title: Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability.
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 x 10(-43) in European ancestry; p = 1.1 x 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 x 10(-5)) and familiality (p = 6.2 x 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.
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Eileen Sproat
authors.initials: ES
authors.lastname: Emison
authors.forename: Merce
authors.initials: M
authors.lastname: Garcia-Barcelo
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grice
authors.forename: Francesca
authors.initials: F
authors.lastname: Lantieri
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Burzynski
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Fernandez
authors.forename: Li
authors.initials: L
authors.lastname: Hao
authors.forename: Carl
authors.initials: C
authors.lastname: Kashuk
authors.forename: Kristen
authors.initials: K
authors.lastname: West
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Miao
authors.forename: Paul K H
authors.initials: PK
authors.lastname: Tam
authors.forename: Paola
authors.initials: P
authors.lastname: Griseri
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
authors.forename: Anna
authors.initials: A
authors.lastname: Pelet
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Jannot
authors.forename: Loic
authors.initials: L
authors.lastname: de Pontual
authors.forename: Alexandra
authors.initials: A
authors.lastname: Henrion-Caude
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Joke B G M
authors.initials: JB
authors.lastname: Verheij
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McCallion
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
mesh_terms: D044466:Asian People; D001483:Base Sequence; D016022:Case-Control Studies; D004742:Enhancer Elements, Genetic; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006627:Hirschsprung Disease / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D009154:Mutation; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D055757:SOXE Transcription Factors / Q000378:metabolism; D012737:Sex Factors; D015533:Transcriptional Activation; D044465:White People
chemical_list: D055757:SOXE Transcription Factors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human