News Finding: Individuals with ASD carried more of these CNVs than individuals in the control group, and some of them were inherited while others were only present in offspring with ASD.
Paper Finding: Our data (1) confirm excess burden of genome-wide rare genic CNVs in an independent set of ASD subjects versus control subjects; (2) further reveal an extreme degree of etiological heterogeneity (36 different genetic loci were found among 82 individuals with pathogenic CNVs); (3) confirm the contribution of de novo CNVs to the etiology of autism and highlight the contribution of inherited pathogenic imbalances (36%); (4) show an increased proportion of females among carriers of highly penetrant pathogenic CNVs, as well as among carriers of deletions affecting FMRP targets; show no significant difference in the frequency of de novo CNVs between simplex and multiplex families; show that both deletions and duplications involving FMRP targets and PSD genes increase ASD risk; (7) show evidence of multigene contributions to ASD; show that ASD-associated deletions impair synapse function and neurodevelopmental processes; (9) implicate chromatin and transcription regulation genes in ASD in a network analysis of de novo CNVs; and show that genes affected by de novo CNVs and de novo LoF SNVs converge on functional gene networks.
News Context: The researchers reported numerous CNVs affecting genes, and found that these genes are part of similar cellular pathways involved in brain development, synapse function and chromatin regulation. Individuals with ASD carried more of these CNVs than individuals in the control group, and some of them were inherited while others were only present in offspring with ASD. By further aggregating CNVs and SNVs (the latter identified in other studies), Mount Sinai researchers discovered many additional genes and pathways involved in ASD.
Paper Context: Thus, despite little overlap in genes, the strong interconnectedness between the resulting networks identifies pathways through which the effects of distinct mutations might converge. Our data (1) confirm excess burden of genome-wide rare genic CNVs in an independent set of ASD subjects versus control subjects; (2) further reveal an extreme degree of etiological heterogeneity (36 different genetic loci were found among 82 individuals with pathogenic CNVs); (3) confirm the contribution of de novo CNVs to the etiology of autism and highlight the contribution of inherited pathogenic imbalances (36%); (4) show an increased proportion of females among carriers of highly penetrant pathogenic CNVs, as well as among carriers of deletions affecting FMRP targets; show no significant difference in the frequency of de novo CNVs between simplex and multiplex families; show that both deletions and duplications involving FMRP targets and PSD genes increase ASD risk; (7) show evidence of multigene contributions to ASD; show that ASD-associated deletions impair synapse function and neurodevelopmental processes; (9) implicate chromatin and transcription regulation genes in ASD in a network analysis of de novo CNVs; and show that genes affected by de novo CNVs and de novo LoF SNVs converge on functional gene networks. Importantly, when considering highly penetrant pathogenic CNVs, we found a 2:1 male-to-female ratio (deviating from the overall ratio of 6:1 in the study sample).