Premium
A family‐based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia
Author(s) -
Arrington Cammon B.,
Bleyl Steven B.,
Matsunami Nori,
Bowles Neil E.,
Leppert Tami I.,
Demarest Bradley L.,
Osborne Karen,
Yoder Bradley A.,
Byrne Janice L.,
Schiffman Joshua D.,
Donald M.,
DiGeronimo Robert,
Rollins Michael,
Faix Roger,
Comstock Jessica,
Camp Nicola J.,
Leppert Mark F.,
Yost H. Joseph,
Brunelli Luca
Publication year - 2012
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.35664
Subject(s) - congenital diaphragmatic hernia , genetics , biology , gata4 , candidate gene , locus (genetics) , chromosomal region , haplotype , allele , gene , fetus , pregnancy , gene expression
Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non‐syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family‐based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high‐density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, that is, 2q11.2–q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, that is, 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2 , two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2 , but a rare shared variant was found in intron 1 of GATA4 . This work shows the role of heritability in isolated CDH. Our family‐based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non‐coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH. © 2012 Wiley Periodicals, Inc.