Prevalence and Spectrum of PITX2c Mutations Associated with Congenital Heart Disease

Abstract

Congenital heart disease (CHD) is the most common form of birth defect and is the leading noninfectious cause of infant death. A growing body of evidence demonstrates that genetic risk factors are involved in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic defects underlying CHD in an overwhelming majority of patients remain unclear. In this study, the whole coding region and splice junction sites of the PITX2c gene, which encodes variant 3 of paired-like homeodomain transcription factor 2 crucial for normal cardiovascular morphogenesis, were sequenced in 382 unrelated patients with CHD, and 2 novel heterozygous mutations, p.W147X and p.N153D, were identified in 2 unrelated patients with CHD, respectively, including a 1-year-old male patient with double outlet right ventricle in combination with ventricular septal defect and a 4-year-old female patient with ventricular septal defect. The mutations were absent in 400 control chromosomes and were both predicted to be disease-causing by MutationTaster. Multiple alignments of PITX2c proteins across species displayed that the altered amino acids were completely conserved evolutionarily. Functional analysis revealed that the mutated PITX2c proteins were associated with a significantly reduced transactivational activity compared with their wild-type counterpart. These findings provide a novel insight into the molecular mechanisms implicated in CHD, suggesting potential implications for the antenatal prophylaxis and allele-specific treatment of CHD.

Axenfeld‐Rieger syndrome

“…Having either too little or too much of PITX2 impairs the regulation of other genes required for normal development . PITX2 mutations (particularly missense variants) have also been associated with other, non‐ARS diseases, such as congenital heart disease …”

PITX2 Loss-of-Function Mutation Contributes to Congenital Endocardial Cushion Defect and Axenfeld-Rieger Syndrome

“…The primer pairs used to amplify the coding exons and intron–exon boundaries of PITX2 by polymerase chain reaction (PCR) were shown in Table 1 . The PCR was performed and the PCR product was sequenced as previously described [ 82 ]. A sequence variation was verified by re-sequencing an independent PCR-amplified product from the same subject.…”

“…In mice, targeted disruption of PITX2c resulted in embryonic lethality with different kinds of congenital cardiovascular malformations, including ECD, atrial isomerism, double-outlet right ventricle, transposition of the great artery and abnormal aortic arch [ 80 , 81 ]. In humans, PITX2cmutations have been causatively associated with isolated congenital heart diseases [ 82 – 84 ]. These findings justified screening PITX2 as a preferred candidate gene for CHD in other cohorts of patients.…”

Genetics of Primary Inherited Disorders of the Optic Nerve: Clinical Applications

“…Patients with early-onset glaucoma related to Anridia caused by deletion of PAX6 may also be at risk for Wilm's tumor and should have a screening renal ultrasound (Hingorani et al 2012). Patients with mutations in FOXC1 or PITX2 can also have cardiac abnormalities (Gripp et al 2013;Wang et al 2013) and hearing loss (D'haene et al 2011).…”