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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

We find modest associations of several polymorphisms with the efficiency of executive attention but not with overall performance measures such as reaction time.

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.

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.

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.

"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.

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.

"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."

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…

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.

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.

This study once again stress the need for a thorough medical evaluation of all children and adults with an autistic or autistic-like disorder.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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'.

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.

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.

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.

The report adds to the literature supporting the argument that individuals with autistic spectrum disorders should be re-examined for chromosomal abnormalities.

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?

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.

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.

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.

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.

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.

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.

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

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.

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.

(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.

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.

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.

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.

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.

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.

"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.

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.

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.

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.

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.

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.

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.

Extracts from EJAIB and EEIN since January 1994.

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.

The restricted sample comprises a population that is more genetically homogeneous, which could therefore increase the likelihood of positional cloning of susceptibility loci.

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..

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.

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.

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.

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...

Our results indicate that using samples selected for components of the autism phenotype may be a useful adjunct to autism genetics.

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.

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.

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.

American Journal of Orthopsychiatry, Volume XXVII, pp. 715-724 (1957)

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.

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.

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.

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.

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.

I suggest that words are simply less lateralised in those genetically predisposed to suffer from schizophrenic symptoms.

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.

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.

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.