Novel compound heterozygous mutations in the KLHL24 gene (c.532del and c.1514A>G) caused severe, early-onset recessive hypertrophic cardiomyopathy in two siblings.
Case Report (n=4)
No
This case expands the genetic spectrum of hypertrophic cardiomyopathy by identifying novel compound heterozygous mutations in KLHL24 that cause a severe, early-onset recessive phenotype.
Hypertrophic cardiomyopathy (HCM) is a common hereditary cardiovascular disease, but the genetic etiology of nearly 50% of cases remains unclear. This case report describes two siblings in a non-consanguineous family who presented with HCM caused by novel compound heterozygous mutations in the KLHL24 gene. The proband, a 30-year-old male, initially presented with recurrent syncope at the age of 20, leading to the implantation of a permanent pacemaker. Serial clinical evaluations showed progressive left ventricular hypertrophy, diastolic dysfunction, and a gradual decline in left ventricular ejection fraction. His 20-year-old younger brother, identified through family screening, had no obvious clinical symptoms but exhibited severe biventricular hypertrophy, significantly elevated levels of B-type natriuretic peptide and high-sensitivity troponin T, indicating subclinical myocardial injury and heart failure. Genetic testing confirmed that both siblings carried two heterozygous mutations in KLHL24 : a frameshift mutation (c.532del:p.His178Ilefs*66) in the BACK domain and a missense mutation (c.1514AG:p.Tyr505Cys) in the KELCH domain. Family verification revealed a recessive inheritance pattern, with each parent carrying one of the mutations. Bioinformatics analysis predicted the pathogenicity of these mutations, which have not been previously reported. This case expands the genetic spectrum of HCM and highlights the importance of genetic testing and family screening for KLHL24 -related cardiomyopathies. Regular cardiac monitoring is crucial for carriers of such mutations to enable early intervention and improve outcomes.
Zhou et al. (2026) conducted a case report in Hypertrophic cardiomyopathy (n=4). Whole-exome sequencing was evaluated. Novel compound heterozygous mutations in the KLHL24 gene (c.532del and c.1514A>G) caused severe, early-onset recessive hypertrophic cardiomyopathy in two siblings.