clinical phenotype is variable despite an almost identical deletion size. The phenotype includes mild-to-moderate mental retardation, with only slightly dysmorphic facial features that are similar in most patients: a long and narrow face, short philtrum, and high nasal bridge. Autism, gait ataxia, chest-wall deformity, and long and tapering fingers were noted in at least two of six patients. Additional featuresmdashincluding microcephaly, cleft lip and palate, horseshoe kidney and hypospadias, ligamentous laxity, recurrent middle ear infections, and abnormal pigmentationmdashwere observed, but each feature was only found once, in a single patient. The microdeletion is sim1.5 Mb in length, with molecular boundaries mapping within the same or adjacent bacterial artificial chromosome (BAC) clones at either end of the deletion in all patients. The deletion encompasses 22 genes, including PAK2 and DLG1, which are autosomal homologues of two known X-linked mental retardation genes, PAK3 and DLG3. The presence of two nearly identical low-copy repeat sequences in BAC clones on each side of the deletion breakpoint suggests that nonallelic homologous recombination is the likely mechanism of disease causation in this syndrome.
Lionel Willatt et al
The finding that, in a clinic for children with developmental disorders, 2 of 40 male referrals had 47,XYY karyotypes suggests that the rate of this sex chromosome anomaly may be increased in PDD's.
Rob Nicolson, Shree Bhalerao, Leon Sloman
A premise of the approaches we describe is that gene expression is regulated in cells from autistic individuals as a consequence of the disease process. It may be useful to detect such changes in order to identify selective biological markers for autism.
Amy Purcell et al
Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.
L. Feuk et al
Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVDmdash5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.
Lars Feuk et al
In autism, a specific aetiological diagnosis is of considerable value, both to establish prognosis and to provide adequate care, as well as for genetic counselling and for unravelling its pathogenetic mechanisms. The present study shows that an extensive, structured work up yields a diagnosis in at least 20%, and possibly up to 36% of adult autistic subjects with mental retardation.
C.D.M. van Karnebeek et al, Journal of Medical Genetics
Affymetrix also announced the microarray platform is part of what sponsors are calling the largest study ever conducted to find the genes associated with autism and determine its causes.
Small Times
Santa Clara-based Affymetrix (NASDAQ:AFFX) said the Autism Gene Discovery Project will be conducted by the Autism Consortium and the Broad Institute of the Massachusetts Institute of Technology and Harvard University. Researchers will use Affymetrix applications to perform whole-genome association studies across 3,700 samples collected from autistic subjects.
Silicon Valley Business Journal
These results demonstrate that: (1) UBE3A is imprinted in fibroblasts, lymphoblasts and neural-precursor cells; (2) allelic imprint status is maintained in the majority of cells upon duplication both in cis and in trans; and (3) alleles on specific types of duplications may exhibit an increase in expression levels/loss of expression constraints.
Laura B.K. Herzing, Edwin H. Cook, Jr, David H. Ledbetter
15q11– q13 contains many imprinted genes, and undergoes duplicon-mediated rearrangements, including deletions, duplications and triplications, and generation of marker chromosomes. Abnormal phenotypes, including language delays and autism spectrum disorders, are primarily observed with maternal 15q11-q13 duplication... Results demonstrate that: (1) UBE3A is imprinted in fibroblasts, lymphoblasts and neural-precursor cells; (2) allelic imprint status is maintained in the majority of cells upon duplication both in cis and in trans; and (3) alleles on specific types of duplications may exhibit an increase in expression levels/loss of expression constraints.
Laura Herzing et al
Autism is a spectrum of neurodevelopmental disorders with a primarily genetic etiology exhibiting deficits in (1) development of language and (2) social relationships and (3) patterns of repetitive, restricted behaviors or interests and resistance to change. Elevated platelet serotonin (5-HT) in 20%-25% of cases and efficacy of selective 5-HT reuptake inhibitors (SSRIs) in treating anxiety, depression, and repetitive behaviors points to the 5-HT transporter (5-HTT; SERT) as a strong candidate gene. Association studies involving the functional insertion/deletion polymorphism in the promoter (5-HTTLPR) and a polymorphism in intron 2 are inconclusive, possibly because of phenotypic heterogeneity. Nonetheless, mounting evidence for genetic linkage of autism to the chromosome 17q11.2 region that harbors the SERT locus (SLC6A4) supports a genetic effect at or near this gene. We confirm recent reports of sex-biased genetic effects in 17q by showing highly significant linkage driven by families with only affected males. Association with common alleles fails to explain observed linkage; therefore, we hypothesized that preferential transmission of multiple alleles does explain it. From 120 families, most contributing to linkage at 17q11.2, we found four coding substitutions at highly conserved positions and 15 other variants in 5' noncoding and other intronic regions transmitted in families exhibiting increased rigid-compulsive behaviors. In the aggregate, these variants show significant linkage to and association with autism. Our data provide strong support for a collection of multiple, often rare, alleles at SLC6A4 as imposing risk of autism.
J.S. Sutcliffe et al
Certain loci on the human genome, such as glutathione S-transferase M1 (GSTM1), do not permit heterozygotes to be reliably determined by commonly used methods. Association of such a locus with a disease is therefore generally tested with a case-control design. When subjects have already been ascertained in a case-parent design however, the question arises as to whether the data can still be used to test disease association at such a locus. A likelihood ratio test was constructed that can be used with a case-parents design but has somewhat less power than a Pearson's chi-squared test that uses a case-control design. The test is illustrated on a novel dataset showing a genotype relative risk near 2 for the homozygous GSTM1 deletion genotype and autism. Although the case-control design will remain the mainstay for a locus with a deletion, the likelihood ratio test will be useful for such a locus analyzed as part of a larger case-parent study design. The likelihood ratio test has the advantage that it can incorporate complete and incomplete case-parent trios as well as independent cases and controls. Both analyses support (p = 0.046 for the proposed test, p = 0.028 for the case-control analysis) an association of the homozygous GSTM1 deletion genotype with autism.
Steven Buyske et al
Linkage studies in autism have identified susceptibility loci on chromosomes 2q and 7q, regions containing the DLX1/2 and DLX5/6 bigene clusters. The DLX genes encode homeodomain transcription factors that control craniofacial patterning and differentiation and survival of forebrain inhibitory neurons. We investigated the role that sequence variants in DLX genes play in autism by in-depth resequencing of these genes in 161 autism probands from the AGRE collection. Sequencing of exons, exon/intron boundaries and known enhancers of DLX1, 2, 5 and 6 identified several nonsynonymous variants in DLX2 and DLX5 and a variant in a DLX5/6intragenic enhancer. The nonsynonymous variants were detected in 4 of 95 families from which samples were sequenced. Two of these four SNPs were not observed in 378 undiagnosed samples from North American populations, while the remaining 2 were seen in one sample each. Segregation of these variants in pedigrees did not generally support a contribution to autism susceptibility by these genes, although functional analyses may provide insight into the biological understanding of these important proteins.
Steven P. Hamilton et al
Genetic studies indicate that chromosome 7q is likely to contain an autism susceptibility locus (AUTS1). We have followed a positional candidate gene approach to identify relevant gene(s) and report here the analysis of reelin (RELN), a gene located under our peak of linkage.
E. Bonora et al
Several genome-wide screens have indicated the presence of an autism susceptibility locus within the distal long arm of chromosome 7 (7q). Mapping at 7q22 within this region is the candidate gene reelin (RELN). RELN encodes a signaling protein that plays a pivotal role in the migration of several neuronal cell types and in the development of neural connections. Given these neurodevelopmental functions, recent reports that RELN influences genetic risk for autism are of significant interest. The total data set consists of 218 Caucasian families collected by our group, 85 Caucasian families collected by AGRE, and 68 Caucasian families collected at Tufts University were tested for genetic association of RELN variants to autism. Markers included five single-nucleotide polymorphisms (SNPs) and a repeat in the 5'-untranslated region (5'-UTR). Tests for association in Duke and AGRE families were also performed on four additional SNPs in the genes PSMC2 and ORC5L, which flank RELN. Family-based association analyses (PDT, Geno-PDT, and FBAT) were used to test for association of single-locus markers and multilocus haplotypes with autism. The most significant association identified from this combined data set was for the 5'-UTR repeat (PDT P-value=0.002). These analyses show the potential of RELN as an important contributor to genetic risk in autism.
DA Skaar et al
It is with deep regret that I tender my resignation today. When I began my work in the field of autism genetic research, I felt very fortunate to be able to pursue my lifelong interest in neuroscience. I hoped to make a substantial contribution to the public health by identifying genetic markers that would enable the development of a prenatal test and, ultimately, the worldwide eradication of autism. (The above "letter" is actually a work of fiction. Any resemblance to actual people or events is purely coincidental. The issues raised, however, are very real.)
Method Molecular approaches to complex disorders are reviewed, with examples from autism, reading disability and attention-deficit hyperactivity disorder.
Philip Asherson, Sarah Curran
These results suggest that genetic variation contributes to normal individual differences in higher order executive attention involving dopamine rich frontal areas including the anterior cingulate.
Jin Fan, Yanhong Wu, John Fossella, Michael Posner
We find modest associations of several polymorphisms with the efficiency of executive attention but not with overall performance measures such as reaction time.
John Fossella, Tobias Sommer et al
OBJECTIVES: An autism susceptibility locus (AUTS1, MIMmusical sharp608636) has been identified in chromosome 7q31. NrCAM is a candidate gene for AUTS1 because it is expressed in the brain and encodes a receptor involved in nervous system development. Polymorphisms in NrCAM have been reported to be associated with autism susceptibility and with substance abuse, implicating NrCAM in reward circuitry. Self-stimulatory, perseverative behavior in autism might be due to defects in reward circuitry. In addition, models of drug addiction have also borrowed from models of obsessive-compulsive behavior designed to reduce anxiety. Thus, our goals were to replicate previous associations of NrCAM with autism, making use of a large cohort, and to clarify whether NrCAM was associated with a specific endophenotype of autism in the repetitive behaviors and stereotyped interests domains. METHODS: We genotyped six NrCAM single nucleotide polymorphisms in 352 families and we tested for association between these polymorphisms and autism in the entire cohort and in two subsets, one with severe obsessive-compulsive behaviors and one with pronounced self-stimulatory behaviors. RESULTS: We found no association between single nucleotide polymorphisms of NrCAM and autism in our large cohort, or in the severe obsessive-compulsive behavior and self-stimulatory behavior subsets. However, we observed a significant overtransmission (21 transmitted vs 6 nontransmitted, chi=12.054, P=0.0005) of the haplotype G-G-A-G-C-A of rs722519-rs1269622-rs405945-rs6958498-rs401433-rs439587 in the severe obsessive-compulsive behavior subset, likely driven by the G-C haplotype of rs6958498-rs401433, which itself showed significant overtransmission (31 transmitted vs 13 nontransmitted, chi=8.844, P=0.003). CONCLUSIONS: Overtransmission of particular haplotypes of NrCAM, that may relate to the expression level of NrCAM in the brain, appeared to be associated with autism in the severe obsessive-compulsive behavior subset.
T. Sakurai et al
Overall, the data show an increased risk of autism spectrum disorder (ASD) associated with common mutations affecting the folate/methylation cycle. These associations by themselves may provide a partial explanation for a subgroup of children genomically at risk for ASD disorders. Increased folinic acid during pregnancy and early development may offset the genomic risk factors, and this deserves further study.
Marvin Boris, Allan Goldblatt, Joseph Galanko, S. Jill James
FOXP2 (forkhead box P2) was the first gene characterized in which a mutation affects human speech and language abilities. A common developmental language disorder, specific language impairment (SLI), affects 6%ndash7% of children with normal nonverbal intelligence and has evidence of a genetic basis in familial and twin studies. FOXP2 is located on chromosome 7q31, and studies of other disorders with speech and language impairment, including autism, have found linkage to this region. In the present study, samples from children with SLI and their family members were used to study linkage and association of SLI to markers within and around FOXP2, and samples from 96 probands with SLI were directly sequenced for the mutation in exon 14 of FOXP2. No mutations were found in exon 14 of FOXP2, but strong association was found to a marker within the CFTR gene and another marker on 7q31, D7S3052, both adjacent to FOXP2, suggesting that genetic factors for regulation of common language impairment reside in the vicinity of FOXP2.
Erin K. O'Brien
"My new theory is that it's not just a genetic condition, but it might be the result of two particular types of parents, who are both contributing genes. This might be controversially received. This is because there are a number of different theories out there -- one of which is an environmental theory, such as autism being caused by vaccine damage. Another environmental theory is that autism is due to toxic levels of mercury building up in the child's brain. But the genetic theory has a lot of evidence, and what we are now testing is that if two "systemizers" have a child, this will increase the risk of the child having autism. That's it in a nutshell.
Edge Magazine
Behavior now considered inappropriate in a classroom may be related to behavior that once helped humans overcome their environment.
Because of differences in peoples' symptoms, researchers believe that autism is the result of many genes interacting with each other. At this point, it seems that some children are born with a genetic susceptibility to autism.
National Institute of Child Health and Human Development
"I smell a rat! I think the bottom line will be the elimination of autism as we know it. Autism tampering will be like dropping the atom bomb. Genetic tampering is wrong. We must spend money on understanding autism, instead of genetic tampering."
Sue Lehr, Autism National Committee
To cling to a genetic explanation for autism is a desperate attempt tomaintain the illusion that one lives in a comfortable and rational world where all is basically well,new chemicals and technologies always mean progress, experts are always objective…
Martha Herbert, Chloe Silverman
Autism is familial, as reflected in an empiric sibling recurrence risk of 3% and pooled monozygotic and dizygotic concordance rates of 64% and 9%, respectively, which are much greater than the population prevalence of 0.02% to 0.05%. Genetic heterogeneity is pronounced with potential genetic subgroups, including autosomal recessive inheritance, X-linked inheritance, and sporadic chromosomal anomalies.
S.L. Smalley et al
If the genes responsible could be identified the possibility of new types of treatment and preventing the more severe manifestations of the disorder becomes stronger.
National Autistic Society
This study once again stress the need for a thorough medical evaluation of all children and adults with an autistic or autistic-like disorder.
A. Swillen, Hellemans, J.P. Fryns
As such, the biological functions of GRPR are consistent with a role in the pathophysiology of autism. Although we have found GRPR to clearly escape X-inactivation, the gene from the inactive X chromosome may nevertheless be expressed at only a fraction of the active allele (45 ). Such a low dosage might still be sufficient to cause autism in this patient.
