Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model

Abstract

BackgroundWe previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype–phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent.MethodsWe sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes.ResultsWe validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (ZNF292), one novel gene with recurrent LGD DNMs (RALGAPB), as well as genes associated with macrocephaly (GIGYF2 and WDFY3). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes.ConclusionsWe identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk.Electronic supplementary materialThe online version of this article (10.1186/s13229-018-0247-z) contains supplementary material, which is available to authorized users.

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

“…Diverse rare CNV, such as 15q11.2 and 16p12.1 deletions, have been implicated in multiple neurodevelopmental disorders, and a multi-hit model has been suggested (Abdelmoity et al, 2012;Girirajan et al, 2010). Furthermore, a multifactorial model has been proposed to explain the heritability of ASD, where rare de novo and inherited variations act within the context of a common-variant genetic load (Chaste, Roeder, & Devlin, 2017;Guo et al, 2018). This might also explain the variable clinical outcomes Furthermore, different mutations in the same gene can have different effects on the gene product, and therefore different pathological consequences (Barabási et al, 2011).…”

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

“…Loss of function of ITPR1 has been found by multiple groups to be a rare single gene cause of autism 106,[153][154][155][156] . This prompted Gargus and colleagues to look at functional deficits in IP3-mediated calcium signaling in primary skin fibroblasts from Fragile X patients as they represent a common syndromic cause of autism 157 .…”

“…and Top3b have been linked to autism 106,156,207,[227][228][229][230] . Top3b has topoisomerase activity on both DNA and RNA 207,228 and is the major RNA topoisomerase for mRNAs 231 .…”

Noncoding de novo mutations contribute to autism spectrum disorder via chromatin interactions

“…The trend was not found for sibling NCD genes or for proband nearest genes to noncoding DNMs. Taken together, these results supported that multi-hits from diverse mutation sources including noncoding regions give rise to ASD with intellectual disability, and the NCD genes dysregulated by noncoding variants via chromatin interactions contribute to the oligogenic nature of the disorder 47 .…”