TY - JOUR
T1 - Differential contributions of rare and common, coding and noncoding ret mutations to multifactorial hirschsprung disease liability
AU - Emison, Eileen Sproat
AU - Garcia-Barcelo, Merce
AU - Grice, Elizabeth A.
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
AU - Ceccherini, Isabella
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.
AU - Antiñolo, Guillermo
AU - Borrego, Salud
AU - McCallion, Andrew S.
AU - Chakravarti, Aravinda
N1 - Funding Information:
We wish to thank the numerous patients, their families, and the referring physicians across the world that have participated in studies of Hirschsprung disease in our laboratories over the past 20 years, and the numerous laboratory members who have contributed to discussion of these results. This study is a contribution from The International Hirschsprung Disease Consortium. Grant support is as follows: (USA) National Institutes of Health, HD28088 to A.C. and GM71648 to A.S.M.; and the “Holes for Hirschsprung” fundraiser to A.C.; (Italy) Italian Telethon (GGP04257) and European “E-Rare” program—Istituto Superiore di Sanità (Italy) to I.C.; (France) ANR (Eranet and Maladies Rares Grants) and FRM (Fondation pour la Recherche Médicale) to S.L.; (Hong Kong) HKU 765407 from the Hong Kong Research Grant Council to M.G.-B. and P.K.H.T.; (Netherlands) NWO (no. 901-04-225) Bernoulle Foundation and Ubbo Emmius Foundation to R.M.W.H.; and (Spain) Fondo de Investigación Sanitaria, Spain (PI070080), European E-Rare program (PI071315), and Consejeria de Educación Ciencia Y Empresa de la Junta de Andalucía (CTS2590) to S.B. Author contributions are as follows. (USA) A.C. designed the study and ascertained families; E.S.E. and K.W. performed all genotyping; L.H. and E.S.E. performed DNA sequence analysis; E.A.G. and A.S.M. designed and performed the functional enhancer biological analyses; C.K., E.S.E., and A.C. conducted statistical analysis of the data; and E.S.E., A.S.M., and A.C. participated in data interpretation and writing the manuscript. We gratefully acknowledge the work of Erick Kaufmann, Jennifer (Scott) Bubb, Maura Kenton, Julie Albertus, and Courtney Nichols in family ascertainment. (Italy) F.L. and I.C. ascertained families; F.L. conducted statistical analysis of data; and F.L., P.G., and I.C. participated in data interpretation and editing the manuscript. (France) J.A., A.P., and L.d.P. performed DNA sequencing; A.-S.J. conducted statistical analyses of data; and J.A. and S.L. participated in the study design, data interpretation, and ascertainment of families. (Hong Kong) M.G.-B. and X.M. performed DNA sequencing and genotyping of the sporadic Chinese HSCR patients and control samples; M.G.-B. conducted statistical analysis of data, and together with P.K.H.T., data interpretation; and P.K.H.T. ascertained all Chinese HSCR patients. (Netherlands) G.B. performed all genotyping; R.M.W.H. participated in data interpretation and manuscript editing; and J.B.G.M.V. was involved in ascertaining families. (Spain) S.B. and G.A. ascertained Spanish HSCR families; R.M.F. performed DNA sequencing for mutation detection; and R.M.F., G.A., and S.B. participated in manuscript editing.
PY - 2010/7/9
Y1 - 2010/7/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2010.06.007
DO - 10.1016/j.ajhg.2010.06.007
M3 - Article
C2 - 20598273
AN - SCOPUS:77955081986
SN - 0002-9297
VL - 87
SP - 60
EP - 74
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -