Case#: Patient 1; 89-year-old female; identical twin (Patient 2) with mild HCM
DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) associated with the pathogenic MYBPC3 nonsense variant NM_000256.3.787G>T (p.Gly263Ter). Patient 1 is an 89-year-old female with severe symptomatic obstructive HCM, previously requiring septal ablation. Her maximum reported left ventricular wall thickness was 29 mm by echocardiography in 2015.
FamilyInfo: Patient 1 belongs to a family with hereditary hypertrophic cardiomyopathy associated with the MYBPC3 p.Gly263Ter founder variant. Her monozygotic twin sister (Patient 2) carries the same pathogenic variant but has a substantially milder HCM phenotype, with a maximum left ventricular wall thickness of 13 mm and no reported symptoms at an advanced age. The twin pair belongs to the extended family that also includes Patients 3 and 4, another pair of monozygotic twins carrying the same variant. The pedigree documents additional affected relatives and a history of sudden death, although not all family members have confirmed genetic testing.
ParentalTesting: NR – The family pedigree supports familial occurrence of hypertrophic cardiomyopathy, but the specific parent from whom Patient 1 inherited the MYBPC3 p.Gly263Ter variant cannot be conclusively determined from the available genetic testing data. Her monozygotic twin sister (Patient 2) was confirmed to carry the same variant.
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0002094 (Dyspnea); HP:0001712 (Left ventricular hypertrophy); HP:0032092 (Left ventricular outflow tract obstruction)
CaseHPOFreeText: Echocardiography documented a maximum left ventricular wall thickness of 29 mm in 2015. She previously experienced significant dyspnea, with symptoms classified as NYHA III/IV, associated with severe left ventricular outflow tract obstruction. She underwent septal ablation, which improved her clinical symptoms. At the time of the study, she remained minimally symptomatic.
CaseNotHPOs: HP:0000822 (Hypertension)
CaseNotHPOFreeText: Explicitly reported that Patient 1 did not have hypertension. No additional negative phenotypic findings were specifically documented for this patient.
CasePreviousTesting: Previous cardiac evaluations included echocardiography demonstrating severe left ventricular hypertrophy, with a maximum wall thickness of 29 mm in 2015, and clinical identification of severe left ventricular outflow tract obstruction. The patient underwent septal ablation for symptomatic obstructive hypertrophic cardiomyopathy. Electrocardiographic findings were also evaluated following the procedure. The article does not provide a detailed history of genetic testing performed before the reported familial MYBPC3 investigation.
Genotyping Method: Genetic testing of index cases was performed using targeted next-generation sequencing (NGS) with Ion Torrent technology. The earlier index cases were evaluated using a nine-gene sarcomeric panel, including MYBPC3. Familial screening for the MYBPC3 NM_000256.3.787G>T (p.Gly263Ter) variant was performed using Sanger sequencing on an ABI3130XL sequencer. Monozygosity of the twin pairs was independently confirmed using the PowerPlex 16 HS System, which analyzes 16 microsatellite markers. Article does not specify whether Patient 1's individual MYBPC3 genotype was initially established through NGS or other targeted Sanger sequencing.
FunctionalAnalysis: The MYBPC3 NM_000256.3.787G>T (p.Gly263Ter) variant is a nonsense mutation that introduces a premature termination codon. The authors classified this founder variant as pathogenic based on its predicted loss-of-function effect, absence from the population reference databases examined, and segregation among affected family members. Computational evidence supported a deleterious effect. However, no patient-specific functional assays measuring MYBPC3 RNA expression, protein abundance, or protein function were reported in this study. The molecular consequences were inferred from the variant type and existing evidence rather than directly demonstrated experimentally in Patient 1.
Variant: MYBPC3 NM_000256.3:c.787G>T p.Gly263Ter; Nonsense; Autosomal dominant; Clinical significance: Pathogenic (1 submission). Review status: 1 out of 4 stars (criteria provided, single submitter).
ClinVar: 1460339
CAID: CA380333920
gnomAD: GRCh38 variant 11-47347891-C-A. African/African American population: AC = 0; AF = 0.0000.
AdditionalInfo: Patient’s monozygotic twin sister (Patient 2) carries the same variant but exhibits a substantially milder clinical phenotype. Patient 1 had a maximum left ventricular wall thickness of 29 mm in 2015, severe left ventricular outflow tract obstruction, and symptomatic dyspnea requiring septal ablation. In contrast, Patient 2 had a maximum wall thickness of 13 mm and was asymptomatic. This illustrates variable expressivity of MYBPC3-associated hypertrophic cardiomyopathy, even among genetically identical individuals. The authors discuss environmental and epigenetic factors as possible contributors to phenotypic variability, although no specific modifying mechanism was experimentally demonstrated in these patients.