Highlights d 102 genes implicated in risk for autism spectrum disorder (ASD genes, FDR % 0.1) d Most are expressed and enriched early in excitatory and inhibitory neuronal lineages d Most affect synapses or regulate other genes; how these roles dovetail is unknown d Some ASD genes alter early development broadly, others appear more specific to ASD

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SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

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Objective-To conduct an open-label, multinational, multicenter study examining the safety and efficacy of recombinant human acid α-glucosidase (rhGAA) in treatment of infantile-onset Pompe disease.Study design-We enrolled 8 infant patients who had Pompe disease with GAA activity <1% of normal, cardiomyopathy, and hypotonia. In the 52-week initial phase, rhGAA was infused intravenously at 10 mg/kg weekly; an extension phase continued survivors' treatment with 10 to 20 mg/kg of rhGAA weekly or 20 mg/kg every 2 weeks for as long as 153 weeks. Safety measurements included adverse events, laboratory tests, and anti-rhGAA antibody titers. Efficacy evaluations included survival, ventilator use, echo-cardiograms, growth, and motor and cognitive function.Result-After 52 weeks of treatment, 6 of 8 patients were alive, and 5 patients were free of invasive ventilator support. Clinical improvements included ameliorated cardiomyopathy and improved growth and cognition. Five patients acquired new motor milestones; 3 patients walked independently. Four patients died after the initial study phase; the median age at death or treatment withdrawal for all patients was 21.7 months, significantly later than expected for patients who were not treated. Treatment was safe and well tolerated; no death was drug-related. Patients with infantile-onset Pompe disease typically present before 12 months of age with progressive, hypertrophic cardiomyopathy that may obstruct left ventricular outflow; profound muscle weakness and hypotonia; non-attainment or loss of motor milestones; difficulty feeding; and failure to thrive. These patients have a dramatically shortened life span. In patients who are not treated, the median age of death ranges from 6.0 to 8.7 months. 4,7 In the most rapidly progressive form, also termed "classic" infantile Pompe disease, the mortality rate is as high as 92% to 95% in the first year of life. 7 In an historical cohort of patients manifesting Pompe disease in the first year of life, irrespective of phenotype, 74% died by 1 year of age, 91% by 2 years of age, and 93% by 3 years of age. 7 Death generally results from cardiac and respiratory failure. 1,3,7No approved specific treatment for Pompe disease currently exists. However, recombinant human GAA (rhGAA) has shown physiological activity both in animal disease models and in early clinical trials. 8-15 In 3 pilot studies in severely affected infants, rhGAA (purified from transgenic rabbit milk 11-14 or from Chinese hamster ovary [CHO] cell cultures 8 ) markedly ameliorated cardiomyopathy and prolonged all patients' survival beyond 1 year. One of 6 patients given rhGAA from rabbit milk (a preparation that is no longer available) and 1 of 3 patients given CHO cell-derived rhGAA walked independently and remained ventilator-free. The remaining 7 patients from these 3 studies showed lesser degrees of motor improvement and eventually required ventilation. As of January 2006, 3 of the 9 patients in these pilot studies had died and 6 remained alive (unpublished data)...

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating (PTV), missense, and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 ASD risk genes at false discovery rate (FDR)≤0.001 (185 at FDR≤0.05). De novo PTVs, damaging missense variants, and CNVs represented 57.5%, 21.1%, and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD, N=91,605) yielded 373 ASD/DD risk genes at FDR≤0.001 (664 at FDR≤0.05), some of which differed in relative frequency of mutation between ASD and DD. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells whereas genes displaying stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophreniaassociated genes, emphasizing that these neuropsychiatric disorders share common pathways to risk.

Purpose:To define the prevalence of PTEN mutations in a clinical cohort of pediatric subjects with autism spectrum disorders (ASDs), developmental delay/mental retardation (DD/MR), and/or macrocephaly and to assess genotype-phenotype correlations. Methods: Medical records of patients who had clinical PTEN gene sequencing ordered through our institution between January 1, 2005 and December 31, 2007 were abstracted to confirm genetic test results and medical diagnoses. Phenotypic information related to the diagnoses, prenatal history, early developmental milestones, physical characteristics, and family history for those with a confirmed PTEN mutation was also recorded. Results:One hundred fourteen patients were tested during this time period for indications of ASDs (N ϭ 60), DD/MR (N ϭ 49), or macrocephaly only (N ϭ 5). Eleven mutations were identified: five in patients with ASDs and six in those with DD/MR, resulting in a prevalence of 8.3% and 12.2% in these respective clinical populations. All individuals with a PTEN mutation had significant macrocephaly (Ͼ2.0 SD) Conclusions: These data illustrate that PTEN gene sequencing has a high diagnostic yield when performed in a selected population of individuals with ASDs or DD/MR and macrocephaly. Germline mutations in PTEN are an important, identifiable etiology among these patients. Genet Med 2009: 11(2):111-117.