| Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains | Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,600 NDD patients identified 21 new patients with identical missense mutations. One recurrent site (p.Ala636Thr) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology. | 1/18812 | Primary Analysis | Shared |
| Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci | Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1). | 4111/9975 | Secondary Analysis | Shared |
| Recurrent de novo mutations implicate novel genes underlying simplex autism risk. | Autism spectrum disorder (ASD) has a strong but complex genetic component. Here we report on the resequencing of 64 candidate neurodevelopmental disorder risk genes in 5,979 individuals: 3,486 probands and 2,493 unaffected siblings. We find a strong burden of de novo point mutations for these genes and specifically implicate nine genes. These include CHD2 and SYNGAP1, genes previously reported in related disorders, and novel genes TRIP12 and PAX5. We also show that mutation carriers generally have lower IQs and enrichment for seizures. These data begin to distinguish genetically distinct subtypes of autism important for aetiological classification and future therapeutics. | 1888/6400 | Primary Analysis | Shared |
| The evolution and population diversity of human-specific segmental duplications | Segmental duplications contribute to human evolution, adaptation and genomic instability but are often poorly characterized. We investigate the evolution, genetic variation and coding potential of human-specific segmental duplications (HSDs). We identify 218 HSDs based on analysis of 322 deeply sequenced archaic and contemporary hominid genomes. We sequence 550 human and nonhuman primate genomic clones to reconstruct the evolution of the largest, most complex regions with protein-coding potential (n=80 genes/33 gene families). We show that HSDs are non-randomly organized, associate preferentially with ancestral ape duplications termed “core duplicons”, and evolved primarily in an interspersed inverted orientation. In addition to Homo sapiens-specific gene expansions (e.g., TCAF1/2), we highlight ten gene families (e.g., ARHGAP11B and SRGAP2C) where copy number never returns to the ancestral state, there is evidence of mRNA splicing, and no common gene-disruptive mutations are observed in the general population. Such duplicates are candidates for the evolution of human-specific adaptive traits. | 743/6360 | Primary Analysis | Shared |
| Mitochondrial DNA mutations in Autism Spectrum Disorder | Mitochondrial dysfunction is frequently observed in Autism Spectrum Disorders (ASD). Thus, variations in the mitochondrial DNA (mtDNA) sequences may contribute to increased ASD risks. In the current study, we evaluated mtDNA variations, including homoplasmy and heteroplasmy, in 903 ASD individuals along with their mothers and non-ASD siblings by using off-target reads from whole-exome sequencing data sets of Simons Foundation Autism Research Initiative (SFARI) Simons Collection available on NDAR. We found that heteroplasmic mutations in ASD individuals were enriched at non-polymorphic mtDNA sites (P = 0.0015) compared to their non-ASD siblings, which were more likely to confer deleterious effects than heteroplasmies at polymorphic mtDNA sites. Accordingly, we observed a ~1.5-fold enrichment of nonsynonymous mutations as well as a ~2.2-fold enrichment of predicted pathogenic mutations (P < 0.003) in ASD individuals compared to their non-ASD siblings. Our genetic findings substantiate pathogenic mtDNA mutations as a potential cause for ASD and synergize with recent work calling attention to their unique metabolic phenotypes for diagnosis and treatment of ASD. | 2709/2709 | Secondary Analysis | Shared |
| Transmission disequilibrium of small CNVs in simplex autism. | Cohorts:
411 ASD Quads from Simons Simplex Collection
177 Quads from Sanders et al. (PubMed ID: 22495306)
166 Quads from I. Iossifov et al. (PubMed ID: 22542183)
71 Quads from O'Roak et al. (PubMed ID: 22495309)
Publication Abstract:
We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ¿2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD. | 462/1644 | Secondary Analysis | Shared |
| Brain-based sex differences in autism spectrum disorder across the lifespan: A systematic review of structural MRI, fMRI, and DTI findings | Females with autism spectrum disorder (ASD) have been long overlooked in neuroscience research, but emerging evidence suggests they show distinct phenotypic trajectories and age-related brain differences. Sex-related biological factors (e.g., hormones, genes) may play a role in ASD etiology and have been shown to influence neurodevelopmental trajectories. Thus, a lifespan approach is warranted to understand brain-based sex differences in ASD. This systematic review on MRI-based sex differences in ASD was conducted to elucidate variations across the lifespan and inform biomarker discovery of ASD in females. We identified articles through two database searches. Fifty studies met criteria and underwent integrative review. We found that regions expressing replicable sex-by-diagnosis differences across studies overlapped with regions showing sex differences in neurotypical (NT) cohorts, in particular regions showing NT male>female volumes. Furthermore, studies investigating age-related brain differences across a broad age-span suggest distinct neurodevelopmental patterns in females with ASD. Qualitative comparison across youth and adult studies also supported this hypothesis. However, many studies collapsed across age, which may mask differences. Furthermore, accumulating evidence supports the female protective effect in ASD, although only one study examined brain circuits implicated in “protection.” When synthesized with the broader literature, brain-based sex differences in ASD may come from various sources, including genetic and endocrine processes involved in brain “masculinization” and “feminization” across early development, puberty, and other lifespan windows of hormonal transition. Furthermore, sex-related biology may interact with peripheral processes, in particular the stress axis and brain arousal system, to produce distinct neurodevelopmental patterns in males and females with ASD. Future research on neuroimaging-based sex differences in ASD would benefit from a lifespan approach in well-controlled and multivariate studies. Possible relationships between behavior, sex hormones, and brain development in ASD remain largely unexamined. | 3/759 | Secondary Analysis | Shared |
| Identification of differentially methylated regions (DMRs) and cytosine sites (DMCs) in DNA methylation data of autism cases and unaffected siblings | We compared blood-based DNA methylation profiles between children with autism spectrum disorder (ASD) and carefully matched, unrelated neurotypical control children. Using sequencing-based method, we identified ASD-specific differentially methylated regions (DMRs) and cytosine sites (DMCs). We carried out comparative analyses with datasets from the NDA Collection 1650 (SFARI - DNA Methylation Analysis Cohort) that measured blood DNA methylation in ASD using microarray technology. We also identified DMRs and DMCs using metilene and minfi pipelines in the DNAm datasets from the NDA Collection 1650. | 292/728 | Secondary Analysis | Shared |
| Phenotypic subtyping and re-analysis of existing methylation data from autistic probands in simplex families reveal ASD subtype-associated differentially methylated genes and biological functions | Autism spectrum disorder (ASD) describes a group of neurodevelopmental disorders with core deficits in social communication and manifestation of restricted, repetitive, and stereotyped behaviors. Despite the core symptomatology, ASD is extremely heterogeneous with respect to the severity of symptoms and behaviors. This heterogeneity presents an inherent challenge to all large-scale genome-wide 'omics analyses. In the present study, we address this heterogeneity by stratifying ASD probands from simplex families according to severity of behavioral scores on the Autism Diagnostic Interview-Revised diagnostic instrument, followed by re-analysis of existing DNA methylation data from individuals in three ASD subphenotypes in comparison to that of their respective unaffected siblings. We demonstrate that subphenotyping of cases enables the identification of over 1.6 times the number of statistically significant differentially methylated genes (DMGs) between cases and controls, compared to that identified when all cases are combined. Our analyses also reveal ASD-related neurological functions and comorbidities that are enriched among DMGs in each phenotypic subgroup but not in the combined case group. These findings may aid in the development of subtype-directed diagnostics and therapeutics. | 70/584 | Secondary Analysis | Shared |
