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Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks
Author(s) -
Longoni Mauro,
Lage Kasper,
Russell Meaghan K.,
Loscertales Maria,
AbdulRahman Omar A.,
Baynam Gareth,
Bleyl Steven B.,
Brady Paul D.,
Breckpot Jeroen,
Chen Chih P.,
Devriendt Koenraad,
GillessenKaesbach Gabriele,
Grix Arthur W.,
Rope Alan F.,
Shimokawa Osamu,
Strauss Bernarda,
Wieczorek Dagmar,
Zackai Elaine H.,
Coletti Caroline M.,
Maalouf Faouzi I.,
Noonan Kristin M.,
Park Ji H.,
Tracy Adam A.,
Lee Charles,
Donahoe Patricia K.,
Pober Barbara R.
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.35665
Subject(s) - congenital diaphragmatic hernia , diaphragmatic hernia , phenotype , gene , biology , gata4 , genetics , diaphragmatic breathing , chromosome , congenital malformations , bioinformatics , pathology , medicine , hernia , fetus , gene expression , pregnancy , alternative medicine , surgery
Chromosome 8p23.1 is a common hotspot associated with major congenital malformations, including congenital diaphragmatic hernia (CDH) and cardiac defects. We present findings from high‐resolution arrays in patients who carry a loss (n = 18) or a gain (n = 1) of sub‐band 8p23.1. We confirm a region involved in both diaphragmatic and heart malformations. Results from a novel CNVConnect algorithm, prioritizing protein–protein interactions between products of genes in the 8p23.1 hotspot and products of previously known CDH causing genes, implicated GATA4 , NEIL2 , and SOX7 in diaphragmatic defects. Sequence analysis of these genes in 226 chromosomally normal CDH patients, as well as in a small number of deletion 8p23.1 patients, showed rare unreported variants in the coding region; these may be contributing to the diaphragmatic phenotype. We also demonstrated that two of these three genes were expressed in the E11.5–12.5 primordial mouse diaphragm, the developmental stage at which CDH is thought to occur. This combination of bioinformatics and expression studies can be applied to other chromosomal hotspots, as well as private microdeletions or microduplications, to identify causative genes and their interaction networks. © 2012 Wiley Periodicals, Inc.