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

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Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model
Molecular Autism ( IF 6.2 ) Pub Date : 2018-12-13 , DOI: 10.1186/s13229-018-0247-z
Hui Guo _{1,

2,

3} , Tianyun Wang _{1,

2} , Huidan Wu ₁ , Min Long ₁ , Bradley P Coe ₂ , Honghui Li ₄ , Guanglei Xun ₅ , Jianjun Ou ₃ , Biyuan Chen ₆ , Guiqin Duan ₇ , Ting Bai ₁ , Ningxia Zhao ₈ , Yidong Shen ₃ , Yun Li ₉ , Yazhe Wang ₇ , Yu Zhang ₄ , Carl Baker ₂ , Yanling Liu ₁ , Nan Pang ₁₀ , Lian Huang ₁ , Lin Han ₁ , Xiangbin Jia ₁ , Cenying Liu ₁ , Hailun Ni ₁ , Xinyi Yang ₁ , Lu Xia ₁ , Jingjing Chen ₁ , Lu Shen ₁ , Ying Li ₁ , Rongjuan Zhao ₁ , Wenjing Zhao ₁ , Jing Peng ₁₀ , Qian Pan ₁ , Zhigao Long ₁ , Wei Su ₁ , Jieqiong Tan ₁ , Xiaogang Du ₈ , Xiaoyan Ke ₉ , Meiling Yao ₇ , Zhengmao Hu ₁ , Xiaobing Zou ₆ , Jingping Zhao ₃ , Raphael A Bernier ₁₁ , Evan E Eichler _{2,

12} , Kun Xia _{1,

13,

14}

Affiliation

1Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China.
2Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA USA.
3Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, Hunan China.
4Key Laboratory of Developmental Disorders in Children, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, Guangxi China.
Mental Health Center of Shandong Province, Jinan, Shandong China.
6Children Development Behavior Center of the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong China.
7Center of Children Psychology and Behavior, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan China.
Xi'an Encephalopathy Hospital of Traditional Chinese Medicine, Xi'an, Shaanxi China.
9Child Mental Health Research Center, Nanjing Brain Hospital Affiliated of Nanjing Medical University, Nanjing, Jiangsu China.
10Department of Pediatrics, the Xiangya Hospital, Central South University, Changsha, China.
11Department of Psychiatry, University of Washington, Seattle, WA USA.
12Howard Hughes Medical Institute, University of Washington, Seattle, WA USA.
13Key Laboratory of Medical Information Research, Central South University, Changsha, Hunan China.
Collaborative Innovation Center for Genetics and Development, Shanghai, China.

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. 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. 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. 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.

更新日期：2018-12-13

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