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.
Background - Cardiac troponin I ( TNNI3 ) gene mutations account for 3% of hypertrophic cardiomyopathy and carriers have a heterogeneous phenotype, with increased risk of sudden cardiac death. Only one mutation (p.Arg21Cys) has been reported in the N-terminus of the protein. In model organisms, it impairs protein kinase A phosphorylation, increases calcium sensitivity, and causes diastolic dysfunction. The phenotype of this unique mutation in hypertrophic cardiomyopathy patients remains unknown. Methods - We sequenced 29 families with hypertrophic cardiomyopathy enriched for pediatric-onset disease and identified 5 families with the TNNI3 p.Arg21Cys mutation. Using cascade screening, we studied the clinical phenotype of 57 individuals from the 5 families with TNNI3 p.Arg21Cys-related cardiomyopathy. We performed survival analysis investigating the age at first sudden cardiac death in carriers of the mutation. Results - All five families with TNNI3 p.Arg21Cys were from south Lebanon. TNNI3 p.Arg21Cys-related cardiomyopathy manifested a malignant phenotype - sudden cardiac death occurred in 30 (53%) of 57 affected individuals at median age of 22.5 years. In select carriers without left ventricular hypertrophy on echocardiogram, sudden cardiac death occurred, myocyte disarray was found on autopsy heart, and tissue doppler and cardiac magnetic resonance imaging identified subclinical disease features such as diastolic dysfunction and late-gadolinium enhancement. Conclusions - The TNNI3 p.Arg21Cys mutation has a founder effect in south Lebanon and causes malignant hypertrophic cardiomyopathy with early sudden cardiac death even in the absence of hypertrophy. Genetic diagnosis with this mutation may be sufficient for risk stratification for sudden cardiac death.
Hypertrophic Cardiomyopathy (HCM) occurs in 1 of every 500 people and has a wide phenotypic variability. In the majority of cases, HCM is caused by known mutations in genes that code for sarcomere proteins. Although gene testing is widely available for HCM, knowing the phenotype caused by different gene mutations remains a challenging task. We recruited 28 families with HCM, of which 19 (67.8%) have at least one patient with pediatric onset. Index patients from 20 families received targeted sequencing for a panel of genes including TNNI3 , and 7 families received Sanger sequencing for the TNNI3 . We identified a missense mutation p.R21C in TNNI3 segregating with HCM in four families from South Lebanon. Through cascade screening, we identified 30 patients from the four families; twenty of them (67%) had a clinical diagnosis of HCM with a median age of 37 years, while 9 (30%), with a median age 21 years, had no evidence of HCM on echocardiography. An additional 27 members of the families had evidence of HCM, including 22 with SCD in the setting of no past medical history, and their carrier status for p.R21C was implied from the pedigrees. Survival analysis for 57 HCM patients with the mutation revealed a markedly decreased age at first adverse event as compared to 47 HCM patients with the MYBPC3 p.R502W mutation. Founder mutations in HCM that cause a severe phenotype are uncommon. The p.R21C mutation in TNNI3 is the first HCM mutation described in the Lebanese population and has a founder effect in South Lebanon. Early and more frequent screening with different imaging modalities as well as tailored management might be warranted for carriers of this mutation.
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