PO102 A Decade of Genetic Testing in Hypertrophic Cardiomyopathy: Insights from an Ultraperipheral Region

Abstract Hypertrophic cardiomyopathy (HCM) is an inherited cardiomyopathy usually caused by autosomal dominant variants in sarcomeric genes. This report summarises a 10-year retrospective study of HCM genetic testing in an ultraperipheral region. In our analysis we included all adult patients who underwent genetic testing for HCM between January 2015 and August 2025. Variants were classified according to the ACMG/AMP guidelines and the ClinGen Inherited Cardiomyopathy Expert Panel guidelines, with only likely pathogenic (LP) or pathogenic (P) findings considered as a positive test result. Patients with negative results, variants of uncertain significance, or phenocopies were excluded. Over this period, 140 patients with HCM underwent genetic testing, of whom 54 (39%) were found to carry a P or LP variant. Sixty-eight percent of cases were familial, representing a total of 15 families. Genetic analysis identified 9 distinct variants across 4 sarcomeric genes, 1 non-sarcomeric gene and 1 mitochondrial gene. Variants in MYH7 accounted for the majority of positive results. Most patients were single heterozygotes, with 2 exceptions: 1 patient was homozygous for a TNNT2 variant, and another harboured variants in both MYH7 and TNNT2. Regarding the MYH7, we identified 2 missense variants: the P c.1750G>C (p.Gly584Arg) detected in 39 patients from 11 families and the P/LP c.2389G>A (p.Ala797Thr), found in 4 patients from 2 families. Two LP variants in the MYBPC3 gene were detected: a missense variant, c.1484G>A (p.Arg495Gln), with 1 familial transmission; and 1 sporadic case, a multiexon deletion involving at least exons 26 to 32. A LP TNNI3 variant (c.586G>T, p.Asp196Tyr) was also identified in one patient. A consanguineous family with 4 affected members was found to carry the TNNT2 missense variant c.842A>T (p.Asn281Ile). One individual also carried the MYH7 variant c.1750G>C (p.Gly584Arg), representing a case of composite digenic heterozygosity. The coexistence of 2 variants was associated with earlier disease onset, greater atrial dilation but less hypertrophy compared to relatives carrying only one variant. Beyond the sarcomeric spectrum, we identified a rare truncating variant in the ALPK3 gene (c.3292G>T,p.Glu1098*;P) in a patient presenting with high-risk phenotypic features, including apical aneurysm, impaired systolic function and sustained ventricular arrhythmia. Additionally, we detected a homoplasmic LP mitochondrial variant in MT-TI (m.4300A>G) in a 40-year-old male with severe HCM and an implantable cardioverter-defibrillator (ICD). Given the maternal inheritance pattern and a family history of HCM in the mother and ICD implantation in a maternal uncle, this variant could provide a plausible explanation for the phenotype. In conclusion, genetic testing for HCM in our ultraperipheral region has revealed a diverse and unique spectrum of variants, illustrating the genetic heterogeneity and clinical complexity present in our geographically isolated population.