Yumiko Ishikawa-Brush et al
In summary, in a large population, ascertained on the basis of a child with autism, 39% of families had a high incidence of alcoholism in patterns consistent with genetic inheritance. Families with an apparent genetic cluster of alcoholism were more apt to have children with a normal head circumference (not macrocephalic) and with regressive onset autism. Regressive autism was associated with maternal alcoholism, supporting the hypothesis that there is a maternal effect on the development of autism.
Judith H. Miles et al
Dr Eric Peterson, from the University of Colorado in Denver, USA, compared the brain scans of 40 parents with autistic children with those of 40 matched parents whose children were normal. The parents of autistic children shared several differences in brain structure with their offspring. These included an unexpected increase in the size of the motor cortex and basal ganglia, both areas linked to movement planning and imitation. The neighbouring somatosensory cortex, by contrast, was smaller than average.
Daily Mail
Collaborative gene bank for autism research.
In this letter, we describe the Autism Genetic Resource Exchange (AGRE), a resource for the study of autism and pervasive developmental disorder (PDD). Autism presents within the first 3 years of life, is characterized by qualitative impairments in communication and social interaction—in the presence of restricted repetitive and stereotyped patterns of behavior, interests, and activities—and is part of a spectrum of disorders that includes Asperger syndrome and PDD (American Psychiatric Association 1994). Estimates of the prevalence of autism in the general population ranges from 0.04% to >0.l%. Twin and family studies have demonstrated that the genetic contribution to autism and PDD is significant, with an MZ-twin concordance of 60%–90% and a 45- to 150-fold increase in risk to siblings. Thus, molecular genetic studies of autism-spectrum disorders are likely to contribute significantly to our understanding of this condition, as the recent results of several independent genome scans suggest.
Daniel H. Geschwind et al
Money from NAAR will go to researchers at computer chip company Affymetrix Inc., as well as Phoenix-based Translational Genomics Research Institute. (They) will receive $1 million to scan 6,000 samples of DNA from 1,500 families.
Associated Press
Researchers at the University of Texas Southwestern Medical Center, Dallas, deleted the PTEN gene in parts of the brain of mice and found they exhibited autistic-like traits. The researchers deleted the PTEN gene from parts of the hippocampus and the front of the brain. The hippocampus is an important part of the brain for memory, as well as for some other functions. They found the mice exhibited deficits in social interaction. They were also much more sensitive to some stimuli which most mice would not normally be bothered with.
Medical News Today
Eight children with four different disorders with autistic features were studied by the Sahlgrenska Academy at Göteborg University in Sweden and all had an extra chromosome, one damaged chromosome or pieces of chromosomes missing in their genes. The children in the study had Asperger's syndrome, infantile autism, ADHD, and Rett's syndrome.
Parents of autistic children tend to be more highly qualified than parents of children with other mental problems, according to a controversial study for the Department of Health. It also links a wide range of "clinically recognisable" mental health problems in youngsters to divorce and family breakdown.
Sarah Womack
A team of researchers at Trinity College Dublin has identified several genes which may be linked to autism. Dr Louise Gallagher, consultant and lecturer in child psychiatry at TCD, believes one of the genes may affect the ability of nerve cells in the brain to make connections. Another is thought to influence an enzyme in the blood which could contribute to the severity of autism.
RTE News
I expect that we will have substantial advances in understanding the brain and behavioral phenotypes in autism—with, in particular, research advances in structural and functional imaging and perhaps in the area of animal models. My hope is that over the next 10 years we will have convincingly identified some of the major susceptibility genes in autism.
ESI Special Topics
Strong evidence from twin and family studies indicates the importance of genetic factors in the development of idiopathic autism, although it is clear that these influences are complex. This review focuses on recent molecular investigations to identify susceptibility loci implicated in autistic disorder.
Janine A. Lamb et al
Scientists have taken a promising step forward in untangling the genetic roots of autism. Inheritance of a common variant of a gene that influences immunity, gastrointestinal repair, and brain growth substantially raises the chances of developing autism, at least in families with more than one child diagnosed with the severe brain disorder, a study finds. Children with autism show severe social difficulties, language problems, and repetitive behaviors. The gene, called MET, regulates production of a protein that influences cell proliferation in various parts of the body.
Bruce Bower, Science News
One system used in autism literature divides autistics into primary and secondary types, with the primary group having no known cause for their autism, and the secondary being those with diagnosed genetic disorders or conditions. Another system divdes autistics into essential and complex. In the essential/complex system anyone who has an odd (dysmorphic) appearance or a small head goes into the "complex" category. If the person has an obviously different (dysmorphic) appearance, with the possible exception of having a larger head, it is more likely that that person's autism has a knowable cause. The complex group is much more likely to have seizures, too.
Autism Diva
There is evidence that several genes may be involved in the causation and pathogenesis of autism. One of these genes may be located on 7q31.
Victor McKusick
The incidence of autistic spectrum conditions is approximately 1 in 110. This equates to a global autistic population of about 55 million. It is likely that millions more are genetically autistic and, because of a favorable combination of genes or the good fortune to avoid environmental stresses, have not developed any problems significant enough to warrant a diagnosis. The number of people whose genes would be identified as "defective" by a test such as Dr. Buxbaum describes could easily be more than 100 million. That is equivalent to more than one-third of the US population, or the total populations of the UK, Canada, and Australia combined.
Bonnie Ventura
This is the home page for the archives of the BGnews list. There is one archive for each year of BGnews. The BGnews archive for the current year is updated within two hours of when a new article is found.
Although neither the genome nor the environment can be manipulated in research on human behaviour, some of the new tools of molecular genetics can be brought to bear on human behavioural disorders. In addition, because they are the consequences of known genetic alterations, behavioral phenotypes can be potentially highly valuable clues to the identification of genes in the population that are important to determination of cognitive skills or deficits, personality determinants, behavioral abnormalities, or psychiatric disorders.
Marjaneh Akbarzadeh et al
The use of the term "behavioural phenotype" to describe the features of a disorder in which the genetic anomaly is only suspected, but where it has not been demonstrated, is liable to cause confusion. The danger is a widening of the concept to include the cognitive and behavioural features of all conditions that are highly heritable.
David Skuse, Archives of Disease in Childhood
Gestational and genetic factors can contribute to autism during infancy and early childhood through their effects on fetal brain development. Previous twin studies have shown strong genetic components for the development of autism, a disorder that can have multiple causes. We investigated the effects of prenatal overstimulation of the ß2-adrenergic receptor in dizygotic twins who were exposed to terbutaline, a selective ß2-adrenergic receptor agonist used to treat premature labor, as a gestational factor. As a possible genetic mechanism, we studied two ß2-adrenergic receptor polymorphisms in twins from whom DNA was available: glycine substitution at codon 16 (16G) and glutamic acid substitution at codon 27 (27E), which show diminished desensitization in vivo compared with the wild-type receptor. Continuous terbutaline exposure for 2 weeks or longer was associated with increased concordance for autism spectrum disorders in dizygotic twins (relative risk = 2.0), with a further increase in the risk for male twins with no other affected siblings (relative risk = 4.4). A significant association was found between the presence of 16G and 27E polymorphisms in autistic patients compared with population controls (P = .006). Prenatal overstimulation of the ß2-adrenergic receptor by terbutaline or by increased signaling of genetic polymorphisms of the ß2-adrenergic receptor that have diminished desensitization can affect cellular responses and developmental programs in the fetal brain, leading to autism.
Susan L. Connors et al
It is estimated that upwards of 90% of an individual's liability to develop autism or ASD is determined by genetic factors, yet the disease liability attributable to any single genetic variant may be so small that it is undetectable by current gene mapping strategies.
A. L. Yonan et al
Now, at the century's close, the influence of breeding is back in fashion, bringing the implacable effects of genetic determinism and bad blood. The implications for the successes and failings of the 'normal' population are far-reaching. In learning disability, many of these ideas are contained in the concept of the 'behavioural phenotype'.
T.P. Berney
To date there have been few accounts of psychotherapeutic work with individuals with autistic conditions such as Asperger syndrome, yet this group often presents with high levels of psychological distress and confusion which they find difficult to communicate to others. The use of clinical assessment techniques derived from personal construct psychology is described and four case studies are presented to illustrate the potential utility of this approach. The advantages and disadvantages of such an approach are discussed.
N. Micali, S. Chakrabarti, E. Fombonne
Autism is a highly heritable neurodevelopmental disorder whose underlying genetic causes have yet to be identified. To date, there have been eight genome screens for autism, two of which identified a putative susceptibility locus on chromosome 16p. In the present study, 10 positional candidate genes that map to 16p11-13 were examined for coding variants: A2BP1, ABAT, BFAR, CREBBP, EMP2, GRIN2A, MRTF-B, SSTR5, TBX6, and UBN1. Screening of all coding and regulatory regions by denaturing high-performance liquid chromatography identified seven nonsynonymous changes. Five of these mutations were found to cosegregate with autism, but the mutations are not predicted to have deleterious effects on protein structure and are unlikely to represent significant etiological variants. Selected variants from candidate genes were genotyped in the entire International Molecular Genetics Study of Autism Consortium collection of 239 multiplex families and were tested for association with autism by use of the pedigree disequilibrium test. Additionally, genotype frequencies were compared between 239 unrelated affected individuals and 192 controls. Patterns of linkage disequilibrium were investigated, and the transmission of haplotypes across candidate genes was tested for association. Evidence of single-marker association was found for variants in ABAT, CREBBP, and GRIN2A. Within these genes, 12 single-nucleotide polymorphisms (SNPs) were subsequently genotyped in 91 autism trios (one affected individual and two unaffected parents), and the association was replicated within GRIN2A (Fisher's exact test, P<.0001). Logistic regression analysis of SNP data across GRIN2A and ABAT showed a trend toward haplotypic differences between cases and controls.
Gabrielle Barnby et al
The deletion in this autistic subject serves to highlight specific autism candidate genes. He is hemizygous for AMPA 2, GLRA3, GLRB, NPY1R and NPY5R. GluR2 is the major determinant of AMPA receptor structure.
Subhadra Ramanathan et al
The report adds to the literature supporting the argument that individuals with autistic spectrum disorders should be re-examined for chromosomal abnormalities.
M. Sabaratnam, J. Turk, P. Vroegop
Are we born evil -- natural born killers or the most creative and compassionate of all animals? Are we both? Does our best and our worst come from our genes or from our learning? Nature or nurture?
Bruce Perry
The most common chromosomal abnormalities were Fragile X, other sex chromosome anomalies, and chromosome 15 abnormalities. These data support the contribution of chromosomal abnormalities to a small but significant number of cases of autism, and highlight the involvement of chromosome 15 and the sex chromosomes.
Thomas Wassink et al
We review the different strategies currently used to try to identify susceptibility genes for idiopathic autism. Although identification of genes is usually straightforward in Mendelian disorders, it has proved to be much more difficult to establish in polygenic disorders like autism. Neither genome screens of affected siblings nor the large number of association studies using candidate genes have resulted in finding autism susceptibility genes. We focus on the alternative approach of 'positional cloning' through chromosomal aberrations in individuals with autism. In particular, balanced aberrations such as reciprocal translocations or inversions offer a unique opportunity, since only the genes in the breakpoint regions are candidate genes. This approach, in combination with others, is likely to produce results in the coming years.
Dries Castermans et al
Autism and SLI appear to be genetically related; both disorders occur much more often than expected by chance within the same family, and some cases exist that have phenotypes that cannot be distinctly differentiated.
Susan Folstein, Raymond Mankoski
It is useful to look at the more common genetic disorders associated with learning disabilities in some detail. Terms used in describing how common diseases are include incidence and prevalence. The incidence of a disease is the rate of occurrence of new cases in a defined population over a given period of time, while prevalence is the proportion of a defined population that has the disease at a given point in time or period of time. The birth defect rate is the proportion of live births that has a given disease and is a type of prevalence.
David Clarke
Autism and Tourette syndrome are complex enigmatic disorders. Both are childhood neurological syndromes affecting behavior, social interaction, movement, and language. Like many complex disorders, autism and Tourette syndrome are thought to have complex genetic and environmental etiologies. Similarly, autoimmune and inflammatory (AI) disorders have complex multigenic and environmental origins. Genetic loci for AI disorders have previously been shown to cluster non-randomly in several regions throughout the human genome, suggesting in some cases, shared genetic etiologies. Here, we show that genetic loci for autism and Tourette syndrome tend to cluster with each other and also tend to cluster with previously defined loci for inflammatory disorders. This suggests a genetic relationship between autism and Tourette syndrome, as well as a genetic relationship of both with disorders of immune dysregulaton.
Kevin G. Becker et al
Autism is a neurodevelopmental disorder with childhood onset and a known major genetic component. A recent study identified a highly significant association between autism and a two-single-nucleotide-polymorphism haplotype in the SLC25A12 gene, with a homozygote genotype relative risk between 2.4 and 4.8. The authors' goal was to investigate this association with autism in Irish affected child-parent trios because replication in an independent sample is essential in the validation of such potentially important findings. Markers rs2056202 and rs2292813 were genotyped in a total of 158 trios (442 individuals). The Transmission Disequilibrium Test was used to examine these markers for association with autism. In agreement with the recent study, the authors found significant association between autism and the C alleles of both rs2056202 and rs2292813 as well as the two-marker haplotype. These findings provide replication of the association between autism and SLC25A12.
Ricardo Segurado et al
A study of 57 autism patients found that 40 percent carry a mutated version of the HOXA1 gene, which plays a crucial role in early brain development, University of Rochester scientists reported Monday.
Six candidate broader phenotype autism traits are proposed: face processing, social affiliation, motor imitation ability, memory, executive function, language ability
Geraldine Dawson et al
We have expanded on the descriptive epidemiology of Rett syndrome and shown different patterns according to the severity scale selected. Although all affected children are severely functionally dependent, it is still possible to identify some variation in ability, even in children with identified MECP2 mutations.
L. Colvin et al, Archives of Disease in Childhood
This paper focuses on designing studies that will compare children with developmental language disorders (DLD) drawn from several syndromes in which there are primary impairments in the acquisition of language. This kind of research can be used to address four key questions: (a) What are the developing language phenotypes that characterize specific disorders? (b) What factors are key precursors and predictors of language acquisition in DLD? (c) What are the genes that contribute to DLD in different syndromes? (d) What environmental factors influence the trajectories of language development in DLD? Several design issues are discussed including an overall study design, subject selection and recruitment, matching and comparisons across groups, and methodologies. A number of important challenges to the design and implementation of these kinds of studies are presented in the final section of the paper.
Helen Tager Flusberg
(W)e must persuade professionals to change what they tell prospective parents about life with disability; convince those parents to learn about how children and adults in today's world survive and thrive; and then endorse the choices people make about their reproductive and family lives.
