Case#: 80-year-old male (I-1) diagnosed with HCM at approximately 50–55 years of age; familial case with his 3 adult offspring (II-2, II-3, and II-4)

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) associated with a heterozygous frameshift variant in MYBPC3.

FamilyInfo: The proband (I-1) is an elderly male with familial hypertrophic cardiomyopathy. Three adult offspring (II-2, II-3, and II-4) were evaluated and diagnosed with HCM based on interventricular septal hypertrophy. All four individuals carried the heterozygous MYBPC3 c.1042_1043insCGGCA variant. Individual II-2 experienced chest discomfort and palpitations, whereas II-3 and II-4 were asymptomatic at evaluation. These findings demonstrate segregation of the variant with HCM in the examined family members and are consistent with autosomal dominant inheritance.

ParentalTesting: NR – Genetic testing of the proband's parents was not reported but the variant was identified in his three adult offspring, supporting familial segregation.

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0002094 (Dyspnea); HP:0001635 (Congestive heart failure)

CaseHPOFreeText: The proband experienced chest tightness, dyspnea, and recurrent heart failure. Echocardiography demonstrated marked interventricular septal hypertrophy (39 mm during diastole and 41 mm during systole), a left atrial diameter of 44 mm, and a left ventricular ejection fraction of 60%. Additional findings included premature atrial beats, intraventricular conduction block, and NYHA functional class II. A history of hypertension was reported.

CaseNotHPOs: HP:0001279 (Syncope); HP:0001681 (Angina pectoris); HP:0001695 (Cardiac arrest)

CaseNotHPOFreeText: The proband had no reported history of syncope, angina pectoris, or cardiac arrest. No surgical myectomy was reported.

CasePreviousTesting: NR – Previous genetic testing was not reported but the proband underwent clinical cardiovascular evaluation, including electrocardiography, echocardiography, and BNP measurement.

Genotyping Method: Whole-genome sequencing (WGS) was performed using peripheral blood DNA on an Illumina NovaSeq 6000 platform with 150-bp paired-end reads and approximately 30× sequencing depth. Reads were aligned to the hs37d5 reference genome using BWA, and variants were annotated using ANNOVAR.

FunctionalAnalysis: Cardiac tissue from the proband was analyzed using RT-qPCR and Western blotting. MYBPC3 mRNA expression and cardiac myosin-binding protein C (cMyBP-C) abundance were significantly reduced (P < 0.05), supporting a haploinsufficiency mechanism. These findings do not independently establish the functional effect of the specific variant, and the Western blot analysis lacked biological replicates.

Variant: MYBPC3 NM_000256.3.1038_1042dup (p.Met348ThrfsTer4). Five-base-pair duplication resulting in a frameshift and premature termination codon. Reported in Zhang et al. (2025) as c.1042_1043insCGGCA.

ClinVar: No exact match identified for MYBPC3 c.1042_1043insCGGCA using the reported HGVS notation. ClinVar Variation ID not established.

CAID: CA273429

gnomAD: No exact matching entry identified in gnomAD v4 for MYBPC3 NM_000256.3:c.1038_1042dup (CA273429). Population allele frequency could not be established.

AdditionalInfo: The variant was identified in the proband and three adult offspring with interventricular septal thickening. The study proposed MYBPC3 haploinsufficiency as a disease mechanism based on reduced transcript and protein abundance. The available familial and functional evidence supports an association with HCM, although the specific variant's pathogenicity requires interpretation alongside the limitations of the study.