Dataset Information

RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients.

ABSTRACT: 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.

SUBMITTER: So MT

PROVIDER: S-EPMC3235168 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients.

So Man-Ting MT Leon Thomas Yuk-Yu TY Cheng Guo G Tang Clara Sze-Man CS Miao Xiao-Ping XP Cornes Belinda K BK Diem Ngoc Ngo NN Cui Long L Ngan Elly Sau-Wai ES Lui Vincent Chai-Hang VC Wu Xuan-Zhao XZ Wang Bin B Wang Hualong H Yuan Zheng-Wei ZW Huang Liu-Ming LM Li Long L Xia Huimin H Zhu Deli D Liu Juncheng J Nguyen Thanh Liem TL Chan Ivy Hau-Yee IH Chung Patrick Ho-Yu PH Liu Xue-Lai XL Zhang Ruizhong R Wong Kenneth Kak-Yuen KK Sham Pak-Chung PC Cherny Stacey S SS Tam Paul Kwong-Hang PK Garcia-Barcelo Maria-Mercè MM

PloS one 20111209 12

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/ ...[more]

PMID: 22174939

Similar Datasets

Project description:Hirschsprung disease (HSCR, OMIM 142623) is a developmental disorder characterized by the absence of ganglion cells along variable lengths of the distal gastrointestinal tract, which results in tonic contraction of the aganglionic colon segment and functional intestinal obstruction. The RET proto-oncogene is the major gene associated to HSCR with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. In addition, many other genes have been described to be associated with this pathology, including the semaphorins class III genes SEMA3A (7p12.1) and SEMA3D (7q21.11) through SNP array analyses and by next-generation sequencing technologies. Semaphorins are guidance cues for developing neurons implicated in the axonal projections and in the determination of the migratory pathway for neural-crest derived neural precursors during enteric nervous system development. In addition, it has been described that increased SEMA3A expression may be a risk factor for HSCR through the upregulation of the gene in the aganglionic smooth muscle layer of the colon in HSCR patients. Here we present the results of a comprehensive analysis of SEMA3A and SEMA3D in a series of 200 Spanish HSCR patients by the mutational screening of its coding sequence, which has led to find a number of potentially deleterious variants. RET mutations have been also detected in some of those patients carrying SEMAs variants. We have evaluated the A131T-SEMA3A, S598G-SEMA3A and E198K-SEMA3D mutations using colon tissue sections of these patients by immunohistochemistry. All mutants presented increased protein expression in smooth muscle layer of ganglionic segments. Moreover, A131T-SEMA3A also maintained higher protein levels in the aganglionic muscle layers. These findings strongly suggest that these mutants have a pathogenic effect on the disease. Furthermore, because of their coexistence with RET mutations, our data substantiate the additive genetic model proposed for this rare disorder and further support the association of SEMAs genes with HSCR.

Dataset Information

RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients.

Publications

RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets