Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks

TY - JOUR

T1 - Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks

AU - Longoni, Mauro

AU - Hansen, Kasper Lage

AU - Russell, Meaghan K

AU - Loscertales, Maria

AU - Abdul-Rahman, Omar A

AU - Baynam, Gareth

AU - Bleyl, Steven B

AU - Brady, Paul D

AU - Breckpot, Jeroen

AU - Chen, Chih P

AU - Devriendt, Koenraad

AU - Gillessen-Kaesbach, Gabriele

AU - Grix, Arthur W

AU - Rope, Alan F

AU - Shimokawa, Osamu

AU - Strauss, Bernarda

AU - Wieczorek, Dagmar

AU - Zackai, Elaine H

AU - Coletti, Caroline M

AU - Maalouf, Faouzi I

AU - Noonan, Kristin M

AU - Park, Ji H

AU - Tracy, Adam A

AU - Lee, Charles

AU - Donahoe, Patricia K

AU - Pober, Barbara R

N1 - Copyright © 2012 Wiley Periodicals, Inc.

PY - 2012/12

Y1 - 2012/12

N2 - 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.

AB - 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.

KW - Animals

KW - Chromosome Deletion

KW - Chromosomes, Human, Pair 8

KW - DNA

KW - DNA Glycosylases

KW - DNA-(Apurinic or Apyrimidinic Site) Lyase

KW - Female

KW - GATA4 Transcription Factor

KW - Heart Defects, Congenital

KW - Hernia, Diaphragmatic

KW - Hernias, Diaphragmatic, Congenital

KW - Humans

KW - Karyotyping

KW - Mice

KW - Mice, Inbred C57BL

KW - Phenotype

KW - Pregnancy

KW - Protein Interaction Maps

KW - SOXF Transcription Factors

U2 - 10.1002/ajmg.a.35665

DO - 10.1002/ajmg.a.35665

M3 - Journal article

C2 - 23165946

SN - 1552-4825

VL - 158A

SP - 3148

EP - 3158

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

IS - 12

ER -