Mutations in PITX2 may contribute to cases of omphalocele and VATER‐like syndromes

Abstract

Omphalocele is a congenital anomaly with substantial morbidity. Rieger syndrome, an autosomal dominant disorder, is characterized by craniofacial abnormalities and abdominal wall defects. PITX2 mutations are etiologic in >40% of cases of Rieger syndrome. We demonstrate that the birth prevalence of omphalocele is significantly higher in Rieger syndrome than in the general population, with omphaloceles found in 0.03% in the Iowa newborn population and 4.3% of patients with Rieger syndrome. Our objective was to screen coding and conserved non-coding regions of PITX2 for mutations in 209 patients with omphalocele. We identified remarkable evolutionarily conserved regions by comparing the 3'UTR of Pitx2 in 13 vertebrate and 3 invertebrate species. No mutations changing the amino acid sequence were found within the omphalocele population. In one case of omphalocele with VATER-like additional anomalies, a three nucleotide deletion was found in the 3'UTR. This deletion was not seen in 1,186 controls. Also in the 3'UTR, we identified a single nucleotide polymorphism at a highly conserved residue. Our findings suggest additional studies of PITX2 conserved regions will be valuable. We also screened the omphalocele cases for mutations in exon 5 of the gene FLNA. Mutations in FLNA have been shown to cause a broad range of congenital malformations, including otopalatodigital syndrome type 2 in which a missense mutation occurring in exon 5 of FLNA results in omphalocele as part of the phenotype. We did not find any mutations in exon 5 of FLNA in 179 omphalocele cases studied.

Genetic Analysis of Hedgehog Signaling in Ventral Body Wall Development and the Onset of Omphalocele Formation

“…Likewise, abnormal Alk3 -mediated BMP signaling in mesodermal tissues caused prenatal omphalocele-like defects [26]. Moreover, the phenotypes of Pitx2 knockout mice and PITX2 mutation in humans indicate a correlation with the omphalocele formation [33], [86]. The Pitx2 gene, which is expressed in abdominal muscles such as the rectus abdominis and oblique abdominis, has pivotal roles in muscle anlagen formation and maintenance [23], [87]–[89].…”

Genome-wide linkage and copy number variation analysis reveals 710 kb duplication on chromosome 1p31.3 responsible for autosomal dominant omphalocele

“…Although there have been a number of studies undertaken to identify the genetic variations responsible for omphalocele, no single susceptibility gene has been identified to date that plays a major role in this disorder 28. Here, we report the results of the first genome-wide linkage scan and other genetic analysis, providing significant evidence of a novel omphalocele susceptibility locus on chromosome 1p31.3 in a large pedigree (UR0114).…”

Axenfeld–Rieger syndrome as rare cause of umbilical abnormality

“…The association between ARS and omphalocele has been described previously; the birth prevalence of omphalocele is 4.3% in fetuses with ARS versus 0.03% in the general population. It is hypothesized that mutations in PITX2 in particular may cause omphalocele, as PITX2 ‐knockout mice exhibit failure of ventral wall closure.…”