Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability.
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.
Emison
Eileen Sproat
ES
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Garcia-Barcelo
Merce
M
Grice
Elizabeth A
EA
Lantieri
Francesca
F
Amiel
Jeanne
J
Burzynski
Grzegorz
G
Fernandez
Raquel M
RM
Hao
Li
L
Kashuk
Carl
C
West
Kristen
K
Miao
Xiaoping
X
Tam
Paul K H
PK
Griseri
Paola
P
Ceccherini
Isabella
I
Pelet
Anna
A
Jannot
Anne-Sophie
AS
de Pontual
Loic
L
Henrion-Caude
Alexandra
A
Lyonnet
Stanislas
S
Verheij
Joke B G M
JB
Hofstra
Robert M W
RM
Antiñolo
Guillermo
G
Borrego
Salud
S
McCallion
Andrew S
AS
Chakravarti
Aravinda
A
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
D055757:SOXE Transcription Factors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human