Adrienne Asch
If one thinks for even a moment about the history of our society's treatment of people with disabilities, it is not difficult to appreciate why people identified with the disability rights movement might regard such testing as dangerous. For the members of this movement, including people with and without disabilities and both issue-focused and disability-focused groups, living with disabling traits need not be detrimental either to an individual's prospects of leading a worthwhile life, or to the families in which they grow up, or to society at large.
Erik Parens, Adrienne Asch
Autism is a neuro-developmental syndrome that affects 0.1–0.5% of the population. It has been proposed that alterations in neuronal circuitry and/or neuronal signaling are responsible for the behavioral and cognitive aberrations in autism patients. However, the cellular basis of such alterations is unknown. Recently, point mutations in a family of neuronal cell adhesion molecules called neuroligins have been linked to autism-spectrum disorders and mental retardation. We investigated the consequences of these disease-associated mutations on neuroligin function. We demonstrate that the point mutation at arginine 451 and a nonsense mutation at aspartate 396 of neuroligin-3 and -4 (NL3 and NL4), respectively, result in intracellular retention of the mutant proteins. Over-expression of wild-type NL3 and NL4 proteins in hippocampal neurons stimulates the formation of presynaptic terminals, whereas the disease-associated mutations result in a loss of this synaptic function. Our findings suggest that the previously identified mutations in neuroligin genes are likely to be relevant for the neuro-developmental defects in autism-spectrum disorders and mental retardation since they impair the function of a synaptic cell adhesion molecule.
Ben Chih et al
Methylation of cytosine in human DNA has been studied for over 60 years, but has only recently been confirmed as an important player in human disease. Rett syndrome is a neurological disorder caused by mutations in the MeCP2 protein, which has been shown to bind methylated DNA and repress transcription. This review will focus on experiments addressing the basic properties of MeCP2 and on mouse models of Rett syndrome that are starting to yield insights into this condition.
Skirmantas Kriaucionis, Adrian Bird
The amygdala, which plays a critical role in emotional learning and social cognition, is structurally and functionally sexually dimorphic in humans. We used magnetic neuroimaging and molecular genetic analyses with healthy subjects and patients possessing X-chromosome anomalies to find dosage-sensitive genes that might influence amygdala development... We show that the thrombocytic activity of MAOB is proportionate to the number of X-chromosomes, and hypothesize that haploinsufficiency of this enzyme in 45,X females predisposes to their deficits in social cognition.
Catriona D. Good et al
As reported cases of autism continue to rise, the hottest public debates center on the causes, with some pointing to toxic substances or vaccines. But Minshew says respected studies have discredited those beliefs, and she says it's time to move on.
Virginia Linn, Pittsburgh Post-Gazette
"We will look for a relationship between gene variation and variation in the brain," says John Gabrieli, an MIT neuroscientist. Gabrieli will use fMRI, a type of MRI that shows which areas of the brain are active when people think about specific problems, to compare brain activity in normal individuals and in those with different forms of the suspected autism genes. Specifically, his group will look at how people deal with social functions, by imaging brain activity in response to faces and facial expressions.
Emily Singer, MIT Technology Review
A few companies have begun offering genetic testing combined with guidance on diet, supplement strategies, lifestyle changes, and/or drug usage which they claim can improve health outcomes. This article explains why such testing should be avoided.
Stephen Barrett
Results of autism linkage studies have been difficult to interpret across research groups, prompting the use of ever-increasing sample sizes to increase power. However, increasing sample size by pooling disparate collections for a single analysis may, in fact, not increase power in the face of genetic heterogeneity. Here, we applied the posterior probability of linkage (PPL), a method designed specifically to analyze multiple heterogeneous data sets, to the Autism Genetic Resource Exchange collection of families by analyzing six clinically defined subsets of the data and updating the PPL sequentially over the subsets. Our results indicate a substantial probability of linkage to chromosome 1, which had been previously overlooked; our findings also provide a further characterization of the possible parent-of-origin effects at the 17q11 locus that were previously described in this sample. This analysis illustrates that the way in which heterogeneity is addressed in linkage analysis can dramatically affect the overall conclusions of a linkage study.
C.W. Bartlett et al
Latent genetically influenced traits, which may be related only indirectly to the classic disease symptoms defined in ICD-10 or DSM-IV are known as endophenotypes. They reflect an underlying susceptibility to the disease phenotype.
David Skuse
Getting into other people's heads requires empathy, a virtue that sometimes does not come naturally to engineers. Our profession tends toward the opposing mental disposition, called systemizing, which attends mainly to rule-based systems, such as those that govern machinery. The author of the theory, Simon Baron-Cohen, a professor of developmental psycho­pathology at the University of Cambridge, argues that in generations past, engineers, mathematicians, and other systemizers had little opportunity to meet potential spouses who thought as they did. Now, however, schools and professions sort both sexes by psychological types, raising the chances that people of like minds will marry and bear children. Baron-Cohen, cousin to comic actor Sacha Baron ?Cohen, says that such “assortative mating” is concentrating the genes that predispose to systemizing thought. That, in turn, ought to be increasing the likelihood of having a child with the most extreme systemizing: autism.
IEEE Spectrum
Genetic variability implies unpredictable vulnerability. Among the 3.2 billion base pairs in the human genome, <1% uniquely identifies each human being (18). Single nucleotide polymorphisms (SNPs) are predicted to occur at least every 300 base pairs. Although only 40% of these SNPs will result in amino acid changes, these SNPs provide the genetic diversity that underlies the variable susceptibility to environmental stimuli and the variable risk of disease development and progression (18). In this review, we will illustrate how gene-environment interactions can be used to identify key regulatory genes and pathways, discover susceptibility genes, and define disease phenotypes.
David Schwartz et al
Complex autism consists of individuals in whom there is evidence of some abnormality of early morphogenesis, manifested by either significant dysmorphology or microcephaly. Essential autism defines the more heritable group with higher sib recurrence (4% vs. 0%), more relatives with autism (20% vs. 9%),and higher male to female ratio (6.5:1vs.3.2:1). Their outcome was better with higher Iqs (P ¼ 0.02) and fewer seizures (P ¼ 0.0008). They were more apt to develop autism with a regressive onset.
J.H. Miles, T.N. Takahashi, S. Bagby, P.K. Sahota, D.F. Vaslow, C.H. Wang, R.E. Hillman, J.E. Farmer
Extracts from EJAIB and EEIN since January 1994.
Eubios Ethics Institute
Autism is a syndrome characterized by deficits in language and social skills and by repetitive behaviors. We hypothesized that potential quantitative trait loci (QTLs) related to component autism endophenotypes might underlie putative or significant regions of autism linkage. We performed nonparametric multipoint linkage analyses, in 152 families from the Autism Genetic Resource Exchange, focusing on three traits derived from the Autism Diagnostic Interview: "age at first word," "age at first phrase," and a composite measure of "repetitive and stereotyped behavior." Families were genotyped for 335 markers, and multipoint sib pair linkage analyses were conducted. Using nonparametric multipoint linkage analysis, we found the strongest QTL evidence for age at first word on chromosome 7q (nonparametric test statistic [Z] 2.98; P=.001), and subsequent linkage analyses of additional markers and association analyses in the same region supported the initial result (Z=2.85, P=.002; chi2=18.84, df 8, P=.016). Moreover, the peak fine-mapping result for repetitive behavior (Z=2.48; P=.007) localized to a region overlapping this language QTL. The putative autism-susceptibility locus on chromosome 7 may be the result of separate QTLs for the language and repetitive or stereotyped behavior deficits that are associated with the disorder.
Maricela Alarcón et al
The restricted sample comprises a population that is more genetically homogeneous, which could therefore increase the likelihood of positional cloning of susceptibility loci.
Joseph Buxbaum et al
The serotonin transporter gene (HTT) is a likely candidate in autistic disorder based on efficacy of potent serotonin transporter inhibitors in reducing rituals and routines, a corebehavioral characteristic of autism. Additionally, elevated serotonin levels have been consistently found in 30%±50% of autistic patients and may represent a marker for familial autism..
Nurit Yirmiya, et al
We investigated the genetic aspects of the large sex bias in the prevalence of autism spectrum disorder by monitoring changes in linkage when the family set for an affected sibling pair genome scan is subdivided on the basis of the sex of affected children. This produces a significant excess in the total number of linkage peaks (P=1.3×10-8) and identifies a major male-specific linkage peak at chromosome 17q11 (P<.01). These results suggest that sexual dichotomy is an important factor in the genetics of autism; the same strategy can be used to explore this possibility in other complex disorders that exhibit significant sex biases.
Jennifer L. Stone et al
Our observations suggest that there is a genetic locus for social cognition, which is imprinted and is not expressed from the maternally derived X chromosome.
D.H. Skuse et al
Because MMR vaccine is administered just before the peak age of onset of autism, a temporal relationship between vaccination and onset of autism is expected to be common.
Charles Prober
Results from various genomic screens implicate a region on chromosome 7q31 as harboring an autism susceptibility variant. Four candidate genes were chosen for examination based on proximity to the marker most consistently cosegregating with autism...
Holli Hutcheson, Lana Olson, Yuki Bradford, Susan Folstein, Susan Santangelo, James Sutcliffe, Jonathan L Haines
Our results indicate that using samples selected for components of the autism phenotype may be a useful adjunct to autism genetics.
Christopher Bartlett et al
Rather than working towards a more social or sociopolitical 'model', modern genetics is forcing the perception of disability into becoming increasingly a medical approach both practically and publicly. This has devalued the lives of people with impairments and rather than celebrate the birth of all children, through the very notion of screening, genetic testing and selective abortion, we are portraying impairment as 'wrong' and increasing societies prejudices.
Louise Smyth
A trend was observed for an association between IQ in the probands and the MAO A genotype that just attained significance (F 3.5, P 0.046, N28) in the small group of autism subjects recruited from families with two affected siblings.
Nurit Yirmiya, et al
The TPH1 and TPH2 genes encode the rate-limiting enzymes that control serotonin biosynthesis, and serotonin is clearly altered in autism. In the current study, eight SNPs in the TPH1 gene region and eight SNPs within the TPH2 gene were examined by family-based association tests in a large cohort of 352 families with autism and in clinically defined subsets of these families with either severe obsessive-compulsive behaviors (sOCB) or self-stimulatory behaviors (SSB). We found no evidence for association between autism and single SNPs or haplotypes of the TPH1 and TPH2 genes in the cohort of all families or in the sOCB and SSB subsets. In particular, we failed to replicate the association between autism and variants of the TPH2 gene, rs4341581 (TRANSMIT P = 1; PDT P = 0.323; FBAT P = 0.446) and rs11179000 (TRANSMIT P = 0.174; PDT P = 0.293; FBAT P = 0.374). Furthermore, no evidence for linkage was observed between autism and SNPs in the TPH1 and TPH2 genes (although linkage at the TPH2 locus was observed in the SSB subset). Thus, it appears unlikely that the TPH1 and TPH2 genes play a significant role in the susceptibility to autism or to autism endophenotypes including sOCB and SSB.
N. Ramoz et al
American Journal of Orthopsychiatry, Volume XXVII, pp. 715-724 (1957)
Leon Eisenberg
Autistic disorder (AutD) is a complex genetic disease. Available evidence suggests that several genes contribute to the underlying genetic risk for the development of AutD. However, both etiologic heterogeneity and genetic heterogeneity confound the discovery of AutD-susceptibility genes. Chromosome 15q11-q13 has been identified as a strong candidate region on the basis of both the frequent occurrence of chromosomal abnormalities in that region and numerous suggestive linkage and association findings. Ordered-subset analysis (OSA) is a novel statistical method to identify a homogeneous subset of families that contribute to overall linkage at a given chromosomal location and thus to potentially help in the fine mapping and localization of the susceptibility gene within a chromosomal area. For the present analysis, a factor that represents insistence on sameness (IS)mdashderived from a principal-component factor analysis using data on 221 patients with AutD from the repetitive behaviors/stereotyped patterns domain in the Autism Diagnostic InterviewndashRevisedmdashwas used as a covariate in OSA. Analysis of families sharing high scores on the IS factor increased linkage evidence for the 15q11-q13 region, at the GABRB3 locus, from a LOD score of 1.45 to a LOD score of 4.71. These results narrow our region of interest on chromosome 15 to an area surrounding the gamma-aminobutyric acidndashreceptor subunit genes, in AutD, and support the hypothesis that the analysis of phenotypic homogeneous subtypes may be a powerful tool for the mapping of disease-susceptibility genes in complex traits.
Yujun Shao et al
The team's findings implicate the so-called GABA receptor genes, which are genes that code for key components of "off switches" in the brain's neurons. GABA, or gamma aminobutyric acid, is a neurotransmitter - a chemical that one neuron fires at receptors on another neuron to trigger a response - in this case an inhibitory response. GABA receptors are protein switches nestled in nerve cell membranes that are triggered by GABA to cause such inhibition.
The FOXP2 gene, located on human 7q31 (at the SPCH1 locus), encodes a transcription factor containing a polyglutamine tract and a forkhead domain. FOXP2 is mutated in a severe monogenic form of speech and language impairment, segregating within a single large pedigree, and is also disrupted by a translocation in an isolated case. Several studies of autistic disorder have demonstrated linkage to a similar region of 7q (the AUTS1 locus), leading to the proposal that a single genetic factor on 7q31 contributes to both autism and language disorders. In the present study, we directly evaluate the impact of the FOXP2 gene with regard to both complex language impairments and autism, through use of association and mutation screening analyses. We conclude that coding-region variants in FOXP2 do not underlie the AUTS1 linkage and that the gene is unlikely to play a role in autism or more common forms of language impairment.
D.F. Newbury, et al
Combination of prenatal or pre-implantation diagnosis, allowing potential elimination of all serious diseases, including autism and chromosomal defects, before birth...would result without any doubt (in) a dull, depressing, boring life for all citizens.
Robert Pigache, Cees Smit
The end result of germline intervention and genetic enhancement will likely lead to the impoverishment of gene variants in the human population and deprive us of one of our most valued assets for survival in the future, our genetic diversity.
Jurgen Brosius
In summary, the first full genome scan in autism has revealed several interesting loci, one of which achieves an MLS of 3.55 in the largest subset of relative-pair families. Further families, including singleton cases, are currently being ascertained to replicate these findings. Fine mapping, tests for linkage disequilibrium and analysis of candidate genes in these regions are underway.
International Molecular Genetic Study of Autism Consortium
I suggest that words are simply less lateralised in those genetically predisposed to suffer from schizophrenic symptoms.
