title: CNV analysis in Chinese children of mental retardation highlights a sex differentiation in parental contribution to de novo and inherited mutational burdens.
abstract: Rare copy number variations (CNVs) are a known genetic etiology in neurodevelopmental disorders (NDD). Comprehensive CNV analysis was performed in 287 Chinese children with mental retardation and/or development delay (MR/DD) and their unaffected parents. When compared with 5,866 ancestry-matched controls, 11~12% more MR/DD children carried rare and large CNVs. The increased CNV burden in MR/DD was predominantly due to de novo CNVs, the majority of which (62%) arose in the paternal germline. We observed a 2~3 fold increase of large CNV burden in the mothers of affected children. By implementing an evidence-based review approach, pathogenic structural variants were identified in 14.3% patients and 2.4% parents, respectively. Pathogenic CNVs in parents were all carried by mothers. The maternal transmission bias of deleterious CNVs was further replicated in a published dataset. Our study confirms the pathogenic role of rare CNVs in MR/DD, and provides additional evidence to evaluate the dosage sensitivity of some candidate genes. It also supports a population model of MR/DD that spontaneous mutations in males' germline are major contributor to the de novo mutational burden in offspring, with higher penetrance in male than female; unaffected carriers of causative mutations, mostly females, then contribute to the inherited mutational burden.
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, China.|National Research Institute of Family Planning, Beijing, China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors.forename: Taoyun
authors.initials: T
authors.lastname: Ji
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.|Department of Psychiatry and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Xueya
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Medical Genetics, The Capital Medical University, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: National Research Institute of Family Planning, Beijing, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors.forename: Jingmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Hypertension, Shanghai, China.
authors.forename: Dingliang
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Institute of Dermatology and Department of Dermatology at No.1 Hospital, Anhui Medical University, Heifei, Anhui, China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Pak Chung
authors.initials: PC
authors.lastname: Sham
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.
authors.forename: Xuegong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: National Research Institute of Family Planning, Beijing, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors.forename: Yuwu
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D044466:Asian People / Q000235:genetics*; D002648:Child; D002681:China; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D000072740:Paternal Inheritance; D019683:Penetrance; D012727:Sex Characteristics