Candidate genes for congenital diaphragmatic hernia from animal models: sequencing of FOG2 and PDGFRα reveals rare variants in diaphragmatic hernia patients

Abstract

Congenital diaphragmatic hernia (CDH) is a common, life threatening birth defect. Although there is strong evidence implicating genetic factors in its pathogenesis, few causative genes have been identified, and in isolated CDH, only one de novo, nonsense mutation has been reported in FOG2 in a female with posterior diaphragmatic eventration. We report here that the homozygous null mouse for the Pdgfra gene has posterolateral diaphragmatic defects and thus is a model for human CDH. We hypothesized that mutations in this gene could cause human CDH. We sequenced PDGFRa and FOG2 in 96 patients with CDH, of which 53 had isolated CDH (55.2%), 36 had CDH and additional anomalies (37.5%), and 7 had CDH and known chromosome aberrations (7.3%). For FOG2, we identified novel sequence alterations predicting p.M703L and p.T843A in two patients with isolated CDH that were absent in 526 and 564 control chromosomes respectively. These altered amino acids were highly conserved. However, due to the lack of available parental DNA samples we were not able to determine if the sequence alterations were de novo. For PDGFRa, we found a single variant predicting p.L967V in a patient with CDH and multiple anomalies that was absent in 768 control chromosomes. This patient also had one cell with trisomy 15 on skin fibroblast culture, a finding of uncertain significance. Although our study identified sequence variants in FOG2 and PDGFRa, we have not definitively established the variants as mutations and we found no evidence that CDH commonly results from mutations in these genes.

Retinoid Pathway and Congenital Diaphragmatic Hernia: Hypothesis from the Analysis of Chromosomal Abnormalities

“…To date, no mutation could be identified in COUP-TFII [38,41] . A de novo mutation and sequence alterations in FOG2 were found in three patients, reinforcing the hypothesis that FOG2 is critical in diaphragmatic and lung development in humans [91,92] .…”

“…Based on this result, the authors identified a de novo R112X heterozygous mutation in an infant who died shortly after birth with diaphragmatic defect and severe pulmonary hypoplasia. More recently, Bleyl et al [92] have identified two novel sequence alterations in FOG2 in two patients with isolated CDH, reinforcing the hypothesis that FOG2 is critical for normal development of the diaphragm.…”

Gene expression in the developing diaphragm: significance for congenital diaphragmatic hernia

“…It is important to point out here that FOG2 is a transcriptional coregulator of GATA4 transcriptional activity such that FOG2 can enhance and/or inhibit GATA4 activity, depending on the cellular context (18). FOG2 is considered a strong candidate responsible for the development of Bochdalek hernia in infants harboring microdeletions encompassing 8q22-8q23, and this hypothesis is supported by the recent identification of two infants with unique sequence variations in FOG2 who had isolated Bochdalek CDH (16,33,43). GATA4 has also been singled out as an important gene in the context of infants harboring microdeletions in the region of 8p23.1 (33,43).…”

The effects of imatinib on pregnancy outcome

“…Mice homozygous for null mutations in PDGFR␣ show combinations of birth defects, including facial clefting, severe spina bifida occulta, cardiac defects, omphalocele, renal and urogenital anomalies, and vertebral and rib fusion abnormalities. 10,11 PDGFR␣ also appears to play a role in lung development, as shown in studies with PDGFR␣-null mice that also carried a human YAC PDGFR␣ transgene, with pups dying soon after birth due to lung hypoplasia. 12 …”