Tim Crow
Autism is a neurodevelopmental disorder that usually arises on the basis of a complex genetic predisposition. The most significant susceptibility region in the first whole genome screen of multiplex families was on chromosome 7q, although this linkage was evident only in UK IMGSAC families. Subsequently all other genome screens of non-UK families have found some evidence of increased allele sharing in an overlapping 40 cM region of 7q.
International Molecular Genetic Study of Autism Consortium
The autism spectrum encompasses a set of complex multigenic developmental disorders that severely impact the development of language, non-verbal communication, and social skills, and are associated with odd, stereotyped, repetitive behavior and restricted interests. To date, diagnosis of these neurologically based disorders relies predominantly upon behavioral observations often prompted by delayed speech or aberrant behavior, and there are no known genes that can serve as definitive biomarkers for the disorders. Here we demonstrate, for the first time, that lymphoblastoid cell lines from monozygotic twins discordant with respect to severity of autism and/or language impairment exhibit differential gene expression patterns on DNA microarrays. Furthermore, we show that genes important to the development, structure, and/or function of the nervous system are among the most differentially expressed genes, and that many of these genes map closely in silico to chromosomal regions containing previously reported autism candidate genes or quantitative trait loci. Our results provide evidence that novel candidate genes for autism may be differentially expressed in lymphoid cell lines from individuals with autism spectrum disorders. This finding further suggests the possibility of developing a molecular screen for autism based on expressed biomarkers in peripheral blood lymphocytes, an easily accessible tissue. In addition, gene networks are identified that may play a role in the pathophysiology of autism.
Valerie W. Hu et al
Researchers said on Thursday they had found a genetic mutation that causes obsessive-compulsive disorder and other mental illnesses and said some patients had a second mutation that made their conditions worse.
Scientists say they've identified two variants of a single gene that might raise a child's risk of autism by twofold or more.
Associated Press
The statistical technique of ordered subset analysis revealed that those families whose children had high scores in the IS category had a strong link to the GABRB3 gene on chromosome 15q.
Laurie Barclay
A new study shows that a certain gene may be involved in autism. The study, published in Neuron, doesn't prove that that particular gene -- which is called the Pten gene -- causes autism. Many other genetic factors have also been linked to autism, the study also notes. The study states that when researchers deleted the Pten gene in certain parts of mice's brains, those mice showed some autism-like symptoms, including "abnormal social interaction and exaggerated responses to sensory stimuli."
Miranda Hitti, Medscape
The researchers investigated MET as a possible autism susceptibility gene based on previous neurobiological findings and its location within a candidate gene region. The gene was analyzed in a family-based autism study, which included 1231 cases of the disorder. In an analysis of data from 204 autism families, the researchers identified an association between the disease and a common C allele in the MET gene promoter region. This association was then confirmed in a separate set of 539 autism families.
Reuters, Medscape
Here we have three studies said to link genes to different behaviours, but we need to remember correlation does not necessarily imply causation. Only in the first has an actual causation been shown and, even then, it was variable.
We are still only able to observe the development of the brain or study its functioning in a relatively unsophisticated way, particularly in young children, which is when autism first shows itself.
Anthony Bailey
Research in the last 2 decades indicates that autism is largely caused by genetic factors that lead to abnormal brain development. This article reviews research into the genetic and neurodevelopmental factors underlying autism.
Rob Nicolson, Peter Szatmari
The molecular basis of human cognition is still poorly understood, but recent advances in finding genetic mutations that result in cognitive impairment may provide insights into the neurobiology of cognitive function. Here we review the progress that has been made so far and assess what has been learnt from this work on the relation between genes and cognitive processes. We review evidence that the pathway from genetic lesion to cognitive impairment can be dissected, that some genetic effects on cognition are relatively direct and we argue that the study of mental retardation syndromes is giving us new clues about the biological bases of cognition.
P Nokelainen, J Flint
Since 1977, when the first autism twin study demonstrated higher concordance rates of autism among identical twins than fraternal twins, the evidence for inherited factors in autism has gained widespread recognition among researchers.
Brian Winklosky, MA
The role of genetics in Autism is unknown and very debatable. The search for genetic causes of Autism/PDD is described here.
Floyd Tilton
Unlike such psychiatric disorders as depression, schizophrenia, and bipolar illness, which generally have their onset in adulthood, there are a few psychiatric disorders in which onset in childhood is part of the diagnostic criteria. Two of these childhood-onset conditions, autistic disorder (AD) and attention-deficit/hyperactivity disorder (ADHD), illustrate both the behavioral heterogeneity that makes diagnosis a challenge and the potential of genetic analysis in the study of normal and abnormal behaviors. AD, while rare, is probably the best-validated psychiatric disorder in childhood (Rutter and Schopler 1988), whereas ADHD is the most common such disorder. These two conditions illustrate the diversity of behavioral phenotypes yet also exemplify some common aspects of the childhood-onset conditions.
Susan Smalley
The neural basis of social cognition has been the subject of intensive research in both human and non-human primates. Exciting, provocative and yet consistent findings are emerging. A major focus of interest is the role of efferent and afferent connectivity between the amygdala and the neocortical brain regions, now believed to be critical for the processing of social and emotional perceptions. One possible component is a subcortical neural pathway, which permits rapid and preconscious processing of potentially threatening stimuli, and it leads from the retina to the superior colliculus, to the pulvinar nucleus of the thalamus and then to the amygdala. This pathway is activated by direct eye contact, one of many classes of potential threat, and may be particularly responsive to the 'whites of the eyes'. In humans, autonomic arousal evoked by this stimulus is associated with the activity in specific cortical regions concerned with processing visual information from faces. The integrated functioning of these pathways is modulated by one or more X-linked genes, yet to be identified. The emotional responsiveness of the amygdala, and its associated circuits, to social threat is also influenced by functional polymorphisms in the promoter of the serotonin transporter gene. We still do not have a clear account of how specific allelic variation, in candidate genes, increases susceptibility to developmental disorders, such as autism, or psychiatric conditions, such as anxiety or depressive illness. However, the regulation of emotional responsiveness to social cues lies at the heart of the problem, and recent research indicates that we may be nearing a deeper and more comprehensive understanding.
D. Skuse
Autism is a severe developmental disorder of unknown etiology but with evidence for genetic influences. Here, we provide evidence for a genetic basis of several quantitative traits that are related to autism. These traits, from the Broader Phenotype Autism Symptom Scale (BPASS), were measured in nuclear families, each ascertained through two probands affected by autism spectrum disorder. This finding suggests a shared genetic basis of these two traits and that they may be most promising for future gene mapping and for extending pedigrees by phenotyping additional relatives.
Y.J. Sung et al
Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed behavioral disorder in childhood and likely represents an extreme of normal behavior. ADHD significantly impacts learning in school-age children and leads to impaired functioning throughout the life span. There is strong evidence for a genetic etiology of the disorder, although putative alleles, principally in dopamine-related pathways suggested by candidate-gene studies, have very small effect sizes. We use affected-sib-pair analysis in 203 families to localize the first major susceptibility locus for ADHD to a 12-cM region on chromosome 16p13 (maximum LOD score 4.2; P=.000005), building upon an earlier genomewide scan of this disorder. The region overlaps that highlighted in three genome scans for autism, a disorder in which inattention and hyperactivity are common, and physically maps to a 7-Mb region on 16p13. These findings suggest that variations in a gene on 16p13 may contribute to common deficits found in both ADHD and autism.
Susan L. Smalley et al
OBJECTIVE: The study examined the genetic structure of deficits in reciprocal social behavior in an epidemiologic sample of male twins. METHOD: Parents of 232 pairs of 7-15-year-old male twins completed the Social Reciprocity Scale to provide data on their children's reciprocal social behavior. Scale scores were analyzed by using structural equation modeling. RESULTS: Intraclass (twin-twin) correlations for scores on the Social Reciprocity Scale were 0.73 for monozygotic twins (N=98 pairs) and 0.37 for dizygotic twins (N=134 pairs). The best fitting model of causal influences on reciprocal social behavior incorporated additive genetic influences and unique environmental influences. CONCLUSIONS: For school-age boys in the general population, reciprocal social behavior is highly heritable, with a genetic structure similar to that reported for autism in clinical samples. Continuous measures of reciprocal social behavior may be useful for characterizing the broader autism phenotype and may enhance the statistical power of genetic studies of autism.
John N. Constantino, Richard D. Todd
For school-age boys in the general population, reciprocal social behavior is highly heritable, with a genetic structure similar to that reported for autism in clinical samples. Continuous measures of reciprocal social behavior may be useful for characterizing the broader autism phenotype and may enhance the statistical power of genetic studies of autism.
John N. Constantino, Richard D. Todd
We know that genetic influences are hugely important in the liability to autism, they involve the operation of several interacting genes, and that the liability extends well beyond traditional concepts of a handicapping disorder (J. Abnormal Child Psych.)
Michael Rutter
Diagnostic data gathered on cases of autism in the CVCR using Spanish versions of the ADI-R and ADOS look similar to that generated by studies of English-speaking cases. However, only 17% of our cases have IQs within the normal range, compared to the figure of 25% seen in most studies. This result reflects an ascertainment bias in that only severe cases of autism come to treatment in the CVCR because there are no government-sponsored support programs or early intervention programs providing an incentive to diagnose autism. The severity of mental retardation seen in most of our cases may also be exaggerated by the lack of early intervention programs and the use of IQ tests without Costa Rican norms. Still, we must formally train healthcare providers and teachers to recognize and refer autistic cases with normal or near normal IQs that are not seen in treatment.
L Alison McInnes et al
There is strong evidence for a genetic predisposition to autism and an intense interest in discovering heritable risk factors that disrupt gene function. Based on neurobiological findings and location within a chromosome 7q31 autism candidate gene region, we analyzed the gene encoding the pleiotropic MET receptor tyrosine kinase in a family based study of autism including 1,231 cases. MET signaling participates in neocortical and cerebellar growth and maturation, immune function, and gastrointestinal repair, consistent with reported medical complications in some children with autism. Here, we show genetic association (P = 0.0005) of a common C allele in the promoter region of the MET gene in 204 autism families. The allelic association at this MET variant was confirmed in a replication sample of 539 autism families (P = 0.001) and in the combined sample (P = 0.000005). Multiplex families, in which more than one child has autism, exhibited the strongest allelic association (P = 0.000007). In case-control analyses, the autism diagnosis relative risk was 2.27 (95% confidence interval: 1.41-3.65; P = 0.0006) for the CC genotype and 1.67 (95% confidence interval: 1.11-2.49; P = 0.012) for the CG genotype compared with the GG genotype. Functional assays showed that the C allele results in a 2-fold decrease in MET promoter activity and altered binding of specific transcription factor complexes. These data implicate reduced MET gene expression in autism susceptibility, providing evidence of a previously undescribed pathophysiological basis for this behaviorally and medically complex disorder.
DB Campbell et al
The Amish, and their neighbors the Mennonites, have been studied by geneticists for some time because they are a genetically isolated community. Although they accept converts, they don't get very many and so they don't get much "new blood" (genes). In addition, they don't move around much and their members tend to marry within the community - those who don't often leave and join their "English" (as they call people outside their communities, regardless of ethnicity) spouse outside of the community.
It is quite reasonable to assume that the Amish have different alleles (more precisely, different allele frequencies) than the general population because they are pretty much genetically isolated from the rest of us. The genetic work done on the Amish and Mennonites confirms this - the only stretch is assuming that this difference will have no effect on the prevalence of a certain disorder, namely autism.
Prometheus: A Photon in the Darkness
Proponents of the myriad autism causation hypotheses - mercury, vaccines, gluten, casein, plasticizers, etc. - all insist that exposure to these substances cause autism in a subset of children. None of them has said (or even implied) that any of these substances causes autism in every child who is exposed to them. The reason they don't (and can't) say that is that it would be painfully easy to refute such a claim. It is obvious that the majority of children exposed to these substances do not develop autism - since even the highest estimates of autism prevalence can only claim that a third of a percent of children are autistic. This leaves 99.7% of children - most of whom have the same exposures as the autistic children - who are not autistic.
A basic understanding of these genetic connections is important for all learning disability psychiatrists if they are to follow the rapid changes — already beginning to influence our practice — that hold immense promise for the future.
Walter J. Muir
Powerpoint presentation
Bennett Leventhal
Every human carries between 80,000 and 100,000 genes; the products of these genes - acting together and in combination with the environment - enable every human characteristic.
National Institute of Mental Health
Children with persistent global developmental delay with or without other birth defects or organ system involvement, with mental retardation, and with unexplained persistent or intermittent neurological symptoms should be considered for evaluation.
Pamela Arn
Autism is usually first noticed by parents or clinicians before two years of age when behaviors, such as onset of speech and social activity, would first appear in normally developing children.
Thomas Wassink
Children with dysmorphic features, congenital anomalies, mental retardation, or family members with developmental disorders are those most likely to benefit from extensive medical testing and genetic consultation. The yield of testing is much less in high-functioning children with a normal appearance and IQ and moderate social and language impairments.
Rebecca Muhle, Stephanie V. Trentacoste, Isabelle Rapin
As it turns out, most behaviors are not linked to single genes -- that is, the patterns typical of Mendelian inheritance (such as the recessive inheritance of PKU) do not often arise in behavioral genetics studies. While a single gene cannot create normal behaviors, mutations in a single gene can disrupt them. This does not mean, however, that behavioral geneticists do not have reliable methods of investigating whether and how genes might influence behavior. In fact, families, adoption, and twinning offer natural experiments in shared inheritance that allow careful study of behaviors.
Michael Dougherty
Very good evidence indicates that autism and ASDs are genetic disorders. Although a significant proportion of ASDs are related to chromosomal abnormalities and causal mutations, a larger proportion result from the interactions of multiple susceptibility loci. The exact nature of the gene variants that are implicated in ASDs -- for example, whether they are common variants or rare variants -- will influence the feasibility of defining specific genetic assays as predictors for the risk for ASDs and determining the exact form the assays would take.
Joseph D. Buxbaum, Medscape
Although autism is considered a disorder with a strong genetic component, the inheritance of autism differs greatly to that of other, better understood, genetic disorders such as cystic fibrosis or Huntington's disease.
John Vincent
Solid evidence is emerging that what psychological tests measure is only a part of the entire portrait of what intelligence is. Although verbal ability is carefully measured by existing tests, social competence is generally not measured at all.
Robert Sternberg, Elena Grigorenko
No test is able to measure all abilities that lie within the complex domain of intelligence. Indeed, they measure only a small portion of skills that might rightfully define the domain of intelligent human behavior.
