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.

Case#: Patient 5; 47-year-old male; identical twin (Patient 6) with less severe hypertrophy

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)

FamilyInfo: Patient has a monozygotic twin brother (Patient 6), who is also affected by HCM. Both individuals carry the same pathogenic MYBPC3 nonsense variant, NM_000256.3.787G>T (p.Gly263Ter). However, Patient 5 demonstrates more pronounced left ventricular hypertrophy than Patient 6. Cardiac magnetic resonance imaging (CMR) revealed maximum left ventricular wall thicknesses of 28 mm and 19 mm, respectively.

ParentalTesting: NR – Parental genetic testing results were not explicitly reported for Patient 5 or his monozygotic twin brother (Patient 6)

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0001712 (Left ventricular hypertrophy)

CaseHPOFreeText: Patient diagnosed with hypertrophic cardiomyopathy (HCM), characterized by substantial left ventricular hypertrophy. Echocardiography performed in 2022 demonstrated a maximum left ventricular wall thickness of 18 mm, while cardiac magnetic resonance imaging (CMR) showed a maximum thickness of 28 mm.

CaseNotHPOs: HP:0032092 (Left ventricular outflow tract obstruction); HP:0000822 (Hypertension)

CaseNotHPOFreeText: Patient 5 did not exhibit left ventricular outflow tract obstruction (LVOTO), even though having substantial left ventricular hypertrophy (max wall thickness of 28 mm). The study also explicitly reports that none of the six patients, including Patient 5, had hypertension.

CasePreviousTesting: Patient 5 underwent clinical cardiac evaluation, including echocardiography, cardiac magnetic resonance imaging (CMR), and electrocardiography (ECG).

Genotyping Method: Genetic analysis was performed using next-generation sequencing (NGS) with Ion Torrent technology for index patients and targeted Sanger sequencing for familial screening. The study reports that recent index cases associated with Patients 5–6 were evaluated using an expanded 195-gene NGS panel, as described in Supplementary Table S2. The pathogenic MYBPC3 variant NM_000256.3.787G>T (p.Gly263Ter) was identified in both monozygotic twins. However, the article does not explicitly specify whether Patient 5 underwent the full NGS panel or targeted familial testing. Monozygosity was independently confirmed using the PowerPlex 16 HS System.

FunctionalAnalysis: NR – No patient-specific functional assays were reported for Patient 5 (computational evidence supporting a deleterious effect, absence from the ESP, 1000 Genomes, and ExAC population databases, and segregation of the variant among affected family members).

Variant: MYBPC3 NM_000256.3:c.787G>T p.Gly263Ter; Premature termination codon; Nonsense; Autosomal dominant; Clinical significance: Pathogenic (1 submission). Review status: 1 out of 4 stars (criteria provided, single submitter).

ClinVar: 1460339

CAID: CA380333920

gnomAD: gnomAD: GRCh38 variant 11-47347891-C-A. African/African American population: AC = 0; AF = 0.0000.

AdditionalInfo: Patient’s monozygotic twin brother (Patient 6) carries the same pathogenic variant but exhibits less pronounced left ventricular hypertrophy. The authors suggest that additional environmental or epigenetic modifiers may influence disease severity, although no specific modifying mechanism was experimentally established.