Case#: Single proband ; 63-year-old female; palpitations at presentation July 2025; HCM diagnosis established at age 63
DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) complicated by apical left ventricular aneurysm and mid-ventricular obstruction
FamilyInfo: No family history of cardiac disease or sudden cardiac death at a young age reported. Both parents deceased (one of cancer, one of natural causes at age 92), neither with reported cardiovascular disease; proband has no siblings. Only first-degree relative is her son, who carries the KCNJ5 c.464G>A variant but not the MYBPC3 c.278delA variant, and has a normal echocardiogram with no myocardial hypertrophy. No pedigree beyond the son (Fig. 3B).
ParentalTesting: Not performed; both parents deceased, no DNA available; authors state a valid familial segregation analysis could not be performed. Only one family member (son) was available for cascade Sanger screening.
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0001649 (Tachycardia), palpitations; HP:0001712 (Left ventricular hypertrophy).
CaseNotHPOFreeText: No history of hypertension, diabetes, or hyperlipidemia.
Phenocopies excluded: no extra-cardiac manifestations of Fabry disease and GLA testing negative; cardiac amyloidosis excluded (no apical sparing, normal serum free light chains, negative serum protein electrophoresis and immunofixation); no significant coronary stenosis on coronary CT angiography. No QT prolongation or features of Andersen–Tawil syndrome on ECG.
CasePreviousTesting: Whole exome sequencing identified both variants; all rare and known variants validated by Sanger sequencing, with cascade Sanger screening in available one family member. No prior genetic testing reported before this episode.
Genotyping Method: Targeted region capture with next-generation high-throughput sequencing (whole exome, exonic plus flanking regions); variants confirmed by bidirectional Sanger sequencing. Cascade screening by Sanger in the son. MYBPC3 variant absent from 1000 Genomes, ESP6500, ExAC, and the Besuper local database. KCNJ5 variant absent from 1000 Genomes and ESP6500, ExAC frequency, absent from local Basenhall controls.
FunctionalAnalysis: None performed; authors list absence of functional studies and lack of mRNA-level validation as limitations. MYBPC3 frameshift predicted to trigger nonsense-mediated decay.
Variant: MYBPC3 NM_000256.3:c.278delA (p.Lys93ArgfsTer3); heterozygous; exon 2; novel, not in ClinVar or HGMD; classified Likely Pathogenic by ACMG (PVS1, PM2). Second variant: KCNJ5 NM_000256.3:c.464G>A (p.Arg155Gln); heterozygous; exon 2; novel, not in ClinVar or HGMD; classified VUS (PM2, PP3). Note the paper's KCNJ5 accession is written as NM_000256.3, which is the MYBPC3 transcript, most likely a typo in the article Pepper please conform for me the correct KCNJ5 accession
ClinVar: No ClinVar record for either variant; nearby KCNJ5 missense variants c.451G>A, c.452G>A, c.470T>G, and c.473C>G are documented as pathogenic/likely pathogenic for long QT syndrome or aldosteronism, and downstream frameshift/nonsense variants at the MYBPC3 locus are classified pathogenic or likely pathogenic.
CAID:Not found.
gnomAD: No allele frequency available, so no MAF to report.
PMID: 42428486
Gene: MYBPC3
HGNC: HGNC:7551
AdditionalInfo:Single-case report, no case numbering system used. Treated with dapagliflozin, metoprolol, rivaroxaban, and recombinant human BNP for 13 days, discharged on the first three; mexiletine added at 1-week follow-up for persistent palpitations. ICD recommended but declined due to financial constraints; 3-month follow-up showed good adherence with occasional palpitations and no serious arrhythmic events. Authors conclude MYBPC3 c.278delA is likely pathogenic for HCM, while the KCNJ5 variant shows no clinical phenotype in the proband or her son and may be incidental or a modifier.