Alan Kaufman
Nearly all genetic data have been obtained using measures developed from this psychometric perspective, primarily IQ tests.
Robert Plomin
Substantial progress has been made in the ability to describe accurately the social-communicative and behavioral deficits that comprise ASD. Measurement tools that allow the categorization of the autistic spectrum in reliable and valid ways are available.
Catherine Lord, Fred Volkmar
Currently, the research data suggest that select aspects of the temporal and frontal lobes, and portions of the amygdala, are key nodes in systems affected by autism.
Robert Schultz, Ami Klin
Pharmacotherapy of autistic disorder and other PDD's currently involves the treatment of target symptoms including hyperactivity, inattention, interfering repetitive thoughts and behavior, and aggression toward self, others, or the environment.
Christopher McDougle, David Posey
Theoretical considerations underlying the rationale for the study of 5-HT in autism include 5-HT's role in neurodevelopment, its especially rich innervation of limbic areas critical for emotional expression and social behavior
George Anderson
Autism is one of the most heritable complex genetic disorders in psychiatry. Despite this high heritability, autism has a heterogeneous etiology, with multiple genes and chromosomal regions likely to be involved.
Jeremy Veenstra-VanDerWeele, Edwin Cook
A different set of genes may confer risk in different families or individuals (genetic heterogeneity), and different siblings in a given family may have a different clinical presentation (clinical heterogeneity).
James Sutcliffe, Erika Nurmi
First, the basic pattern of neuronal organization appears to be largely intrinsic to the developing brain. A second concept is that neuronal activity strengthens immature synaptic connections between neurons, whereas inactive synapses weaken and die away.
Paul Lombroso
Medial temporal lobe structures are essential for just one kind of memory, which has come to be termed declarative memory. Other kinds of memory, collectively termed nondeclarative memory, have been linked to other brain systems.
Stuart Zola, Larry Squire
Pavlovian fear conditioning has served as a powerful animal model of fear and anxiety disorders including phobia, panic disorder, posttraumatic stress disorder, and possibly many of the “neurotic” associations of everyday life.
Kerry Ressler, Michael Davis
The absence of various members of the ERK signaling cascade have dramatic effects on the ability of knock-out mice to learn new tasks.
J. David Sweatt, Edwin Weeber, Paul Lombroso
The configuration of traits of intellect, mental energy, and temperament with which Isaac Newton revolutionized the world of science were the consequence of a genetic lottery that occurred about nine months prior to his birth.
David Lykken
Autism is a neurobehavioral spectrum of phenotypes characterized by deficits in the development of language and social relationships and patterns of repetitive, rigid and compulsive behaviors. Twin and family studies point to a significant genetic etiology, and several groups have performed genomic linkage screens to identify susceptibility loci... Our results further support 19p13 as harboring an autism susceptibility locus, confirm other linkage findings at 17q11.2, and demonstrate the need to analyze more discreet trait-based subsets of complex phenotypes to improve ability to detect genetic effects.
Jacob McCauley et al
Family and twin studies have suggested a genetic component in autism. We performed a genome-wide screen with 264 microsatellites markers in 51 multiplex families, using non-parametric linkage methods. Families were recruited by a collaborative group including clinicians from Sweden, France, Norway, the USA, Italy, Austria and Belgium. Using two- point and multipoint affected sib-pair analyses, 11 regions gave nominal P -values of 0.05 or lower. Four of these regions overlapped with regions on chromosomes 2q, 7q, 16p and 19p identified by the first genome-wide scan of autism performed by the International Molecular Genetic Study of Autism Consortium. Another of our potential susceptibility regions overlapped with the 15q11-q13 region identified in previous candidate gene studies. Our study revealed six additional regions on chromosomes 4q, 5p, 6q, 10q, 18q and Xp. We found that the most significant multipoint linkage was close to marker D6S283 (maximum lod score = 2.23, P = 0.0013).
Anne Philippe et al
Between 40% and 80% of the variation in human intelligence (IQ) is attributable to genetic factors. Except for many rare mutations resulting in severe cognitive dysfunction, attempts to identify these factors have not been successful. We report a genomewide linkage scan involving 634 sibling pairs designed to identify chromosomal regions that explain variation in IQ. Model-free multipoint linkage analysis revealed evidence of a significant quantitative-trait locus for performance IQ at 2q24.1-31.1 (LOD score 4.42), which overlaps the 2q21-33 region that has repeatedly shown linkage to autism. A second region revealed suggestive linkage for both full-scale and verbal IQs on 6p25.3-22.3 (LOD score 3.20 for full-scale IQ and 2.33 for verbal IQ), overlapping marginally with the 6p22.3-21.31 region implicated in reading disability and dyslexia.
Danielle Posthuma et al
Approximately 4% of English-speaking children are affected by specific language impairment (SLI), a disorder in the development of language skills despite adequate opportunity and normal intelligence. Several studies have indicated the importance of genetic factors in SLI; a positive family history confers an increased risk of development, and concordance in monozygotic twins consistently exceeds that in dizygotic twins. However, like many behavioral traits, SLI is assumed to be genetically complex, with several loci contributing to the overall risk. We have compiled 98 families drawn from epidemiological and clinical populations, all with probands whose standard language scores fall ges1.5 SD below the mean for their age. Systematic genomewide quantitative-traitndashlocus analysis of three language-related measures (i.e., the Clinical Evaluation of Language FundamentalsndashRevised [CELF-R] receptive and expressive scales and the nonword repetition [NWR] test) yielded two regions, one on chromosome 16 and one on 19, that both had maximum LOD scores of 3.55. Simulations suggest that, of these two multipoint results, the NWR linkage to chromosome 16q is the most significant, with empirical P values reaching 10-5, under both Haseman-Elston (HE) analysis (LOD score 3.55; P=.00003) and variance-components (VC) analysis (LOD score 2.57; P=.00008). Single-point analyses provided further support for involvement of this locus, with three markers, under the peak of linkage, yielding LOD scores >1.9. The 19q locus was linked to the CELF-R expressive-language score and exceeds the threshold for suggestive linkage under all types of analysis performedmdashmultipoint HE analysis (LOD score 3.55; empirical P=.00004) and VC (LOD score 2.84; empirical P=.00027) and single-point HE analysis (LOD score 2.49) and VC (LOD score 2.22). Furthermore, both the clinical and epidemiological samples showed independent evidence of linkage on both chromosome 16q and chromosome 19q, indicating that these may represent universally important loci in SLI and, thus, general risk factors for language impairment.
SLI Consortium
We report the analysis of 335 microsatellite markers genotyped in 110 multiplex families with autism. All families include at least two "affected" siblings, at least one of whom has autism; the remaining affected sibs carry diagnoses of either Asperger syndrome or pervasive developmental disorder. Affected sib-pair analysis yielded multipoint maximum LOD scores (MLS) that reach the accepted threshold for suggestive linkage on chromosomes 5, X, and 19. Nominal evidence for linkage (point-wise P<.05) was obtained on chromosomes 2, 3, 4, 8, 10, 11, 12, 15, 16, 18, and 20, and secondary loci were found on chromosomes 5 and 19. Analysis of families sharing alleles at the putative X chromosomal linked locus and one or more other putative linked loci produced an MLS of 3.56 for the DXS470-D19S174 marker combination. In an effort to increase power to detect linkage, scan statistics were used to evaluate the significance of peak LOD scores based on statistical evidence at adjacent marker loci. This analysis yielded impressive evidence for linkage to autism and autism-spectrum disorders with significant genomewide P values <.05 for markers on chromosomes 5 and 8 and with suggestive linkage evidence for a marker on chromosome 19.
Jianjun Liu, et al
Autism is characterized by impairments in reciprocal communication and social interaction and by repetitive and stereotyped patterns of activities and interests. Evidence for a strong underlying genetic predisposition comes from twin and family studies, although susceptibility genes have not yet been identified. A whole-genome screen for linkage, using 83 sib pairs with autism, has been completed, and 119 markers have been genotyped in 13 candidate regions in a further 69 sib pairs. The addition of new families and markers provides further support for previous reports of linkages on chromosomes 7q and 16p. Two new regions of linkage have also been identified on chromosomes 2q and 17q. The most significant finding was a multipoint maximum LOD score (MLS) of 3.74 at marker D2S2188 on chromosome 2; this MLS increased to 4.80 when only sib pairs fulfilling strict diagnostic criteria were included. The susceptibility region on chromosome 7 was the next most significant, generating a multipoint MLS of 3.20 at marker D7S477. Chromosome 16 generated a multipoint MLS of 2.93 at D16S3102, whereas chromosome 17 generated a multipoint MLS of 2.34 at HTTINT2. With the addition of new families, there was no increased allele sharing at a number of other loci originally showing some evidence of linkage. These results support the continuing collection of multiplex sib-pair families to identify autism-susceptibility genes.
International Molecular Genetic Study of Autism Consortium
To identify genetic loci for autism-spectrum disorders, we have performed a two-stage genomewide scan in 38 Finnish families. The detailed clinical examination of all family members revealed infantile autism, but also Asperger syndrome (AS) and developmental dysphasia, in the same set of families. The most significant evidence for linkage was found on chromosome 3q25-27, with a maximum two-point LOD score of 4.31 (Zmaxdom) for D3S3037, using infantile autism and AS as an affection status. Six markers flanking over a 5-cM region on 3q gave Zmax dom >3, and a maximum parametric multipoint LOD score (MLS) of 4.81 was obtained in the vicinity of D3S3715 and D3S3037. Association, linkage disequilibrium, and haplotype analyses provided some evidence for shared ancestor alleles on this chromosomal region among affected individuals, especially in the regional subisolate. Additional potential susceptibility loci with two-point LOD scores >2 were observed on chromosomes 1q21-22 and 7q. The region on 1q21-22 overlaps with the previously reported candidate region for infantile autism and schizophrenia, whereas the region on chromosome 7q provided evidence for linkage 58 cM distally from the previously described autism susceptibility locus (AUTS1).
Mari Auranen et al
The present follow-up genome scan, which used a consistent research design across studies and examined the largest ASD sample collection reported to date, gave either equivalent or marginally increased evidence for linkage at several chromosomal regions implicated in our previous scan but eliminated evidence for linkage at other regions.
Amanda L. Yonan et al
We have conducted a genome screen of autism, by linkage analysis in an initial set of 90 multiplex sibships, with parents, containing 97 independent affected sib pairs (ASPs), with follow-up in 49 additional multiplex sibships, containing 50 ASPs. In total, 519 markers were genotyped, including 362 for the initial screen, and an additional 157 were genotyped in the follow-up. As a control, we also included in the analysis unaffected sibs, which provided 51 discordant sib pairs (DSPs) for the initial screen and 29 for the follow-up. In the initial phase of the work, we observed increased identity by descent (IBD) in the ASPs (sharing of 51.6%) compared with the DSPs (sharing of 50.8%). The excess sharing in the ASPs could not be attributed to the effect of a small number of loci but, rather, was due to the modest increase in the entire distribution of IBD. These results are most compatible with a model specifying a large number of loci (perhaps ges15) and are less compatible with models specifying les10 loci. The largest LOD score obtained in the initial scan was for a marker on chromosome 1p; this region also showed positive sharing in the replication family set, giving a maximum multipoint LOD score of 2.15 for both sets combined. Thus, there may exist a gene of moderate effect in this region. We had only modestly positive or negative linkage evidence in candidate regions identified in other studies. Our results suggest that positional cloning of susceptibility loci by linkage analysis may be a formidable task and that other approaches may be necessary.
Neil Risch et al
A review of ASD epidemiology, focusing on what is known about heritable and nonher-itable risk factors and concluding with a discussion of a more novel epidemiologic study design that blends elements of family-based and association studies.
Craig Newschaffer, Daniele Fallin, Nora Lee
Neuroligins are postsynaptic membrane cell-adhesion molecules which bind to beta-neurexins, a family of proteins that act as neuronal cell surface receptors. To explore the possibility that structural variants in the beta-neurexin genes predispose to autism, the coding regions and associated splice junctions of three beta-neurexin genes were scanned with detection of virtually all mutations-SSCP (DOVAM-S) in 72 Caucasian patients with autism. In addition, segments of the neurexin 1beta gene were sequenced in 131 additional Caucasian and 61 Afro-American patients with autism from South Carolina and the Midwest. Two putative missense structural variants were identified in the neurexin 1beta gene in four Caucasian patients with autism and not in 535 healthy Caucasian controls (4/203 vs. 0/535, P=0.0056). Initial family data suggest that incomplete penetrance may occur. In addition, no structural variant was found in the neurexin 2beta gene and the neurexin 3beta gene. In the context of all available data, we conclude that mutations of the neurexin 1beta gene may contribute to autism susceptibility.
J. Feng et al
Genes do NOT cause the development of physical and psychological characteristics directly. They are co-acting levels in a single developmental system, NOT separate influences in development. Genetically influenced characteristics can and do change
Aubrey Baillie
Adenylosuccinate lyase (ADSL) is a bifunctional enzyme acting in de novo purine synthesis and purine nucleotide recycling. ADSL deficiency is a selectively neuronopathic disorder with psychomotor retardation and epilepsy as leading traits. Both dephosphorylated enzyme substrates, succinylaminoimidazole-carboxamide riboside (SAICAr) and succinyladenosine (S-Ado), accumulate in the cerebrospinal fluid (CSF) of affected individuals with S-Ado/SAICAr concentration ratios proportional to the phenotype severity. We studied the disorder at various levels in a group of six patients with ADSL deficiency. We identified the complete ADSL cDNA and its alternatively spliced isoform resulting from exon 12 skipping. Both mRNA isoforms were expressed in all the tissues studied with the non-spliced form 10-fold more abundant. Both cDNAs were expressed in Escherichia coli and functionally characterized at the protein level. The results showed only the unspliced ADSL to be active. The gene consists of 13 exons spanning 23 kb. The promotor region shows typical features of the housekeeping gene. Eight mutations were identified in a group of six patients. The expression studies of the mutant proteins carried out in an attempt to study genotype-phenotype correlation showed that the level of residual enzyme activity correlates with the severity of the clinical phenotype. All the mutant enzymes studied in vitro displayed a proportional decrease in activity against both of their substrates. However, this was not concordant with strikingly different concentration ratios in the CSF of individual patients. This suggests either different in vivo enzyme activities against each of the substrates and/or their different turnover across the CSF-blood barrier, which may be decisive in determining disease severity.
