Autism spectrum disorder (ASD) is a heterogeneous disease where efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in post-mitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.

Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large and the underlying causative gene is unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay versus 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed ten genes enriched for putative loss of function. Patient follow-up on a subset identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. This includes haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in patients with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and neuropsychiatric disease genes despite extensive genetic heterogeneity.

BACKGROUND-Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients.

We report the identification of a recurrent 520-kbp 16p12.1 microdeletion significantly associated with childhood developmental delay. The microdeletion was detected in 20/11,873 cases vs. 2/8,540 controls (p=0.0009, OR=7.2) and replicated in a second series of 22/9,254 cases vs. 6/6,299 controls (p=0.028, OR=2.5). Most deletions were inherited with carrier parents likely to manifest neuropsychiatric phenotypes (p=0.037, OR=6). Probands were more likely to carry an additional large CNV when compared to matched controls (10/42 cases, p=5.7×10-5, OR=6.65). Clinical features of cases with two mutations were distinct from and/or more severe than clinical features of patients carrying only the co-occurring mutation. Our data suggest a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity suggests that this two-hit model may be more generally applicable to neuropsychiatric disease.

We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 × 10 −8 ). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.Idiopathic generalized epilepsies (IGE) are common seizure disorders accounting for up to one-third of all epilepsies 1 . The vast majority of individuals with IGE have a complex genetic etiology2, for which the underlying genetic alterations remain largely unknown. Recently, a 15q13.3 microdeletion syndrome has been identified in 0.2-0.3% of individuals Correspondence should be addressed to T.S. (sandert@uni-koeln.de). Note: Supplementary information is available on the Nature Genetics website. AUTHOR CONTRIBUTIONST.S. and E.E.E. initiated and designed the study; I.H., H.M., S.v.S., I.S., A.A.K.-L., V.G., B.S., K.M.K., P.S.R., F.R., Y.W., H.L., F.Z., L.U., K.F., M. Feucht, F.V., G.-J.d.H., R.S.M., H.H., D. Luciano, C.R., D. Lindhout, C.E.E., U.S. and T.S. recruited and phenotyped the EPICURE sample; H.C.M., A.J.S., M.G., M. Fichera, C.B., P.G., P.T., A.M. and E.E.E. recruited and phenotyped the mixed IGE sample; A.F., M.W., M.N. and S.S. recruited and phenotyped the PopGen control sample; I.H., A.F., C.L., K.L.K., I.S., M.W., M.N., P.N. and T.S. performed the CNV analysis on SNP arrays; H.C.M., A.J.S., M. Fichera, C.B. and D. Luciano performed the qPCR screening; H.C.M., M. Fichera, C.B. and D. Luciano performed the screening using Illumina Genotyping BeadChips; H.C.M., A.J.S. and C.B. performed the confirmation using NimbleGen arrays; C.d.K., B.P.C.K. and D. Lindhout performed the confirmation using Illumina CNV BeadChips; I.H., H.C.M., A.J.S., M.G., M. Fichera, A.F., C.d.K., K.L.K., C.R., B.P.C.K., D. Lindhout, E.E.E. and T.S. coordinated the work and prepared the manuscript. Susceptibility loci for common idiopathic epilepsies, comprising benign epilepsy of childhood with centrotemporal spikes7 and common IGE syndromes8 ,9 , have also been mapped to the 15q13-q14 region. To test whether the 15q13.3 deletion increases risk of common epilepsies, we screened for structural variants within the 15q13.3 region in two independent samples of individuals with IGE and ancestrally matched controls. The first sample comprised 647 unrelated IGE cases of Western European ancestry (EPICURE sample) and 1,202 German controls (PopGen) genotyped using the Affymetrix GenomeWide Human SNP array 6.0. We identified the 15q13.3 microdeletion in 7 of 647 IGE cases ( Supplementary Fig. 1 online) with different IGE syndromes ( Supplementary Fig. 2 online). Thus, our results suggest that the 15q13.3 deletion only, and not the reciprocal duplication, represents a major risk factor for IGE. NIH Public AccessIn our stu...

We report a recurrent microdeletion syndrome causing mental retardation, epilepsy and variable facial and digital dysmorphisms. We describe nine affected individuals, including six probands: two with de novo deletions, two who inherited the deletion from an affected parent and two with unknown inheritance. The proximal breakpoint of the largest deletion is contiguous with breakpoint 3 (BP3) of the Prader-Willi and Angelman syndrome region, extending 3.95 Mb distally to BP5. A smaller 1.5-Mb deletion has a proximal breakpoint within the larger deletion (BP4) and shares the same distal BP5. This recurrent 1.5-Mb deletion contains six genes, including a candidate gene for epilepsy (CHRNA7) that is probably responsible for the observed seizure phenotype. The BP4-BP5 region undergoes frequent inversion, suggesting a possible link between this inversion polymorphism and recurrent deletion. The frequency of these microdeletions in mental retardation cases is approximately 0.3% (6/2,082 tested), a prevalence comparable to that of Williams, Angelman and Prader-Willi syndromes.

Submicroscopic genomic copy number changes have been identified only recently as an important cause of mental retardation. We describe the detection of three interstitial, overlapping 17q21.31 microdeletions in a cohort of 1,200 mentally retarded individuals associated with a clearly recognizable clinical phenotype of mental retardation, hypotonia and a characteristic face. The deletions encompass the MAPT and CRHR1 genes and are associated with a common inversion polymorphism.

Despite a high heritability, a genetic diagnosis can only be established in a minority of patients with autism spectrum disorder (ASD), characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests or activities1. Known genetic causes include chromosomal aberrations, such as the duplication of the 15q11-13 region, and monogenic causes, such as the Rett and Fragile X syndromes. The genetic heterogeneity within ASD is striking, with even the most frequent causes responsible for only 1% of cases at the most. Even with the recent developments in next generation sequencing, for the large majority of cases no molecular diagnosis can be established 2-7. Here, we report 10 patients with ASD and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/SNF remodeling complex. We estimate this gene to be mutated in at least 0.17% of ASD cases, making it one of the most frequent ASD genes known to date.