Genome-wide copy number variation study in anorectal malformations

Emily H.M. Wong, Long Cui, Chun Laam Ng, Clara S.M. Tang, Xue Lai Liu, Man Ting So, Benjamin Hon Kei Yip, Guo Cheng, Ruizhong Zhang, Wai Kiu Tang, Wanling Yang, Yu Lung Lau, Larry Baum, Patrick Kwan, Liang Dan Sun, Xian Bo Zuo, Yun Qing Ren, Xian Yong Yin, Xiao Ping Miao, Jianjun LiuVincent Chi Hang Lui, Elly Sau Wai Ngan, Zhen Wei Yuan, Shi Wei Zhang, Jinglong Xia, Hualong Wang, Xiao Bing Sun, Ruoyi Wang, Tao Chang, Ivy Hau Yee Chan, Patrick Ho Yu Chung, Xue Jun Zhang, Kenneth Kak Yuen Wong, Stacey S. Cherny, Pak Chung Sham, Paul Kwong Hang Tam, Maria Mercè Garcia-Barcelo

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19 Citations (Scopus)


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.

Original languageEnglish
Article numberdds451
Pages (from-to)621-631
Number of pages11
JournalHuman Molecular Genetics
Issue number3
Publication statusPublished - 1 Feb 2013
Externally publishedYes

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