Stanislav Kmoch et al
Maternal duplications of the imprinted 15q11-13 domain result in an estimated 1%ndash2% of autism-spectrum disorders, and linkage to autism has been identified within 15q12-13. UBE3A, the Angelman syndrome gene, has, to date, been the only maternally expressed, imprinted gene identified within this region, but mutations have not been found in autistic patients. Here we describe the characterization of ATP10C, a new human imprinted gene, which encodes a putative protein homologous to the mouse aminophospholipid-transporting ATPase Atp10c. ATP10C maps within 200 kb distal to UBE3A and, like UBE3A, also demonstrates imprinted, preferential maternal expression in human brain. The location and imprinted expression of ATP10C thus make it a candidate for chromosome 15ndashassociated autism and suggest that it may contribute to the Angelman syndrome phenotype.
Laura BK Herzing et al
Questionnaire to be filled out by participants in this project.
Several independent family-based linkage and cytogenetic studies have suggested that an autism-susceptibility gene (or genes) resides on chromosome 7 (103-106). The chromosome 7q21-q35 interval (>60 Mb) appears to be most often implicated but further localization has been complicated owing to the complex nature of the phenotype, as well as the underlying genetics, which can apparently include incomplete penetrance and allelic heterogeneity (107). Moreover, a potential preference for paternal (compared with maternal) linkage disequilibrium and recombination in autism families (compared with controls) has been described suggesting that imprinting or other non-Mendelian mechanisms may be involved (104). Taking all available data into consideration in the simplest explanation, there may be multiple genes on chromosome 7 involved. As with previous studies of many monogenic diseases future analyses of autism and other complex diseases, will benefit from the vast and ever-increasing wealth of resources, data and literature available for human chromosome 7. Ultimately, however, resolution of the aforementioned 'chromosomal' problems and others still to be described would likely benefit from organized efforts by multiple groups or consortia working together.
Stephen Scherer, Eric Green
We are not opposed to genetic research. However, we are opposed to some developments, such as genetic discrimination, cloning and inheritable ('germ line') genetic engineering of human beings.
There's nothing that's that abnormal in the brains of people with autism. If you compared a young autistic person's brain to the brain of his healthy 60-year old grandfather, the grand-child would have the better looking brain.
Catherine Johnson
General information and genetic profile
Victor McKusick
The results of genetic linkage studies for autism have suggested that a susceptibility locus for the disease is located on the long arm of chromosome 7 (7q). An autistic individual carrying a translocation, t(7;13)(q31.3;q21), with the chromosome 7 breakpoint located in the region of 7q implicated by genetic studies was identified. A novel gene known as "RAY1" (or "FAM4A1") was found to be directly interrupted by the translocation breakpoint. The gene, which was found to be encoded by 16 exons with evidence of alternative splicing, spanned > or =220 kb of DNA at 7q31.3. Mutation screening of the entire coding region in a set of 27 unrelated autistic individuals failed to identify phenotype-specific variants, suggesting that coding region mutations are unlikely to be involved in the etiology of autism. Apparent homologues of RAY1 have also been identified in mouse, rat, pig, chicken, fruit fly, and nematode. The human and mouse genes share similar splicing patterns, and their predicted protein products are 98% identical.
J.B. Vincent et al
FOXP2, the first gene to have been implicated in a developmental communication disorder, offers a unique entry point into neuromolecular mechanisms influencing human speech and language acquisition. In multiple members of the well-studied KE family, a heterozygous missense mutation in FOXP2 causes problems in sequencing muscle movements required for articulating speech (developmental verbal dyspraxia), accompanied by wider deficits in linguistic and grammatical processing. Chromosomal rearrangements involving this locus have also been identified. Analyses of FOXP2 coding sequence in typical forms of specific language impairment (SLI), autism, and dyslexia have not uncovered any etiological variants. However, no previous study has performed mutation screening of children with a primary diagnosis of verbal dyspraxia, the most overt feature of the disorder in affected members of the KE family. Here, we report investigations of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia. We detected variants that alter FOXP2 protein sequence in three probands. One such variant is a heterozygous nonsense mutation that yields a dramatically truncated protein product and cosegregates with speech and language difficulties in the proband, his affected sibling, and their mother. Our discovery of the first nonsense mutation in FOXP2 now opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene. This endeavor will be crucial for gaining insight into the role of FOXP2 in human cognition.
Kay D. MacDermot et al
Autism is a common neurodevelopmental disorder with a significant genetic component. Existing research suggests that multiple genes contribute to autism and that epigenetic effects or gene-gene interactions are likely contributors to autism risk. However, these effects have not yet been identified. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, has been implicated in autism etiology. Fourteen known autosomal GABA receptor subunit genes were studied to look for the genes associated with autism and their possible interactions. Single-nucleotide polymorphisms (SNPs) were screened in the following genes: GABRG1, GABRA2, GABRA4, and GABRB1 on chromosome 4p12; GABRB2, GABRA6, GABRA1, GABRG2, and GABRP on 5q34-q35.1; GABRR1 and GABRR2 on 6q15; and GABRA5, GABRB3, and GABRG3 on 15q12. Intronic and/or silent mutation SNPs within each gene were analyzed in 470 white families with autism. Initially, SNPs were used in a family-based study for allelic association analysis--with the pedigree disequilibrium test and the family-based association test--and for genotypic and haplotypic association analysis--with the genotype-pedigree disequilibrium test (geno-PDT), the association in the presence of linkage (APL) test, and the haplotype family-based association test. Next, with the use of five refined independent marker sets, extended multifactor-dimensionality reduction (EMDR) analysis was employed to identify the models with locus joint effects, and interaction was further verified by conditional logistic regression. Significant allelic association was found for markers RS1912960 (in GABRA4; P = .01) and HCV9866022 (in GABRR2; P = .04). The geno-PDT found significant genotypic association for HCV8262334 (in GABRA2), RS1912960 and RS2280073 (in GABRA4), and RS2617503 and RS12187676 (in GABRB2). Consistent with the allelic and genotypic association results, EMDR confirmed the main effect at RS1912960 (in GABRA4). EMDR also identified a significant two-locus gene-gene effect model involving RS1912960 in GABRA4 and RS2351299 in GABRB1. Further support for this two-locus model came from both the multilocus geno-PDT and the APL test, which indicated a common genotype and haplotype combination positively associated with disease. Finally, these results were also consistent with the results from the conditional logistic regression, which confirmed the interaction between GABRA4 and GABRB1 (odds ratio = 2.9 for interaction term; P = .002). Through the convergence of all analyses, we conclude that GABRA4 is involved in the etiology of autism and potentially increases autism risk through interaction with GABRB1. These results support the hypothesis that GABA receptor subunit genes are involved in autism, most likely via complex gene-gene interactions.
D.Q. Ma et al
Presents the hypothesis that autism rates are driven by an interaction between populations. Editorial note: This site contains pseudo-scientific material that appears driven by a racist political agenda.
Jim Bowery
Most diseases are complex in nature and are affected by multiple genes and environmental conditions; it is highly likely that DNA tests alone do not define all the genetic factors responsible for a disease..
Wenlei Liu, Nikolina Icitovic, Michele L Shaffer, Gary A Chase
We are beginning to unravel the Gordian threads that bind imprinted genes with such diverse issues as brain development, vulnerability to mental disease and the battle of the sexes, as played out at the level of cognitive and behavioral functioning.
Anthony Isles, Lawrence Wilkinson
The imprinted-X liability threshold model hypothesizes that the threshold for phenotypic expression of many autistic characteristics is influenced by an imprinted X-linked gene(s) that is protective in nature.
David Skuse
While it has been known that genetic abnormalities are implicated in susceptibility to autism, new research has added another variable – the particular parent who contributes the defective gene can determine whether or not the child acquires autism.
Duke University Medical Center
Basically, Baron-Cohen is saying that people with a propensity for autism are producing autistic children. Sounds obvious but if it turns out to be true then its the death knell for the cure groups and their constant clamouring against environmental agents being the sole cause. Liddle then goes on to propound his own, admittedly unscientific theory, to account for why the factors Baron-Cohen is investigating may lead directly to the so called autism 'epidemic'.
Kevin Leitch
In this letter, I have suggested another explanation for the observed excess of twin pairs among affected sibling pairs; that it is simply the effect of ascertaining pairs of affected siblings. Is multiple birth an important risk factor for autism? The data presented by Greenberg et al. and Betancur et al. do not allow the testing of this hypothesis. A population-based study, in which the incidence of autism among MZ twins, DZ twins, and nontwin siblings is estimated should clarify this important issue.
Peter M. Visscher
This model represents a relatively novel perspective on autism with a focus on epigenetic in addition to genetic changes and on the fact that these changes may be new in the child rather than inherited -- similar to what occurs in the case of Down syndrome.
The notion that the genome contains the blueprint of human nature is akin to an important outlook within Western metaphysics that interprets all living organisms as having "souls," which determine their characteristic traits.
Alex Mauronm Science
These data indicate that JS is a genetically distinct disorder from autism. Different genes with different inheritance patterns that affect neurodevelopment of the cerebellum could explain the clinical similarities previously reported in JS and autism
T.N. Takahashi
Autism has a strong, complex genetic component, most likely involving several genes. Multiple genomic screens have shown evidence suggesting linkage to chromosome 2q31-q33, which includes the SLC25A12 gene. Recently, an association between autism risk and two single nucleotide polymorphisms (SNPs) in SLC25A12 was reported. This study aimed to test for association in SLC25A12 in an independent data set of 327 families with autistic offspring. The authors analyzed two SNPs that were significant in the previous study group, as well as seven additional SNPs within the gene. Association analyses for individual SNPs as well as haplotypes were performed. There was no evidence of an association between SLC25A12 and autism. These results suggest that SLC25A12 is not a major contributor to autism risk in these families.
Raquel Rabionet et al
Linkage analysis in our dataset of 57 New England and 80 AGRE multiplex autism families reveals a multipoint heterogeneity LOD (HLOD) score of 2.74 at D17S1871 in17q11.2.
J.L. McAuley et al
Autistic disorder is a complex genetic disease. Because of previous reports of individuals with autistic disorder with duplications of the Prader-Willi/Angelman syndrome critical region, we screened several markers across the 15q11-13 region, for linkage disequilibrium. One hundred forty families, consisting predominantly of a child with autistic disorder and both parents, were studied. Genotyping was performed by use of multiplex PCR and capillary electrophoresis. Two children were identified who had interstitial chromosome 15 duplications and were excluded from further linkage-disequilibrium analysis. Use of the multiallelic transmission-disequilibrium test (MTDT), for nine loci on 15q11-13, revealed linkage disequilibrium between autistic disorder and a marker in the ggr-aminobutyric acidA receptor subunit gene, GABRB3 155CA-2 (MTDT 28.63, 10 df, P=.0014). No evidence was found for parent-of-origin effects on allelic transmission. The convergence of GABRB3 as a positional and functional candidate along with the linkage-disequilibrium data suggests the need for further investigation of the role of GABRB3 or adjacent genes in autistic disorder.
Edwin H. Cook et al
In an autism diagnosis, two types of behaviours must be displayed; those that reflect social impairment such as a difficulty in making friends and non-social obsessive and repetitive behaviours such as sticking to rigid routines. These two types of symptoms can both have massive impact on children's development. The researchers were motivated to investigate these two components separately because they represent two very different types of behaviours and it is not clear why they co-occur in autism spectrum conditions.
Medical News Today
Researchers studying individuals with autism and their siblings and parents should therefore account for differential characteristics of the probands with autism and their families.
Michal Shaked, Nurit Yirmiya
GRM8 is a member of metabotropic glutamate receptors, which negatively modulate glutamate transmission and thus serve to prevent pathological changes in neuronal hyperexcitability and homeostasis. Thus, dysfunction of the GRM8 gene may result in neuronal damage.
F.J. Serajee et al, Journal of Medical Genetics
Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2), encoding a transcriptional repressor, cause Rett syndrome and a variety of related neurodevelopmental disorders. The vast majority of mutations associated with human disease are loss-of-function mutations, but precisely what aspect of MeCP2 function is responsible for these phenotypes remains unknown. We overexpressed wild-type human protein in transgenic mice using a large genomic clone containing the entire human MECP2 locus. Detailed neurobehavioral and electrophysiological studies in transgenic line MeCP2Tg1, which expresses MeCP2 at ~2-fold wild-type levels, demonstrated onset of phenotypes around 10 weeks of age. Surprisingly, these mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After 20 weeks of age, however, these mice developed seizures, became hypoactive and ~30% of them died by 1 year of age. These data demonstrate that MeCP2 levels must be tightly regulated in vivo, and that even mild overexpression of this protein is detrimental. Furthermore, these results support the possibility that duplications or gain-of-function mutations in MECP2 might underlie some cases of X-linked delayed-onset neurobehavioral disorders.
Ann Collins et al
New Jersey scientists are reporting discoveries they say might lead to cures for such psychiatric disorders as autism and schizophrenia. Scientists at Rutgers, The State University of New Jersey, and The University of Medicine and Dentistry of New Jersey, say they've discovered information regarding the genetic, cellular and neurological bases of those diseases. Using data drawn from the Rutgers Cell and DNA Repository, professors James Millonig and Linda Brzustowicz, assisted by professor Emanuel DiCicco-Bloom, led a team that further substantiated the link between autism and Engrailed 2, or EN2, a gene important in central nervous system development.
Science Daily
Two recent studies suggest that multiple rare mutations within a single gene may increase risk for autism. Their findings also may point to new therapeutic options for this devastating disorder. In this pair of studies, the researchers identify and characterize a number of mutations in the gene that regulate brain levels of serotonin, a neurotransmitter involved in many biological processes including breathing, digestion, sleep, appetite, blood vessel constriction, mood and impulsivity.
Medical Study News
Investigators have identified a syndrome of cortical dysplasia-focal epilepsy (CDFE) that develops in Old Order Amish in early childhood, which is followed by mental retardation and aggressive behavior. The researchers linked the epilepsy to a mutation in the CNTNAP2 gene that expresses contactin-associated protein-like 2 (CASPR2). Dr. Kevin A. Strauss, at the Clinical for Special Children in Strasburg, Pennsylvania, and associates reviewed the records of nine patients with CDFE. During infancy, the children had subtle limitations in physical skills but good language comprehension, cognition, and social development. However, they also had relatively large heads and diminished or absent deep-tendon reflexes. According to their report in the March 30th issue of The New England Journal of Medicine, seizures began at ages 14 to 20 months, and tended to abate several years later. Learning ability and social behavior deteriorated after seizure onset, with patients developing hyperactivity, inattention, aggression, autism, and mental retardation.
