39‐year‐old man presented in 1998 with shortness of breath during exertion
Case#: Pedigree III:2; male; HCM diagnosed clinically at age 39 (1998); heart transplant after progression to end-stage heart failure
DiseaseAssertion: Hypertrophic cardiomyopathy (HCM), progressed to end-stage heart failure with systolic dysfunction
FamilyInfo: No family history of heart disease reported at diagnosis; no known consanguinity. Parents deceased and unavailable for testing. 12 relatives genotyped: one brother (III:3) homozygous, seven first- and second-degree relatives heterozygous. All heterozygotes have normal ECG, normal echo, and no cardiac symptoms. Three children of generation IV (IV:7, IV:8, IV:9) still awaiting results.
ParentalTesting: Not performed; both parents deceased. Absence of consanguinity stated but not genetically confirmed; parental phase therefore inferred rather than tested.
CasePresentingHPOs: HP:0001639; HP:0002094 (Dyspnea); HP:0001658; HP:0001678
CaseHPOFreeText: Exertional dyspnea at age 39 with systolic murmur; IVS 26 mm, posterior wall >16 mm, LVOT peak velocity 2.8 m/s. Pacemaker 1999, extracted 2010 for infection. 2013 circumflex occlusion treated with stent (cholesterol 6.8 mmol/L, LDL 4.6 mmol/L; former smoker). Septum 27 mm, moderate systolic dysfunction, NSVT on Holter → ICD. 2014 AF with severe dyspnea; on beta-blocker, ACE inhibitor, and aldosterone antagonist. 2016 VO₂max 14 mL/kg/min; LVEDP 24 mmHg rising to 38 with exercise, pulmonary pressure 56/27 rising to 70/… systolic. Biopsy: moderate interstitial fibrosis, focal hypertrophy and atrophy, no infiltrative disease.
CaseNotHPOs: HP:0000822; HP:0000819
CaseNotHPOFreeText: BP normal throughout, no hypertension. No storage or infiltrative disease on biopsy. Spirometry normal. Narrow QRS, so CRT not indicated.
CasePreviousTesting: 84-gene cardiomyopathy NGS panel (MYBPC3 100% coverage); MLPA confirmed true homozygosity rather than hemizygous deletion; Sanger cascade in 12 relatives.
Genotyping Method: NGS panel followed by MLPA confirmation of homozygosity; Sanger for family cascade.
FunctionalAnalysis: None performed. Biopsy showed interstitial fibrosis with hypertrophy and atrophy, no infiltrative disease. Dominant-negative mechanism proposed, untested.
Variant: MYBPC3 NM_000256.3:c.2618C>A (p.Pro873His); homozygous missense; C7 domain. (Paper writes "c.2618 G>A" once, C>A is correct.)
ClinVar: Not stated; conflicting interpretations noted in the literature. Pepper please verifiy for me!
CAID: N/A
gnomAD: AF 0.00006781 (14/206,446; 13/97,288 European non-Finnish) per the authors.
AdditionalInfo: ACMG Class 2 (likely pathogenic) heterozygous. Authors argue homozygosity drove progression to end-stage failure; alternative triggers considered, prior myocarditis (1989) and the 2013 infarct; but judged insufficient to explain severity.
PMID: 29663722 Gene: MYBPC3 HGNC: HGNC:7551