Case III.7, a 38-year-old female from family A, was diagnosed with HCM at the age of 26 following dyspnea. Family history was positive for HCM and occurrence of SCD in four family members (Fig. 1a).
Case#: Family A, Case III.7; 38-year-old female; diagnosed at age 26
DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)
FamilyInfo: Positive family history of HCM and SCD. Mother (II.4), brother (III.8), uncle (II.7), and cousin (III.11) died of SCD at ages 55, 26, 57, and 24, respectively. The proband's three children (IV.3, IV.4, IV.5) were homozygous for the MYL3 variant but had normal echocardiograms at ages 18, 13, and 6.
ParentalTesting: Supplementary Table S2 reports parental testing supportive of PM3 (variants in trans). However, DNA was unavailable for the proband's deceased mother (II.4), and individual parental genotypes were not specified in the supplementary genetic findings.
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0002094 (Dyspnea); HP:0001653 (Mitral regurgitation); HP:0001712 (Left ventricular hypertrophy)
CaseHPOFreeText: HCM diagnosed at age 26 following dyspnea. At age 38, echocardiography showed reverse-curvature HCM with asymmetric left ventricular hypertrophy involving anterior, anterolateral, and lateral segments; maximum wall thickness 22 mm; severe mitral regurgitation; LVEF 55%; E/e' ratio 16.4; resting LVOT gradient 9 and post-maneuver gradient 30. Holter monitoring showed no arrhythmias (Supplementary Results, pp. 5–6; Table S1; Fig. S1).
CaseNotHPOs: HP:0001324 (Muscle weakness)
CaseNotHPOFreeText: Neurological evaluation revealed normal muscle tone, strength 5/5 in upper and lower limbs, no distal or proximal muscle atrophy or fasciculations, and normal creatine phosphokinase levels.
CasePreviousTesting: Exome sequencing was performed; no rare, likely pathogenic variants in other cardiomyopathy-associated genes identified after filtering.
Genotyping Method: Exome sequencing identified the MYL3 variant; bidirectional Sanger sequencing validated the variant. Familial genotyping supported recessive inheritance (Fig. 1a).
FunctionalAnalysis: Zebrafish cmlc1 knockdown and rescue experiments were performed using human MYL3 RNA carrying c.170C>A (p.Ala57Asp). Mutant RNA showed partial phenotypic rescue but no statistically significant improvement in ventricular contractility compared with knockdown alone (Fig. 2a-d).
Variant: MYL3 NM_000258.2:c.170C>A (p.Ala57Asp); homozygous missense variant; rs139794067
ClinVar: 43121
CAID: CA013575
gnomAD: Allele frequency 0.000163 (0 homozygotes), as reported in Supplementary Table S2.
AdditionalInfo: Family A, Case III.7. Clinical characteristics and genetic findings described in the Results section (Fig. 1a and 1d-e). Functional experiments described in Fig. 2. The authors classified c.170C>A as a variant of uncertain significance (VUS).