Reuters, Medscape
Genetic studies have provided evidence for an autism susceptibility locus (AUTS1) on chromosome 7q. Screening for mutations in six genes mapping to 7q, CUTL1, SRPK2, SYPL, LAMB1, NRCAM and PTPRZ1 in 48 unrelated individuals with autism led to the identification of several new coding variants in the genes CUTL1, LAMB1 and PTPRZ1. Analysis of genetic variants provided evidence for association with autism for one of the new missense changes identified in LAMB1; this effect was stronger in a subgroup of affected male sibling pair families, implying a possible specific sex-related effect for this variant. Association was also detected for several polymorphisms in the promoter and untranslated region of NRCAM, suggesting that alterations in expression of this gene may be linked to autism susceptibility.
E. Bonora et al
No significant transmission disequilibrium was found, suggesting ATP10C is unlikely to contribute strongly to susceptibility to autism... However, due to limited power to detect genes of modest effect, the possible functional role of the nonsynonymous SNPs and the functional implications of the SNPs identified from 5 ranking region and intron 2 splicing region may be evaluated in further studies.
Soo-Jeong Kim, et al
Autism has a strong genetic background with a higher frequency of affected males suggesting involvement of X-linked genes and possibly also other factors causing the unbalanced sex ratio in the etiology of the disorder. We have identified two missense mutations in the ribosomal protein gene RPL10 located in Xq28 in two independent families with autism. We have obtained evidence that the amino-acid substitutions L206M and H213Q at the C-terminal end of RPL10 confer hypomorphism with respect to the regulation of the translation process while keeping the basic translation functions intact. This suggests the contribution of a novel, possibly modulating aberrant cellular function operative in autism. Previously, we detected high expression of RPL10 by RNA in situ hybridization in mouse hippocampus, a constituent of the brain limbic system known to be afflicted in autism. Based on these findings, we present a model for autistic disorder where a change in translational function is suggested to impact on those cognitive functions that are mediated through the limbic system.
SM Klauck et al
The appropriate conjunction between the words nature and nurture is not versus but and. There is increasing acceptance of the evidence for substantial genetic influence on many behavioral traits, but the same research also provides the best available evidence for the importance of environmental influence and important clues about how the environment works. Because much developmental action is at the interface between genes and environment, genetic research needs to incorporate measures of the environment, and environmental research will be enhanced by collecting DNA.
Robert Plomin, Kathryn Asbury
This theory aims at giving a credible explanation for why up to 10% in some parts of the world are classified by psychiatry as disordered.
Leif Ekblad
Autistic Spectrum and related conditions may in fact be the result of genes carried from Neanderthal interbreeding. My own study and observation has found much to support this idea, however much of it being of an only circumstantial nature.
Although NDNL2/MAGE-G in the broadly defined chromosome 15 autistic disorder susceptibility region, it is not likely to be pathogenic based on its wide expression pattern and lack of imprinted expression.
Thea Chibuk, Jocelyn Bischof, Rachel Wevrick
In this patient with isolated autism, the neurobeachin gene was found to be disrupted by a balanced reciprocal translocation. The neurobeachin gene maps at 26.87 cM near marker D13S624. It is of particular interest that this falls within the 19 cM region that was identified as a candidate region for autism on chromosome 13q/
D. Castermans et al, Journal of Medical Genetics
The findings imply that a majority of children and adolescents with 22q11 deletion syndrome are in need of neuropsychiatric assessment and intervention.
Lena Niklasson et al
A single gene mutation doubles a child's susceptibility to autism, a Vanderbilt-led research team reports. It's a discovery with far-reaching implications. Why? It isn't specifically a brain gene. In fact, it affects multiple systems in the body, including immune function and gut repair. The gene in question is a variant form of a gene called MET.
Daniel DeNoon, Medscape
They suggest that epigenetic and genetic factors (both de novo and inherited) cause autism through dysregulation of two or more principal genes, one of which maps within chromosomes 15q11-q13, with the Angelman gene encoding E6-AP ubiquitin-protein ligase (UBE3A) being the strongest candidate in this region
Yong-hui Jiang, et al
The result of our study does not support the presence of an association between the HOXA1 or HOXB1 genes and autism, unlike the study reported by Ingram et al. Furthermore, statistical analysis also showed lack of any interaction between the observed allelic variants in the two HOX genes and autism.
Z. Talebizadeh et al, Journal of Medical Genetics
In summary, we have identified a novel missense change at a highly conserved residue within the region of GTPase activating domain homology of the TSC2 gene in two four generation TSC pedigrees with a total of more than 40 affected members. This is, to our knowledge, by far the largest known group of TSC patients carrying the same mutation.
Leena Khare et al, Journal of Medical Genetics
Autism is considered by many to be the most strongly genetically influenced multifactorial childhood psychiatric disorder. In the absence of any known gene or genes, the main support for this is derived from family and twin studies. Two recent studies (Greenberg et al. 2001; Betancur et al. 2002) suggested that the twinning process itself is an important risk factor in the development of autism. If true, this would have major consequences for the interpretation of twin studies. Both studies compared the number of affected twin pairs among affected sib pairs to expected values in two separate samples of multiplex families and reported a substantial and significant excess of twin pairs. Using data from our epidemiological study in Western Australia, we investigated the possibility of an increased rate of autism in twins. All children born between 1980 and 1995 with autism, Asperger syndrome, or pervasive developmental disorder not otherwise specified (PDD-NOS) were ascertained. Of the 465 children with a diagnosis, 14 were twin births (rate 30.0/1,000) compared to 9,640 children of multiple births out of a total of 386,637 births in Western Australia between 1980 and 1995 (twin rate weighted to number of children with autism or PDD per year 26.3/1,000). These data clearly do not support twinning as a substantial risk factor in the etiology of autism. We demonstrate that the high proportion of twins found in affected-sib-pair studies can be adequately explained by the high ratio of concordance rates in monozygotic (MZ) twins versus siblings and the distribution of family size in the population studied. Our results are in agreement with those of two similar studies by Croen et al. (2002) in California and Hultman et al. (2002) in Sweden.
Joachim Hallmayer et al
Catalog of human genes and genetic disorders
The theory that both parents of children with autism are strong systemizers is also evident from a study that shows both mothers and fathers score above average on a questionnaire that measures autistic traits. The parents are also faster at "visual search tasks" - in effect they have an unusually sharp eye for detail, just as their child with autism does - compared with the parents of unaffected children. Brain scan studies of mothers and fathers of children with autism have shown that the mothers have a masculinised pattern of brain activity, again suggesting they are strong systemizers. When all the evidence is taken together it suggests a genetic cause of autism, with both parents contributing genes that ultimately relate to a similar kind of mind: one with an affinity for thinking systematically.
Roger Highfield, UK Telegraph
Three genes appear to regulate aspects of impulsiveness and attention-processes that are common to normal personality as well as disturbances reflected in such diverse disorders as autism, ADHD, schizophrenia and addiction.
Richard Ebstein, Jonathan Benjamin, Robert Belmaker
Autistic disorder (AutD) is a neurodevelopmental disorder characterized by significant disturbances in social, communicative, and behavioral functioning. A two-stage genomic screen analysis of 99 families with AutD revealed suggestive evidence for linkage to chromosome 2q (D2S116 nonparametric sib-pair LOD score [MLS] 1.12 at 198 cM). In addition, analysis of linkage disequilibrium for D2S116 showed an allele-specific P value of <.01. Recently, linkage to the same region of 2q was reported in an independent genome screen. This evidence for linkage increased when analysis was restricted to the subset of patients with AutD who had delayed onset (>36 mo) of phrase speech (PSD). We similarly classified our data set of 82 sib pairs with AutD, identifying 45 families with AutD and PSD. Analysis of this PSD subset increased our support for linkage to 2q (MLS 2.86 and HLOD 2.12 for marker D2S116). These data support evidence for a gene on chromosome 2 contributing to risk of AutD, and they suggest that phenotypic homogeneity increases the power to find susceptibility genes for AutD.
Yujun Shao et al
Abnormal serotonergic functioning has been implicated in a number of neuropsychiatric disorders. Studies of autistic disorder have focused on serotonin (5-HT) since the finding of elevated whole blood levels of 5-HT in patients with autism.
J.P. Lassig, K. Vachirasomtoon, K. Hartzell, M. Leventhal, E. Courchesne, R. Courchesne, C. Lord, B.L. Leventhal, E.H. Cook, Jr.
When success is measured by the reduction in the number of people with Down Syndrome that are born, then it is clear that it is not the interests of the disabled individuals that are being considered.
Autism is caused, in part, by inheritance of multiple interacting susceptibility alleles. To identify these inherited factors, linkage analysis of multiplex families is being performed on a sample of 105 families with two or more affected sibs. Segregation patterns of short tandem repeat polymorphic markers from four chromosomes revealed null alleles at four marker sites in 12 families that were the result of deletions ranging in size from 5 to >260 kb. In one family, a deletion at marker D7S630 was complex, with two segments deleted (37 kb and 18 kb) and two retained (2,836 bp and 38 bp). Three families had deletions at D7S517, with each family having a different deletion (96 kb, 183 kb, and >69 kb). Another three families had deletions at D8S264, again with each family having a different deletion, ranging in size from <5.9 kb to >260 kb. At a fourth marker, D8S272, a 192-kb deletion was found in five families. Unrelated subjects and additional families without autism were screened for deletions at these four sites. Families screened included 40 families from Centre d'Etude du Polymorphisme Humaine and 28 families affected with learning disabilities. Unrelated samples were 299 elderly control subjects, 121 younger control subjects, and 248 subjects with Alzheimer disease. The deletion allele at D8S272 was found in all populations screened. For the other three sites, no additional deletions were identified in any of the groups without autism. Thus, these deletions appear to be specific to autism kindreds and are potential autism-susceptibility alleles. An alternative hypothesis is that autism-susceptibility alleles elsewhere cause the deletions detected here, possibly by inducing errors during meiosis.
Chang En Yu et al
The US National Alliance for Autism Research project involves 170 experts from the US, Canada, the UK and Europe. Researchers will use a new technology called DNA microarray to scan the human genome to locate key genes.
British Broadcasting Corporation
Relatives of autistic individuals have high rates of major depression and social phobia that are not associated with the broad autism phenotype and cannot be explained by the increased stress associated with raising an autistic child. Alternative mechanisms and the scientific and clinical implications of these findings are discussed.
Joseph Piven, Pat Palmer
Mice with a central nervous system deletion of Pten, a tumor suppressor gene in the PI3K/AKT pathway, manifest signs similar to those in autism spectrum disorders (ASD), according to a report in the May 4th issue of Neuron. "If the PI3K pathway is validated for a larger ASD population it will make a link between tumor suppressors in cancer and tumor suppressors in nondividing neurons," Dr. Luis F. Parada from the University of Texas Southwestern Medical Center, Dallas, told Reuters Health. "The use of anticancer therapies would then become relevant for some forms of ASD."
Will Boggs, Medscape
This locus on 7q35 may harbor a gene contributing variability in spoken language that is not uniquely related to language delay in autism.
M Alarcon et al
If we are marrying and having our children later, and men are much, much more likely to be working alongside women, because of a greater degree of equality within the job market and a decline of those jobs traditionally associated with women, is it not possible that these days our partners would tend to be drawn from the sphere of work rather than, as before, in a rather more random fashion from within our home communities?
Rod Liddle, Spectator
To date, autism provides the best evidence for this type of multigenic inheritance. The MZ twin concordance rate for autism is close to 100%, yet the dizygotic rate is only 2-10%, suggesting that more than three interacting genes are involved. Risch et al. conducted a genome scan on sibs with autism and came to the stunning conclusion that increased allele sharing is observed over virtually every chromosomal region. These data are best explained if autism is caused by the interaction of >20 different loci, each with a minor effect. Such loci will be extremely difficult to identify and are expected to be quite common, such that everyone probably carries a few 'autism alleles'.
Scott F. Stoltenberg, Margit Burmeister
Autism is a heritable but genetically complex disorder characterized by deficits in language and in reciprocal social interactions, combined with repetitive and stereotypic behaviors. As with many genetically complex disorders, numerous genome scans reveal inconsistent results. A genome scan of 345 families from the Autism Genetic Resource Exchange (AGRE) (AGRE_1), gave the strongest evidence of linkage at 17q11-17q21 in families with no affected females. Here, we report a full-genome scan of an independent sample of 91 AGRE families with 109 affected sibling pairs (AGRE_2) that also shows the strongest evidence of linkage to 17q11-17q21 in families with no affected females. Taken together, these samples provide a replication of linkage to this chromosome region that is, to our knowledge, the first such replication in autism. Fine mapping at 2-centimorgan (cM) intervals in the combined sample of families with no affected females reveals a linkage peak at 66.85 cM, which places this locus at 17q21.
Rita M. Cantor et al
The discovery should speed the search for additional genes that increase susceptibility to autism and enhance understanding of this complex disorder. It could eventually result in more precise diagnosis and possibly better treatments.
Researchers hope this understanding of autism's cognitive causes and effects will point to better treatment methods and comprehension of the challenges autistic individuals face.
E. O'Connor
The goal of AGRE is to facilitate more rapid progress in identification of the genetic causes of ASD's by promoting sharing and collaboration. This collection of a large set of multiplex families is a first step in that direction.
Only recently have mutations in MECP2 been found to be a cause of Rett Syndrome (RTT), a neuro­developmental disorder characterized by mental retardation, loss of expressive speech, deceleration of head growth and loss of acquired skills that almost exclusively affects females. We analysed the MECP2 gene in 31 patients diagnosed with RTT. Sequencing of the coding region and the splice sites revealed mutations in 24 females (77.40%). However, no abnormalities were detected in any of the parents that were available for investigation. Eleven mutations have not been described previously. Confirming two earlier studies, we found that most mutations are truncating and only a few of them are missense mutations. Several females carrying the same mutation display different phenotypes indicating that factors other than the type or position of mutations influence the severity of RTT. Four females with RTT variants were included in the study. Three of these presented with preserved speech while the fourth patient with congenital RTT lacked the initial period of normal development. Detection of mutations in these cases reveals that they are indeed variants of RTT. They represent the mild and the severe extremes of RTT. Conclusions: mutations in MECP2 seem to be the main cause for RTT and can be expected to be found in ~77% of patients that fulfil the criteria for RTT. Therefore analysis of MECP2 should be performed if RTT is suspected. Three mutation hotspots (T158M, R168X and R255X) were confirmed and a further one (R270X) newly identified. We recommend screening for these mutations before analysing the coding region.
F. Huppke et al
We discovered that the genetic anomaly previously found to be associated with alcoholism is also found with increased frequency among people with other addictive, compulsive or impulsive disorders.
