CASZ1 loss-of-function mutation associated with congenital heart disease

摘要: As the most common form of birth defect in humans, congenital heart disease (CHD) is associated with substantial morbidity and mortality both children adults. Increasing evidence demonstrates that genetic defects play a pivotal role pathogenesis CHD. However, CHD great heterogeneity, an overwhelming majority cases, determinants underpinning remain elusive. In present investigation, coding exons flanking introns CASZ1 gene, which codes for zinc finger transcription factor essential cardiovascular morphogenesis, were sequenced 172 unrelated patients result, novel heterozygous mutation, p.L38P, was identified index patient ventricular septal (VSD). Genetic scanning mutation carrier's available family members revealed all affected but absent unaffected individuals. Analysis proband's pedigree showed co-segregated VSD, transmitted as autosomal dominant trait complete penetrance. The missense altered amino acid highly conserved evolutionarily, 200 unrelated, ethnically-matched healthy subjects used controls. Functional deciphers by using dual-luciferase reporter assay system unveiled mutant had significantly reduced transcriptional activity compared its wild-type counterpart. To best our knowledge, current study firstly identifies new gene predisposing to provides insight into molecular mechanisms underlying potential therapeutic target CASZ1-associated CHD, suggesting implications personalized prophylaxis therapy