机构：[1]Center for Medical Genetics, School of Life Sciences, Central SouthUniversity, Changsha, Hunan, China[2]Department of Genome Sciences,University of Washington School of Medicine, Seattle, WA, USA[3]MentalHealth Institute of the Second Xiangya Hospital, Central South University,Changsha, Hunan, China[4]Key Laboratory of Developmental Disorders inChildren, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, Guangxi,China[5]Mental Health Center of Shandong Province, Jinan, Shandong, China[6]Children Development Behavior Center of the Third Affiliated Hospital ofSun Yat-Sen University, Guangzhou, Guangdong, China中山大学附属第三医院[7]Center of ChildrenPsychology and Behavior, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China[8]Xi’an Encephalopathy Hospital ofTraditional Chinese Medicine, Xi’an, Shaanxi, China[9]Child Mental HealthResearch Center, Nanjing Brain Hospital Affiliated of Nanjing MedicalUniversity, Nanjing, Jiangsu, China[10]Department of Pediatrics, the XiangyaHospital, Central South University, Changsha, China[11]Department ofPsychiatry, University of Washington, Seattle, WA, USA[12]Howard HughesMedical Institute, University of Washington, Seattle, WA, USA[13]KeyLaboratory of Medical Information Research, Central South University,Changsha, Hunan, China[14]Collaborative Innovation Center for Genetics andDevelopment, 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.
基金：
the following grants: the National Natural
Science Foundation of China (NSFC) (81330027, 81525007) and the National
Basic Research Program of China (2012CB517900) to KX; the NSFC (31671114,
31400919) to HG; the NSFC (81601197) to JO; the NSFC (81460500) to YZ; the
Simons Foundation Autism Research Initiative (SFARI 303241) and National
Institutes of Health (NIH R01MH101221) to EEE and NIH (R01MH100047) to
RAB. EEE is an investigator of the Howard Hughes Medical Institute.
第一作者机构：[1]Center for Medical Genetics, School of Life Sciences, Central SouthUniversity, Changsha, Hunan, China[2]Department of Genome Sciences,University of Washington School of Medicine, Seattle, WA, USA[3]MentalHealth Institute of the Second Xiangya Hospital, Central South University,Changsha, Hunan, China
共同第一作者：
通讯作者：
通讯机构：[1]Center for Medical Genetics, School of Life Sciences, Central SouthUniversity, Changsha, Hunan, China[2]Department of Genome Sciences,University of Washington School of Medicine, Seattle, WA, USA[3]MentalHealth Institute of the Second Xiangya Hospital, Central South University,Changsha, Hunan, China[12]Howard HughesMedical Institute, University of Washington, Seattle, WA, USA[13]KeyLaboratory of Medical Information Research, Central South University,Changsha, Hunan, China[14]Collaborative Innovation Center for Genetics andDevelopment, Shanghai, China
推荐引用方式(GB/T 7714)：
Hui Guo,Tianyun Wang,Huidan Wu,et al.Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.[J].MOLECULAR AUTISM.2018,9:doi:10.1186/s13229-018-0247-z.
APA：
Hui Guo,Tianyun Wang,Huidan Wu,Min Long,Bradley P. Coe...&Kun Xia.(2018).Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model..MOLECULAR AUTISM,9,
MLA：
Hui Guo,et al."Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.".MOLECULAR AUTISM 9.(2018)
医学