De novo genic mutations among a Chinese autism spectrum disorder cohort.
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.
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Tianyun
T
Wang
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.|Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Hui
H
Guo
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Bo
B
Xiong
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Holly A F
HA
Stessman
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Huidan
H
Wu
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Bradley P
BP
Coe
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Tychele N
0000-0001-8246-6477
TN
Turner
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Yanling
Y
Liu
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Wenjing
W
Zhao
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Kendra
K
Hoekzema
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Laura
L
Vives
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Lu
L
Xia
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Meina
M
Tang
Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Jianjun
J
Ou
Children's Development Behavior Center, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
Biyuan
B
Chen
Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Yidong
Y
Shen
Mental Health Center of Shandong Province, Jinan, Shandong 250014, China.
Guanglei
G
Xun
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Min
M
Long
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Janice
J
Lin
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Zev N
ZN
Kronenberg
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Yu
Y
Peng
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Ting
T
Bai
Child Healthcare Department, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, Guangxi 545000, China.
Honghui
H
Li
Child Mental Health Research Center, Nanjing Brain Hospital Affiliated of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Xiaoyan
X
Ke
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Zhengmao
Z
Hu
Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Jingping
J
Zhao
Children's Development Behavior Center, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
Xiaobing
X
Zou
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.|Collaborative Innovation Center for Genetics and Development, Shanghai 200433, China.|Key Laboratory of Medical Information Research, Central South University, Changsha, Hunan 410013, China.
Kun
K
Xia
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.|Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
Evan E
EE
Eichler
D044466:Asian People / Q000235:genetics; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005843:Geography; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors