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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}
}
  • A characteristic liver scintigraphic finding was observed in a 2-month- old infant with hepatic herniation through a right-sided posterolateral congenital diaphragmatic defect (Bochdalek). The liver scintigrams showed an oblique band of decreased radioactivity dividing the liver into an inferior anteromedial portion and a superior posterolateral portion. In spite of the markedly abnormal liver scintigram, other diagnostic studies, including pneumoperitoneum abdominal radiography, remained negative. The liver scintigram can provide life-saving information in the diagnosis of congenital diaphragmatic hernia, as in the present case. The distinctive liver-scan findings among the various types of common diaphragmatic hernias are also briefly reviewed. (auth)
  • Ehlers-Danlos syndrome (EDS) includes a group of connective tissue disorders with abnormal collagen metabolism and a diverse clinical spectrum. We report two siblings with EDS who both presented with congenital diaphragmatic hernia (CDH). The elder sister suffered from recurrent diaphragmatic hernia twice and EDS was overlooked initially. Echocardiography as well as contrast-enhanced magnetic resonance angiography (MRA) showed dilatation of the pulmonary artery, and marked elongation and tortuosity of the aorta and its branches. A diagnosis of EDS was eventually established when these findings were coupled with the clinical features of hyperelastic skin. Her younger brother also had similar features. Thismore » report emphasizes that EDS may present as CDH in a small child which could easily be overlooked. Without appropriate surgery, diaphragmatic hernia might occur. Echocardiographic screening is recommended in patients with CDH. Contrast-enhanced MRA can be helpful in delineation of abnormally tortuous aortic great vessels that are an important clue to the early diagnosis of EDS.« less
  • No abstract prepared.
  • Allelic frequencies of a microsatellite of the apolipoprotein CII gene (APOCII) and a minisatellite of the apolipoprotein B gene (APOB) were studied by using polymerase chain reaction (PCR). The study was conducted on a random sample of male Moscow inhabitants and a sample of patients with coronary heart disease (CHD) from the same population. Fourteen variants of the APOB minisatellite (the 82% heterozygosity level) and 13 alleles of the APOCII microsatellite (the 85% heterozygosity level) were found. CHD patients significantly differed from the control group in the distributions of alleles in these loci: APOB 32, APOB 46, APOB 48, andmore » APOB 50 as well as APOCII 17 and APOCII 29 were found more frequently. A relationship was found between the distributions of APOB and APOCII in the CHD patients. The CHD patients with alleles APOCII 21 and APOCII 30 very often had the allele APOB 32; and patients with the genotype APOB 34, 36 had the allele APOCII 29 even more often than affected individuals in general. Individuals of the control group with the allele APOCII30 exhibited hypertriglyceridemia without increased levels of total cholesterol and apolipoprotein B in plasma. 14 refs., 3 figs., 6 tabs.« less