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Title: Candidate genes for congenital diaphragmatic hernia from animalmodels: sequencing of fog2 and pdgfra reveals rare variants indiaphragmatic hernia patients

Abstract

Congenital diaphragmatic hernia (CDH) is a common, lifethreatening birth defect. Although there is strong evidence implicatinggenetic factors in its pathogenesis, few causative genes have beenidentified, and in isolated CDH, only one de novo, nonsense mutation hasbeen reported in FOG2 in a female with posterior diaphragmaticeventration. We report here that the homozygous null mouse for the Pdgfragene has posterolateral diaphragmatic defects and thus is a model forhuman CDH. We hypothesized that mutations in this gene could cause humanCDH. We sequenced PDGFRa and FOG2 in 96 patients with CDH, of which 53had isolated CDH (55.2 percent), 36 had CDH and additional anomalies(37.5 percent), and 7 had CDH and known chromosome aberrations (7.3percent). For FOG2, we identified novel sequence alterations predictingp.M703L and p.T843A in two patients with isolated CDH that were absent in526 and 564 control chromosomes respectively. These altered amino acidswere highly conserved. However, due to the lack of available parental DNAsamples we were not able to determine if the sequence alterations were denovo. For PDGFRa, we found a single variant predicting p.L967V in apatient with CDH and multiple anomalies that was absent in 768 controlchromosomes. This patient also had one cell with trisomy 15 on skinfibroblast culture, a finding of uncertainmore » significance. Although ourstudy identified sequence variants in FOG2 and PDGFRa, we have notdefinitively established the variants as mutations and we found noevidence that CDH commonly results from mutations in thesegenes.« less

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
COLLABORATION - University ofUtah
OSTI Identifier:
917408
Report Number(s):
LBNL-62888
R&D Project: Y00071; TRN: US200816%%566
DOE Contract Number:
DE-AC02-05CH11231
Resource Type:
Journal Article
Resource Relation:
Journal Name: European Journal of Human Genetics; Journal Volume: 15; Journal Issue: 9; Related Information: Journal Publication Date: 09/2007
Country of Publication:
United States
Language:
English
Subject:
60; AMINO ACIDS; ANIMALS; CHROMOSOMAL ABERRATIONS; CHROMOSOMES; DEFECTS; DNA; FEMALES; FIBROBLASTS; GENES; GENETICS; MUTATIONS; PATHOGENESIS; PATIENTS; congenital diaphragmatic hernia, FOG2, PDGFR, animal models,mutation detection

Citation Formats

Bleyl, S.B., Moshrefi, A., Shaw, G.M., Saijoh, Y., Schoenwolf,G.C., Pennacchio, L.A., and Slavotinek, A.M.. Candidate genes for congenital diaphragmatic hernia from animalmodels: sequencing of fog2 and pdgfra reveals rare variants indiaphragmatic hernia patients. United States: N. p., 2007. Web. doi:10.1038/sj.ejhg.5201872.
Bleyl, S.B., Moshrefi, A., Shaw, G.M., Saijoh, Y., Schoenwolf,G.C., Pennacchio, L.A., & Slavotinek, A.M.. Candidate genes for congenital diaphragmatic hernia from animalmodels: sequencing of fog2 and pdgfra reveals rare variants indiaphragmatic hernia patients. United States. doi:10.1038/sj.ejhg.5201872.
Bleyl, S.B., Moshrefi, A., Shaw, G.M., Saijoh, Y., Schoenwolf,G.C., Pennacchio, L.A., and Slavotinek, A.M.. Fri . "Candidate genes for congenital diaphragmatic hernia from animalmodels: sequencing of fog2 and pdgfra reveals rare variants indiaphragmatic hernia patients". United States. doi:10.1038/sj.ejhg.5201872.
@article{osti_917408,
title = {Candidate genes for congenital diaphragmatic hernia from animalmodels: sequencing of fog2 and pdgfra reveals rare variants indiaphragmatic hernia patients},
author = {Bleyl, S.B. and Moshrefi, A. and Shaw, G.M. and Saijoh, Y. and Schoenwolf,G.C. and Pennacchio, L.A. and Slavotinek, A.M.},
abstractNote = {Congenital diaphragmatic hernia (CDH) is a common, lifethreatening birth defect. Although there is strong evidence implicatinggenetic factors in its pathogenesis, few causative genes have beenidentified, and in isolated CDH, only one de novo, nonsense mutation hasbeen reported in FOG2 in a female with posterior diaphragmaticeventration. We report here that the homozygous null mouse for the Pdgfragene has posterolateral diaphragmatic defects and thus is a model forhuman CDH. We hypothesized that mutations in this gene could cause humanCDH. We sequenced PDGFRa and FOG2 in 96 patients with CDH, of which 53had isolated CDH (55.2 percent), 36 had CDH and additional anomalies(37.5 percent), and 7 had CDH and known chromosome aberrations (7.3percent). For FOG2, we identified novel sequence alterations predictingp.M703L and p.T843A in two patients with isolated CDH that were absent in526 and 564 control chromosomes respectively. These altered amino acidswere highly conserved. However, due to the lack of available parental DNAsamples we were not able to determine if the sequence alterations were denovo. For PDGFRa, we found a single variant predicting p.L967V in apatient with CDH and multiple anomalies that was absent in 768 controlchromosomes. This patient also had one cell with trisomy 15 on skinfibroblast culture, a finding of uncertain significance. Although ourstudy identified sequence variants in FOG2 and PDGFRa, we have notdefinitively established the variants as mutations and we found noevidence that CDH commonly results from mutations in thesegenes.},
doi = {10.1038/sj.ejhg.5201872},
journal = {European Journal of Human Genetics},
number = 9,
volume = 15,
place = {United States},
year = {Fri May 11 00:00:00 EDT 2007},
month = {Fri May 11 00:00:00 EDT 2007}
}