RESUMEN
AIM: Hypertrophic cardiomyopathy (HCM) exhibits genetic heterogeneity that is dominated by variation in eight sarcomeric genes. Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM. METHODS AND RESULTS: We sequenced known and putative HCM genes in a new large prospective HCM cohort (n = 804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n = 6179), previously published HCM cohorts and reference population samples from the exome aggregation consortium (ExAC, n = 60 706) to assess variation in 31 genes implicated in HCM. We found no significant excess of rare (minor allele frequency < 1:10 000 in ExAC) protein-altering variants over controls for most genes tested and conclude that novel variants in these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, we integrated HCM gene sequence data with aggregated pedigree and functional data and suggest a means of assessing gene pathogenicity in HCM using this evidence. CONCLUSION: We show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority of patients.
Asunto(s)
Cardiomiopatía Hipertrófica/genética , Genes/genética , Sarcómeros/genética , Estudios de Casos y Controles , Femenino , Variación Genética , Humanos , Masculino , Mutación/genética , Estudios ProspectivosRESUMEN
We report a young man who has persistent truncus arteriosus (TA), severe truncal regurgitation and unilateral pulmonary hypertension. Our patient had palliative main pulmonary artery (PA) banding done during infancy that was not followed by definitive corrective surgery. Unilateral irreversible left sided pulmonary hypertension developed due to migration of the PA band to the right PA. The patient presented to us with infective endocarditis of the truncal valve. This had resolved with medical treatment. Discussion was made on general management of TA and specific difficult management issues of palliated TA in adult, as found in our patient.