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. 2016 Nov 8:7:13316.
doi: 10.1038/ncomms13316.

De novo genic mutations among a Chinese autism spectrum disorder cohort

Tianyun Wang  1 , Hui Guo  1   2 , Bo Xiong  3 , Holly A F Stessman  3 , Huidan Wu  1 , Bradley P Coe  3 , Tychele N Turner  3 , Yanling Liu  1 , Wenjing Zhao  1 , Kendra Hoekzema  3 , Laura Vives  3 , Lu Xia  1 , Meina Tang  1 , Jianjun Ou  2 , Biyuan Chen  4 , Yidong Shen  2 , Guanglei Xun  5 , Min Long  1 , Janice Lin  3 , Zev N Kronenberg  3 , Yu Peng  1 , Ting Bai  1 , Honghui Li  6 , Xiaoyan Ke  7 , Zhengmao Hu  1 , Jingping Zhao  2 , Xiaobing Zou  4 , Kun Xia  1   8   9 , Evan E Eichler  3   10
Affiliations

De novo genic mutations among a Chinese autism spectrum disorder cohort

Tianyun Wang et al. Nat Commun. .

Abstract

Recurrent de novo (DN) and likely gene-disruptive (LGD) mutations contribute significantly to autism spectrum disorders (ASDs) but have been primarily investigated in European cohorts. Here, we sequence 189 risk genes in 1,543 Chinese ASD probands (1,045 from trios). We report an 11-fold increase in the odds of DN LGD mutations compared with expectation under an exome-wide neutral model of mutation. In aggregate, ∼4% of ASD patients carry a DN mutation in one of just 29 autism risk genes. The most prevalent gene for recurrent DN mutations is SCN2A (1.1% of patients) followed by CHD8, DSCAM, MECP2, POGZ, WDFY3 and ASH1L. We identify novel DN LGD recurrences (GIGYF2, MYT1L, CUL3, DOCK8 and ZNF292) and DN mutations in previous ASD candidates (ARHGAP32, NCOR1, PHIP, STXBP1, CDKL5 and SHANK1). Phenotypic follow-up confirms potential subtypes and highlights how large global cohorts might be leveraged to prove the pathogenic significance of individually rare mutations.

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Conflict of interest statement

E.E.E. is on the scientific advisory board (SAB) of DNAnexus, Inc. and was an SAB member of Pacific Biosciences, Inc. (2009–2013) and SynapDx Corp. (2011–2013); E.E.E. is a consultant for Kunming University of Science and Technology (KUST) as part of the 1,000 China Talent Program. The other authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Birthplace distribution of ASD cases in the ACGC.
The patients involved in this study are distributed throughout China with the majority recruited from Shandong (n=389), Hunan (n=264) and Guangdong (n=202) provinces. The map was generated from a template downloaded from the public standard map service (http://219.238.166.215/mcp/index.asp) of the National Administration of Surveying, Mapping and Geoinformation of China (http://www.sbsm.gov.cn). The template is freely available for public download and use. Different colours represent different geographical regions, provinces or municipalities in China. The size of the red circles denotes the relative number of patients from each locale. Editor's Note: Nature Communications remains neutral with regard to jurisdictional claims in published maps.
Figure 2
Figure 2. Protein diagram of SCN2A and CHD8 including gene mutation locations.
(a) SCN2A mutations above the diagram were identified in ACGC samples, including seven DN LGD mutations and five DN missense mutations (DN frequency=1.1%). Mutations below the protein diagram were identified in the SSC and ASC samples, including four DN LGD mutations and eight DN missense mutations (DN frequency=0.3%). (b) CHD8 mutations above the diagram were identified in ACGC samples, including three DN LGD mutations and one DN missense mutation. Mutations below the protein diagram were identified in previous large cohort ASD studies, including 13 DN LGD mutations and 10 DN missense mutations.
Figure 3
Figure 3. CNV and single-nucleotide variant DN mutations identify likely autism risk genes.
DN mutation patterns from SSC, AGP and ACGC samples for genes (a) TRIP12, (b) DOCK8, (c) ARHGAP32 and (d) NCOR1 identify the most likely candidate genes from larger pathogenic CNV interval. Gene numbers denote the number of RefGene entries in each corresponding CNV interval. CNV deletions (red horizontal bars) and duplications (blue bars) are shown with respect to DN LGD (red circles) and DN missense (blue circles) mutations.
See this image and copyright information in PMC

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