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

Abstract

Background: We 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.

Methods: We 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.

Results: We 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.

Conclusions: We 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.

Keywords: Autism spectrum disorders; De novo mutations; Genotype–phenotype relationship; Multifactorial model; Multiple hit; Targeted sequencing.

Fig. 1

Distribution of DNMs in two potential novel autism risk genes (ZNF292, RALGAPB) and CTTNBP2. Dagger symbol indicates the DNMs reported in this study. ZNF292: p.R89* was reported in an ASC patient, p.L943Qfs*5 was reported in an ID patient, p. N1741Lfs*25 was reported in DDD study. RALGAPB: p.M289Vfs*3 was reported in an ASC patient, p.S1287* was reported in an EPI4K patient. CTTNBP2: p.V706Efs*14 was reported in an SSC patient

Fig. 2

Multiple-hit model for ASD. a Ten families and corresponding double-hit DNMs in the ACGC, SSC and ASC cohorts are shown. Dagger symbol indicates the genes listed as autism risk genes in SFARI; number sign indicates the variants presented in ExAC database. b The logistic histogram plot shows that both males and females have a higher probability of being affected with an increase in the number of DNMs even after correcting for paternal age effect. Females show a higher odds ratio (OR) than males for this additional DNM effect. c The plot shows the distribution of OR and the corresponding 95% CI of regression models, which predict affected status and different phenotype severity by DNM numbers

Fig. 3

Inheritance of high-risk ASD genes. a The number of inherited and DNMs by autism risk gene within the ACGC. b Families with inherited LGD mutations or gene-disrupting CNVs in ASD high-risk genes, including CHD8 (5), KMT5B (2), DSCAM (2), FOXP1 (2), SCN2A (1), ADNP (1), and WDFY3 (1). c Genomic location of inherited CNV-disrupting CHD8 within an ASD family from the ACGC cohort. LGD, likely gene-disrupting