Kenneth Blum, John Cull, Eric Braverman, David Comings
In an article to be published in a forthcoming issue of Journal of Evolutionary Biology, Dr Christopher Badcock and Professor Bernard Crespi explore the 'imprinted brain hypothesis' to explain the cause and effect of autism and autistic syndromes such as Asperger's syndrome, highlighted by the book The Curious Incident of the Dog in the Night-Time, which involves selective disruption of social behaviour that makes individuals more self-focussed whilst enhancing skills related to mechanistic cognition.
Medical News Today
The 'imprinted brain hypothesis' suggests that competition between maternally and paternally expressed genes leads to conflicts within the autistic individual which could result in an imbalance in the brain's development. This is supported by the fact that there is known to be a strong genomic imprinting component to the genetic and developmental mechanisms of autism and autistic syndromes.
Innovations Report
A study of around 1,000 Australian and Dutch adolescents has pinpointed specific areas of DNA which researchers believe may explain wide variations in intelligence. They identified locations on chromosomes 2 and 6 which they suspect contain genes regulating aspects of intelligence.
Courier Mail
French scientists have identified genetic mutations in a small number of children with autism which could provide insight into the biological basis of the disorder. They sequenced a gene called SHANK3 in more than 200 people with autism spectrum disorders (ASD), which includes autism, and found mutations in the gene in members of three families.
Reuters UK
Gene-hunters say the search has been heating up in the past few years, with more funding luring in more investigators, sophisticated tools and techniques being brought to bear, and an encouraging run of tantalizing results.
A high prevalence of rare dopamine receptor D4 (DRD4) alleles in children diagnosed with attention-deficit hyperactivity disorder (ADHD) has been reported [Grady et al., 2003]. In this prior study, extensive resequencing/haplotype data of the DRD4 locus was used to suggest that population stratification was not the explanation for the high prevalence of rare alleles. In the current study, DNA resequencing/haplotyping was conducted on 136 DRD4 alleles obtained from autism probands, collected from the same geographic population as the prior ADHD probands (Orange County, CA). A number of studies have suggested that the susceptibility genes underlying these two disorders might partially overlap. Rare DRD4 variants were not uncovered in this autism sample beyond that expected by chance. These results suggest strongly that the high prevalence of rare DRD4 alleles in ADHD probands is due to ascertainment of the sample by diagnosis of ADHD.
D.L. Grady et al
Significant linkage exists between autism and markers in 16p13.3 (18,19) although the peak probability of linkage lies beyond this 2 Mb region. Autism with Tourette's syndrome has been reported in patients trisomic for 16p13.1-pter (17).
Rachael Daniels et al
We have sequenced 1949 kb from the terminal Giemsa light band of human chromosome 16p, enabling us to fully annotate the region extending from the telomeric repeats to the previously published tuberous sclerosis disease 2 (TSC2) and polycystic kidney disease 1 (PKD1) genes. This region can be subdivided into two GC-rich, Alu-rich domains and one GC-rich, Alu-poor domain. The entire region is extremely gene rich, containing 100 confirmed genes and 20 predicted genes. Many of the genes encode widely expressed proteins orchestrating basic cellular processes (e.g. DNA recombination, repair, transcription, RNA processing, signal transduction, intracellular signalling and mRNA translation). Others, such as the {alpha} globin genes (HBA1 and HBA2), PDIP and BAIAP3, are specialized tissue-restricted genes. Some of the genes have been previously implicated in the pathophysiology of important human genetic diseases (e.g. asthma, cataracts and the ATR-16 syndrome). Others are known disease genes for {alpha} thalassaemia, adult polycystic kidney disease and tuberous sclerosis. There is also linkage evidence for bipolar affective disorder, epilepsy and autism in this region. Sixty-three chromosomal deletions reported here and elsewhere allow us to interpret the results of removing progressively larger numbers of genes from this well defined human telomeric region.
Rachel Daniels et al
An association study was performed to elucidate the role of the serotonin transporter (5-HTT) gene as a susceptibility factor for autism as treatment of patients with antidepressant drugs which selectively target 5-HTT reduced autistic or concomitant symptoms, such as repetitive behavior and aggression, and ameliorate language use... In our study haplotype analysis of the 5-HTTLPR and the VNTR in intron 2 supplied evidence for an association of 5-HTT and autism in the stringent (P = 0.069) and extended patient group (P = 0.049). Overall, we were not able to replicate the findings of the first study on 5-HTT and autism and instead observed a tendency for association of the opposite genetic variant of the gene with the disorder. The implications for genetic variants of the serotonin transporter in the etiology of autism and possible subgroups of patients, therefore, needs clarification in further studies with other and larger patient samples.
Sabine M. Klauck et al
In conclusion, our genomic characterization of the SPCH1 region has provided a framework for the investigations of family KE and the translocation patientspresented in this report. These studies represent further steps towards the isolation of the first gene to be implicated in the development of speech and language.
Cecilia S. L. Lai et al
To date, only three MECP2 mutations have been identified in 17 RTT families.7 8 14 Thus, 14 RTT families do not have mutations in either the coding region or the intron/exon boundaries of MECP2 to account for the disorder.
Ching Wan Lam et al, Journal of Medical Genetics
The gene, tracked to chromosome seven, is a dominant gene, meaning that people only have to inherit one copy to be affected. Males and females are equally affected by it.
Despite a growing body of evidence indicating that speech sound disorder (SSD) has an underlying genetic etiology, researchers have not yet identified specific genes predisposing to this condition. The speech and language deficits associated with SSD are shared with several other disorders, including dyslexia, autism, Prader-Willi Syndrome (PWS), and Angelman's Syndrome (AS), raising the possibility of gene sharing. Furthermore, we previously demonstrated that dyslexia and SSD share genetic susceptibility loci. The present study assesses the hypothesis that SSD also shares susceptibility loci with autism and PWS. To test this hypothesis, we examined linkage between SSD phenotypes and microsatellite markers on the chromosome 15q14-21 region, which has been associated with autism, PWS/AS, and dyslexia. Using SSD as the phenotype, we replicated linkage to the 15q14 region (P = 0.004). Further modeling revealed that this locus influenced oral-motor function, articulation and phonological memory, and that linkage at D15S118 was potentially influenced by a parent-of-origin effect (LOD score increase from 0.97 to 2.17, P = 0.0633). These results suggest shared genetic determinants in this chromosomal region for SSD, autism, and PWS/AS.
CM Stein et al
Our previous research involving 167 nuclear families from the Autism Genetic Resource Exchange (AGRE) demonstrated that two intronic SNPs, rs1861972 and rs1861973, in the homeodomain transcription factor gene ENGRAILED 2 (EN2) are significantly associated with autism spectrum disorder (ASD). In this study, significant replication of association for rs1861972 and rs1861973 is reported for two additional data sets: an independent set of 222 AGRE families (rs1861972–rs1861973 haplotype, ) and a separate sample of 129 National P p .0016 Institutes of Mental Health families rs1861972–rs1861973 haplotype, ). Association analysis of the P p .0431 haplotype in the combined sample of both AGRE data sets (389 families) produced a P value of .0000033, whereas combining all three data sets (518 families) produced a P value of .00000035. Population-attributable risk calculations for the associated haplotype, performed using the entire sample of 518 families, determined that the risk allele contributes to as many as 40% of ASD cases in the general population. Linkage disequilibrium (LD) mapping with the use of polymorphisms distributed throughout the gene has shown that only intronic SNPs are in strong LD with rs1861972 and rs1861973. Resequencing and association analysis of all intronic SNPs have identified alleles associated with ASD, which makes them candidates for future functional analysis. Finally, to begin defining the function of EN2 during development, mouse En2 was ectopically expressed in cortical precursors. Fewer En2- transfected cells than controls displayed a differentiated phenotype. Together, these data provide further genetic evidence that EN2 might act as an ASD susceptibility locus, and they suggest that a risk allele that perturbs the spatial/temporal expression of EN2 could significantly alter normal brain development.
Rym Benayed, et al
Gene affecting aberrant sensorimotor gating dysfunction and abnormal social interaction.
Excessive general impairment of gene expression can be expected to manifest as abnormality of behaviour and appearance, with certain relationships to high parental SES and IQ and environmental factors, and a peculiar sex distribution.
Robin Clarke
Autism is a particularly complex disorder when considered from virtually any methodological framework, including the perspective of human genetics. We first present a review of the genetic analysis principles relevant for discussing autism genetics research. From this body of work we highlight results from three candidate genes, REELIN (RELN), SEROTONIN TRANSPORTER (5HTT), and ENGRAILED 2 (EN2) and discuss the relevant neuroscience, molecular genetics, and statistical results that suggest involvement of these genes in autism susceptibility. As will be shown, the statistical results from genetic analysis, when considered alone, are in apparent conflict across research groups. We use these three candidate genes to illustrate different problems in synthesizing results from non-overlapping research groups examining the same problem. However, when basic genetic principles and results from other scientific disciplines are incorporated into a unified theoretical framework, at least some of the difficulties with interpreting results can be understood and potentially overcome as more data becomes available to the field of autism research. Integrating results from several scientific frameworks provides new hypotheses and alternative data collection strategies for future work.
C.W. Bartlett et al
TIPOgen is an in vitro diagnostic development company that will use modern and novel proteomic approaches to identify sets of molecules (biomarkers). These biomarkers will have the utility to predict autism spectrum disorders (ASDs) earlier and prognose the outcome of behavioral treatments for ASDs. TIPOgen will be the basis for one of the first dedicated research modalities in the world for ASDs. The hope is that through TIPOgen research and diagnostics better autism therapies may be forged.
After a five-year study involving a sample of 260 autistic children, the researchers concluded that 30 percent of the autistic population has complex autism. These children have a small head size or a collection of at least six abnormal physical features, as well as the common symptoms found in all children with autism. These include impaired social interaction, language difficulty and a tendency for repetitive behaviors. "We found that the children with complex autism were different genetically," Miles said. "Their recurrence risk with their siblings was less and they had a more normal male-to-female ratio. You generally read that the sex ratio is four or five males to every female."
Monica Watrous
A new Cincinnati Children's Hospital Medical Center study links regions of two chromosomes to susceptibility for a type of autism characterized by regression in development. Developmental regression can include the loss of previously acquired language, social skills or both. Moreover, the study is the first to identify involvement of chromosome 21 in this type of autism. This may explain the increased prevalence of autism spectrum disorders (ASD) among children with Down syndrome, who have an extra copy of chromosome 21 and are 10 times more likely to have an ASD than the general population.
A tiered diagnostic work-up can double the rate of diagnosis of the syndromes and conditions associated with early-childhood autism.. The reported incidence of autism has increased fourfold, to 4-5 per 1,000... Despite this dramatic increase, only about 20% of patients are now identified with a known syndrome or condition as the underlying cause of the autism. But that can be increased to 40% of patients if a tiered system of diagnosis is used, he said. His group applied the diagnostic system to all children with autism in University of Nebraska clinics over a 3-year period.
Clinical Psychiatry News
From our clinical analysis of a large autism population, we were able to delineate a subgroup of individuals with autism who were phenotypically normal based on a comprehensive physical morphology examination and brain MRI. A second group, which was clearly phenotypically abnormal on physical examination, had a higher probability of having structural brain malformations.
Judith H. Miles, Richard E. Hillman
It may be that autistic people are essentially different from "normal" people, and it is precisely those differences that make them invaluable to the ongoing evolution of the human race.
Donna Rosinski
Groundbreaking research in the controversial field of behavioral genetics suggests that the factors leading an individual to pursue any occupation, including engineering, cannot be explained as a simple tug of war between "nature" and "nurture." The researchers are finding that vocational interests are primarily the products of genetics and unique, or nonshared, environmental factors, with shared family experiences holding less sway. The research may indicate why some individuals are predisposed to careers in engineering. It might also explain the high occurrence of autism in the families of engineers.
Debra Schiff, EE Times
He explained why it has been so difficult to find specific genes that contribute to autism. He also explained how he has joined forces with some mathematicians to develop a model for finding which combinations of genes might lead to autism. He seems to think that it might take, say, 5 or 6 genes working together to create autism, and perhaps, he says there are 15 of these contributing genes all together and that everyone probably has some of these genes for autism.
Autism Diva
Among the children of engineers, autism and related conditions are found twice as often as in the general population, according to British studies, and are unusually common even in the grandchildren of engineers. Anecdotally, hot spots of autism have been reported in major centers of engineering, including Silicon Valley; Austin, Texas; and Boston's Route 128 technology ring.
Philip E. Ross, IEEE Spectrum
A genome scan was performed on 164 Dutch affected sib pairs (ASPs) with attention-deficit/hyperactivity disorder (ADHD). All subjects were white and of Dutch descent and were phenotyped according to criteria set out in the Diagnostic and Statistical Manual Of Mental Disorders, 4th edition. Initially, a narrow phenotype was defined, in which all the sib pairs met the full ADHD criteria (117 ASPs). In a broad phenotype, additional sib pairs were included, in which one child had an autistic-spectrum disorder but also met the full ADHD criteria (164 ASPs). A set of 402 polymorphic microsatellite markers with an average intermarker distance of 10 cM was genotyped and analyzed using the Mapmaker/sibs program. Regions with multipoint maximum likelihood scores (MLSs) >1.5 in both phenotypes were fine mapped with additional markers. This genome scan indicated several regions of interest, two of which showed suggestive evidence for linkage. The most promising chromosome region was located at 15q, with an MLS of 3.54 under the broad phenotype definition. This region was previously implicated in reading disability and autism. In addition, MLSs of 3.04 and 2.05 were found for chromosome regions 7p and 9q in the narrow phenotype. Except for a region on chromosome 5, no overlap was found with regions mentioned in the only other independent genome scan in ADHD reported to date.
S. C. Bakker et al
A large French family including members affected by nonspecific X-linked mental retardation, with or without autism or pervasive developmental disorder in affected male patients, has been found to have a 2ndashbase-pair deletion in the Neuroligin 4 gene (NLGN4) located at Xp22.33. This mutation leads to a premature stop codon in the middle of the sequence of the normal protein and is thought to suppress the transmembrane domain and sequences important for the dimerization of neuroligins that are required for proper cell-cell interaction through binding to beta-neurexins. As the neuroligins are mostly enriched at excitatory synapses, these results suggest that a defect in synaptogenesis may lead to deficits in cognitive development and communication processes. The fact that the deletion was present in both autistic and nonautistic mentally retarded males suggests that the NLGN4 gene is not only involved in autism, as previously described, but also in mental retardation, indicating that some types of autistic disorder and mental retardation may have common genetic origins.
Frédéric Laumonnier et al

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