Abstract 4365022: Identification of a Novel Genetic Mutation in Hypertrophic Cardiomyopathy

Abstract

Background: Mutations in various genes encoding sarcomeric proteins account for 50–60% of familial hypertrophic cardiomyopathy (HCM) cases. However, the molecular pathogenesis underlying the disease in approximately one-third of patients remains unidentified. Case Summary: A 15-year-old Caucasian female with a history of Von Willebrand disease and anxiety presented with intermittent palpitations. Family history was notable for HCM and sudden cardiac arrest requiring implantable cardioverter-defibrillators (ICDs) in her father and uncle. Physical exam revealed a grade I systolic murmur. ECG showed left ventricular hypertrophy, left axis deviation, pathological Q waves, ST elevation in the inferior leads and T wave inversion in the anterolateral leads. Echocardiography revealed severe asymmetric septal hypertrophy (2.7 cm, Z score +9.7), preserved EF (68.5%), and moderate diastolic dysfunction. Genetic testing identified a variant of uncertain significance in exon 7 of the FHL1 gene (c.755G>A, heterozygous), resulting in a cysteine-to-tyrosine substitution at codon 252 (p.Cys252Tyr); and exon 43 of the ANK2 gene (c.11454C>A, heterozygous), leading to a serine-to-arginine substitution at codon 3818 (p.Ser3818Arg). Cardiac MRI confirmed HCM with a reverse curvature phenotype, 2.4 cm septal thickness, and 9.6% total fibrosis of the left ventricular mass. Ambulatory monitoring detected episodes of non-sustained ventricular tachycardia. Stress echo demonstrated a peak left ventricular outflow tract gradient of 15 mmHg. She was started on metoprolol for dyspnea and referred for electrophysiologic evaluation. Cardiac catheterization confirmed a non-obstructive HCM phenotype with elevated LV end-diastolic pressure. Given her arrhythmia history and family background, she is scheduled for ICD placement. Discussion: We identified a novel FHL1 variant in an adolescent with HCM, highlighting the evolving genetic landscape beyond core sarcomeric genes. This underscores the need for accurate phenotyping, vigilant reporting, and ongoing re-evaluation of variants to inform risk stratification, especially in pediatric populations. Take-home Messages: Detailed case reporting of novel genetic variants identified in HCM and longitudinal follow-up are key to improving genetic interpretation and guiding individualized care.