Differential contributions of rare and common, coding and noncoding ret mutations to multifactorial hirschsprung disease liability

Eileen Sproat Emison, Merce Garcia-Barcelo, Elizabeth A. Grice, Francesca Lantieri, Jeanne Amiel, Grzegorz Burzynski, Raquel M. Fernandez, Li Hao, Carl Kashuk, Kristen West, Xiaoping Miao, Paul K H Tam, Paola Griseri, Isabella Ceccherini, Anna Pelet, Anne Sophie Jannot, Loic De Pontual, Alexandra Henrion-Caude, Stanislas Lyonnet, Joke B G M VerheijRobert M W Hofstra, Guillermo Antiñolo, Salud Borrego, Andrew S McCallion, Aravinda Chakravarti

Research output: Contribution to journalArticle

Abstract

The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C→T allele (rs2435357: p = 3.9 × 10-43 in European ancestry; p = 1.1 × 10-21 in Chinese samples) that probably arose once within the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T variant disrupts a SOX10 binding site within MCS+9.7 that compromises RET transactivation. The T allele, with a control frequency of 20%-30%/47% and case frequency of 54%-62%/88% in European/Chinese-ancestry individuals, is involved in all forms of HSCR. It is marginally associated with proband gender (p = 0.13) and significantly so with length of aganglionosis (p = 7.6 × 10-5) and familiality (p = 6.2 × 10-4). The enhancer variant is more frequent in the common forms of male, short-segment, and simplex families whereas multiple, rare, coding mutations are the norm in the less common and more severe forms of female, long-segment, and multiplex families. The T variant also increases penetrance in patients with rare RET coding mutations. Thus, both rare and common mutations, individually and together, make contributions to the risk of HSCR. The distribution of RET variants in diverse HSCR patients suggests a "cellular-recessive" genetic model where both RET alleles' function is compromised. The RET allelic series, and its genotype-phenotype correlations, shows that success in variant identification in complex disorders may strongly depend on which patients are studied.

Original languageEnglish (US)
Pages (from-to)60-74
Number of pages15
JournalAmerican Journal of Human Genetics
Volume87
Issue number1
DOIs
StatePublished - Jul 9 2010

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Hirschsprung Disease
Mutation
Alleles
Proto-Oncogene Proteins c-ret
Penetrance
Genetic Models
Genetic Association Studies
Transcriptional Activation
Parents
Binding Sites
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Differential contributions of rare and common, coding and noncoding ret mutations to multifactorial hirschsprung disease liability. / Emison, Eileen Sproat; Garcia-Barcelo, Merce; Grice, Elizabeth A.; Lantieri, Francesca; Amiel, Jeanne; Burzynski, Grzegorz; Fernandez, Raquel M.; Hao, Li; Kashuk, Carl; West, Kristen; Miao, Xiaoping; Tam, Paul K H; Griseri, Paola; Ceccherini, Isabella; Pelet, Anna; Jannot, Anne Sophie; De Pontual, Loic; Henrion-Caude, Alexandra; Lyonnet, Stanislas; Verheij, Joke B G M; Hofstra, Robert M W; Antiñolo, Guillermo; Borrego, Salud; McCallion, Andrew S; Chakravarti, Aravinda.

In: American Journal of Human Genetics, Vol. 87, No. 1, 09.07.2010, p. 60-74.

Research output: Contribution to journalArticle

Emison, ES, Garcia-Barcelo, M, Grice, EA, Lantieri, F, Amiel, J, Burzynski, G, Fernandez, RM, Hao, L, Kashuk, C, West, K, Miao, X, Tam, PKH, Griseri, P, Ceccherini, I, Pelet, A, Jannot, AS, De Pontual, L, Henrion-Caude, A, Lyonnet, S, Verheij, JBGM, Hofstra, RMW, Antiñolo, G, Borrego, S, McCallion, AS & Chakravarti, A 2010, 'Differential contributions of rare and common, coding and noncoding ret mutations to multifactorial hirschsprung disease liability', American Journal of Human Genetics, vol. 87, no. 1, pp. 60-74. https://doi.org/10.1016/j.ajhg.2010.06.007
Emison, Eileen Sproat ; Garcia-Barcelo, Merce ; Grice, Elizabeth A. ; Lantieri, Francesca ; Amiel, Jeanne ; Burzynski, Grzegorz ; Fernandez, Raquel M. ; Hao, Li ; Kashuk, Carl ; West, Kristen ; Miao, Xiaoping ; Tam, Paul K H ; Griseri, Paola ; Ceccherini, Isabella ; Pelet, Anna ; Jannot, Anne Sophie ; De Pontual, Loic ; Henrion-Caude, Alexandra ; Lyonnet, Stanislas ; Verheij, Joke B G M ; Hofstra, Robert M W ; Antiñolo, Guillermo ; Borrego, Salud ; McCallion, Andrew S ; Chakravarti, Aravinda. / Differential contributions of rare and common, coding and noncoding ret mutations to multifactorial hirschsprung disease liability. In: American Journal of Human Genetics. 2010 ; Vol. 87, No. 1. pp. 60-74.
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AU - Lantieri, Francesca

AU - Amiel, Jeanne

AU - Burzynski, Grzegorz

AU - Fernandez, Raquel M.

AU - Hao, Li

AU - Kashuk, Carl

AU - West, Kristen

AU - Miao, Xiaoping

AU - Tam, Paul K H

AU - Griseri, Paola

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AU - Pelet, Anna

AU - Jannot, Anne Sophie

AU - De Pontual, Loic

AU - Henrion-Caude, Alexandra

AU - Lyonnet, Stanislas

AU - Verheij, Joke B G M

AU - Hofstra, Robert M W

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