SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—warrant its consideration for mutation screening in clinical practice.

SummaryAlthough autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success 1. Genome-wide association studies (GWAS) using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits (http://www.genome.gov/26525384). Consequently, we initiated a linkage and association mapping study using half a million genome-wide SNPs in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed a SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10−7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening while the discovery of a single novel association demonstrates the action of common variants.

Genome Biology 2011, 12(Suppl 1):I18 Deep exome resequencing is a powerful approach for delineating patterns of protein-coding variation among genes, pathways, individuals and populations. We analyzed exome data from 2,440 individuals of European and African ancestry as part of the National Heart, Lung, and Blood Institute's Exome Project, the aim of which is to discover novel genes and mechanisms that contribute to heart, lung and blood disorders. Each exome was sequenced to a mean coverage of 116×, allowing detailed inferences about the population genomic patterns of both common variation and rare coding variation. We identifi ed more than 500,000 single nucleotide variations, the majority of which were novel and rare (76% of variants had a minor allele frequency of less than 0.1%), refl ecting the recent dramatic increase in the size of the human population. The unprecedented magnitude of this dataset allowed us to rigorously characterize the large variation in nucleotide diversity among genes (ranging from 0 to 1.32%), as well as the role of positive and purifying selection in shaping patterns of protein-coding variation and the diff erential signatures of population structure from rare and common variation. This dataset provides a framework for personal genomics and is an important resource that will allow inferences of broad importance to human evolution and health. I2 Abstract not submitted for online publication. I3 Are clinical genomes already becoming semi-routine for patient care?

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Schizophrenia likely results from poorly understood genetic and environmental factors. We studied the gene encoding the synaptic protein SHANK3 in 285 controls and 185 schizophrenia patients with unaffected parents. Two de novo mutations (R1117X and R536W) were identified in two families, one being found in three affected brothers, suggesting germline mosaicism. Zebrafish and rat hippocampal neuron assays revealed behavior and differentiation defects resulting from the R1117X mutant. As mutations in SHANK3 were previously reported in autism, the occurrence of SHANK3 mutations in subjects with a schizophrenia phenotype suggests a molecular genetic link between these two neurodevelopmental disorders. S chizophrenia (SCZ) is a chronic psychiatric disorder characterized by a profound disruption in cognition, behavior, and emotion which begins in adolescence or early adulthood. There is significant clinical variability among SCZ patients, suggesting that it is etiologically heterogeneous. There are several hypotheses to explain genetic factors underlying SCZ, such as polygenic inheritance (1) or, in a fraction of cases, variably penetrant de novo mutations. The de novo hypothesis is based on several observations. One is that relatives of an individual with SCZ have a higher risk of being affected (parents 6%, offspring 13%, and siblings 9% compared with 1% for the general population) (2). The greater frequency in offspring than in parents may occur if new mutations account for a fraction of SCZ cases. Also, there is a significantly increased risk of SCZ with increasing paternal age (3), which could result from the age-related increase in paternal de novo mutations. Furthermore, despite reduced reproductive fitness (4) and extremely variable environmental factors, the incidence of SCZ is maintained at ∼1% worldwide. Interestingly, recent studies reported de novo copy-number variants in SCZ, providing further support for the de novo mutation hypothesis (5, 6).As part of the Synapse to Disease (S2D) project aimed at exploring the de novo mutation hypothesis in brain diseases, we are sequencing synaptic genes in individuals with SCZ and autism spectrum disorder (ASD), two neurodevelopmental disorders. Recently, mutations in the SHANK3 (SH3 and multiple ankyrin repeat domains 3) gene, encoding a scaffolding protein abundant in the postsynaptic density of excitatory synapses on dendritic spines, were found in patients with ASD (7-9). Considering that ASD and SCZ share some features, we decided to screen the SHANK3 gene in our cohort of SCZ probands. Given our hypothesis that a significant fraction of SCZ cases are the result of new mutations, we selected SCZ cases with unaffected parents and screened for de novo mutations.