Abstract
NKX2-5 mutations are associated with different forms of congenital heart disease. Despite the knowledge gained from molecular and animal studies, genotype-phenotype correlations in humans are limited by the lack of large cohorts and the incomplete assessment of family members. We hypothesized that studying the role of NKX2-5 in inbred populations with homogeneous genetic backgrounds and high consanguinity rates such as Lebanon could help closing this gap. We sequenced NKX2-5 in 188 index CHD cases (25 with ASD). Five variants (three segregated in families) were detected in eleven families including the previously documented p.R25C variant, which was found in seven patients from different families, and in one healthy individual. In 3/5 familial dominant ASD cases, we identified an NKX2-5 mutation. In addition to the heterogeneity of NKX2-5 mutations, a diversity of phenotypes occurred within the families with predominant ASD and AV block. We did in fact identify a large prevalence of Sudden Cardiac Death (SCD) in families with truncating mutations, and two patients with coronary sinus disease. NKX2-5 is thus responsible for dominant familial ASD even in consanguineous populations, and a wide genetic and phenotypic diversity is characteristic of NKX2-5 mutations in the Lebanese population.
Highlights
NKX2-5 mutations are associated with different forms of congenital heart disease
NKX2-5 is responsible for dominant familial Atrial Septal Defect (ASD) even in consanguineous populations, and a wide genetic and phenotypic diversity is characteristic of NKX2-5 mutations in the Lebanese population
Studying L-Carnitine Deficiency (LCD), we have shown that a recurrent SLC22A5 mutation (p.R254X) occurs in 3 out of 8 families (37.5%)[25]
Summary
NKX2-5 mutations are associated with different forms of congenital heart disease. Despite the knowledge gained from molecular and animal studies, genotype-phenotype correlations in humans are limited by the lack of large cohorts and the incomplete assessment of family members. The in vitro characterization of NKX2-5 as a master regulator of the transcriptional activity of cardiac-specific genes like NPPA, and the early and broad expression of the gene in the heart was suggestive of a role in cardiogenesis. This was supported by the NKX2-5-/- knock-out mouse model which led to embryonic lethality at embryonic stage 10.5 (e10.5)[5]. One third of all reported missense mutations occur within the homeodomain region Functional studies of these proteins showed reduced DNA binding and/or transcriptional activity without affecting translocation to the nucleus[14,15,16,17,18]. Missense mutations in the non-DNA binding domains affect protein dimerization and interaction with DNA15 resulting in reduction of transcriptional synergistic activity with its partners[16,17,18]
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