RET Mutational Spectrum in Hirschsprung Disease: Evaluation of 601 Chinese Patients

作者：Man‐Ting So, Thomas Yuk-Yu Leon, Guo Cheng, Clara Sze-Man Tang, Xiaoping Miao, Belinda K. Cornes, Diem Ngoc Ngo, Long Cui, Esw Ngan, Vincent Chai-Hang Lui, Xuan-Zhao Wu, Bin Wang, Hualong Wang, Zhengwei Yuan, Liuming Huang, Long Li, Huimin Xia, Deli Zhu, Juncheng Liu, Thanh Liêm Nguyễn, Ivy Hau-Yee Chan, Bhy Chung, Xuelai Liu, Ruizhong Zhang, Kenneth Kak‐Yuen Wong, Pak C. Sham, Stacey S. Cherny, Paul Kwong‐Hang Tam, María-Mercé García-Barceló · 发表于：PLoS ONE · 年份：2011 · DOI：10.1371/journal.pone.0028986 · 被引用次数：31 · 研究领域：Congenital gastrointestinal and neural anomalies、Congenital heart defects research

Rare (RVs) and common variants of the RET gene contribute to Hirschsprung disease (HSCR; congenital aganglionosis). While RET common variants are strongly associated with the commonest manifestation of the disease (males; short-segment aganglionosis; sporadic), rare coding sequence (CDS) variants are more frequently found in the lesser common and more severe forms of the disease (females; long/total colonic aganglionosis; familial).Here we present the screening for RVs in the RET CDS and intron/exon boundaries of 601 Chinese HSCR patients, the largest number of patients ever reported. We identified 61 different heterozygous RVs (50 novel) distributed among 100 patients (16.64%). Those include 14 silent, 29 missense, 5 nonsense, 4 frame-shifts, and one in-frame amino-acid deletion in the CDS, two splice-site deletions, 4 nucleotide substitutions and a 22-bp deletion in the intron/exon boundaries and 1 single-nucleotide substitution in the 5' untranslated region. Exonic variants were mainly clustered in RET the extracellular domain. RET RVs were more frequent among patients with the most severe phenotype (24% vs. 15% in short-HSCR). Phasing RVs with the RET HSCR-associated haplotype suggests that RVs do not underlie the undisputable association of RET common variants with HSCR. None of the variants were found in 250 Chinese controls.