PLoS ONE (Jan 2011)

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

  • Man-Ting So,
  • Thomas Yuk-Yu Leon,
  • Guo Cheng,
  • Clara Sze-Man Tang,
  • Xiao-Ping Miao,
  • Belinda K Cornes,
  • Ngoc Ngo Diem,
  • Long Cui,
  • Elly Sau-Wai Ngan,
  • Vincent Chai-Hang Lui,
  • Xuan-Zhao Wu,
  • Bin Wang,
  • Hualong Wang,
  • Zheng-Wei Yuan,
  • Liu-Ming Huang,
  • Long Li,
  • Huimin Xia,
  • Deli Zhu,
  • Juncheng Liu,
  • Thanh Liem Nguyen,
  • Ivy Hau-Yee Chan,
  • Patrick Ho-Yu Chung,
  • Xue-Lai Liu,
  • Ruizhong Zhang,
  • Kenneth Kak-Yuen Wong,
  • Pak-Chung Sham,
  • Stacey S Cherny,
  • Paul Kwong-Hang Tam,
  • Maria-Mercè Garcia-Barcelo

DOI
https://doi.org/10.1371/journal.pone.0028986
Journal volume & issue
Vol. 6, no. 12
p. e28986

Abstract

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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.