title: Genome-wide copy number variation study in anorectal malformations.
abstract: Anorectal malformations (ARMs, congenital obstruction of the anal opening) are among the most common birth defects requiring surgical treatment (2-5/10 000 live-births) and carry significant chronic morbidity. ARMs present either as isolated or as part of the phenotypic spectrum of some chromosomal abnormalities or monogenic syndromes. The etiology is unknown. To assess the genetic contribution to ARMs, we investigated single-nucleotide polymorphisms and copy number variations (CNVs) at genome-wide scale. A total of 363 Han Chinese sporadic ARM patients and 4006 Han Chinese controls were included. Overall, we detected a 1.3-fold significant excess of rare CNVs in patients. Stratification of patients by presence/absence of other congenital anomalies showed that while syndromic ARM patients carried significantly longer rare duplications than controls (P = 0.049), non-syndromic patients were enriched with both rare deletions and duplications when compared with controls (P = 0.00031). Twelve chromosomal aberrations and 114 rare CNVs were observed in patients but not in 868 controls nor 11 943 healthy individuals from the Database of Genomic Variants. Importantly, these aberrations were observed in isolated ARM patients. Gene-based analysis revealed 79 genes interfered by CNVs in patients only. In particular, we identified a de novo DKK4 duplication. DKK4 is a member of the WNT signaling pathway which is involved in the development of the anorectal region. In mice, Wnt disruption results in ARMs. Our data suggest a role for rare CNVs not only in syndromic but also in isolated ARM patients and provide a list of plausible candidate genes for the disorder.
authors.affiliation: Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Emily H M
authors.initials: EH
authors.lastname: Wong
authors.forename: Long
authors.initials: L
authors.lastname: Cui
authors.forename: Chun-Laam
authors.initials: CL
authors.lastname: Ng
authors.forename: Clara S M
authors.initials: CS
authors.lastname: Tang
authors.forename: Xue-Lai
authors.initials: XL
authors.lastname: Liu
authors.forename: Man-Ting
authors.initials: MT
authors.lastname: So
authors.forename: Benjamin Hon-Kei
authors.initials: BH
authors.lastname: Yip
authors.forename: Guo
authors.initials: G
authors.lastname: Cheng
authors.forename: Ruizhong
authors.initials: R
authors.lastname: Zhang
authors.forename: Wai-Kiu
authors.initials: WK
authors.lastname: Tang
authors.forename: Wanling
authors.initials: W
authors.lastname: Yang
authors.forename: Yu-Lung
authors.initials: YL
authors.lastname: Lau
authors.forename: Larry
authors.initials: L
authors.lastname: Baum
authors.forename: Patrick
authors.initials: P
authors.lastname: Kwan
authors.forename: Liang-Dan
authors.initials: LD
authors.lastname: Sun
authors.forename: Xian-Bo
authors.initials: XB
authors.lastname: Zuo
authors.forename: Yun-Qing
authors.initials: YQ
authors.lastname: Ren
authors.forename: Xian-Yong
authors.initials: XY
authors.lastname: Yin
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Miao
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.forename: Vincent Chi-Hang
authors.initials: VC
authors.lastname: Lui
authors.forename: Elly Sau-Wai
authors.initials: ES
authors.lastname: Ngan
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Yuan
authors.forename: Shi-Wei
authors.initials: SW
authors.lastname: Zhang
authors.forename: Jinglong
authors.initials: J
authors.lastname: Xia
authors.forename: Hualong
authors.initials: H
authors.lastname: Wang
authors.forename: Xiao-bing
authors.initials: XB
authors.lastname: Sun
authors.forename: Ruoyi
authors.initials: R
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Chang
authors.forename: Ivy Hau-Yee
authors.initials: IH
authors.lastname: Chan
authors.forename: Patrick Ho-Yu
authors.initials: PH
authors.lastname: Chung
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Zhang
authors.forename: Kenneth Kak-Yuen
authors.initials: KK
authors.lastname: Wong
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.forename: Paul Kwong-Hang
authors.initials: PK
authors.lastname: Tam
authors.forename: Maria-Mercè
authors.initials: MM
authors.lastname: Garcia-Barcelo
mesh_terms: D000818:Animals; D000071056:Anorectal Malformations; D001006:Anus, Imperforate / Q000235:genetics* / Q000503:physiopathology*; D044466:Asian People; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D060449:Wnt Signaling Pathway
chemical_list: C442333:DKK4 protein, human; D036341:Intercellular Signaling Peptides and Proteins