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    Next-generation sequencing identifies pathogenic and modifier mutations in a consanguineous Chinese family with hypertrophic cardiomyopathy
    2
    1. ClingenBaseline 21 Oct 2026
      The index patient (V-1)

      CaseV-1: Male, 27 yrs onset, China, Asian

      CasePresentingHPOs: HP:0002875, HP:0001639, HP:0002027, HP:0001712, HP:0001671, HP:0032092, HP:0001645 (Exertional dyspnea, Hypertrophic cardiomyopathy, Abdominal pain, Left ventricular hypertrophy, Abnormal cardiac septum morphology, Left ventricular outflow tract obstruction, Sudden cardiac death)

      HPOsFreeText: N/A

      CaseNotHPOs: N/A

      NotHPOsFreeText: N/A

      CaseAddInfo: Family is consanguineous, The MYPBC3 variant was the only one to segregate with the disease, with the CACNB2 variant also being present in individuals with "severe" forms of the disease. CACNB2+ MYH7- individuals showed no symptoms of cardiomyopathy, supporting a modifying effect leading to the clinical heterogeneity of this family, MYBPC3 variant leads to a premature termination and a loss of 49 amino acids which is predicted to undergo NMD but is also associated with incomplete penetrance

      CasePreviousTesting: Marked hypertrophic septum (27  mm) and a left-ventricular outflow obstruction (LVOTO) of 32  mmHg, Clinical features in Table 1, No members showed Brugada syndrome phenotypes, Proband also has polymorphisms in TGFB1 and AKAP9 but no other affected family member contains them suggesting a benign pathogenicity

      CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. PCR amplification was performed and sanger sequencing was performed for MYH7 and MYPBC3 mutations. After positive confirmation of the MYBPC3 mutation, RAAS genes were genotyped for a possible modifying effect. Negative findings led to a targeted NGS for the index patient using all known 104 causing/closely related genes of cardiomyopathy and chanelopathy. These variants were then filtered and analyzed for pathogenicity and confirmed in family members via Sanger sequencing.

      Variant: NM_201597.3:c.1598C>T (p.Ser533Leu)

      ClinVar: 190730 https://www.ncbi.nlm.nih.gov/clinvar/variation/190730/

      gnomAD: 0.01004, https://gnomad.broadinstitute.org/variant/10-18828340-C-T

      MultipleGeneVariants

      MYBPC3 Variant

      Variant: NM_000256.3(MYBPC3):c.3624del (p.Lys1209fs)

      ClinVar: 42727 https://www.ncbi.nlm.nih.gov/clinvar/variation/42727/

      gnomAD: 0.00005140, https://gnomad.broadinstitute.org/variant/11-47354119-TG-T

      DSP Variant

      Variant: NM_004415.4(DSP):c.3923G>A (p.Arg1308Gln)

      ClinVar: 178028 https://www.ncbi.nlm.nih.gov/clinvar/variation/178028/

      gnomAD: 0.01680, https://gnomad.broadinstitute.org/variant/6-7580346-G-A

      Individual Variant GenotypingMethod CaseInfo inferred_gene_hgnc:7551 inferred_gene_source:RefSeq UNC Biocuration Core
    2. ClingenBaseline 21 Oct 2026
      The index patient (V-1)

      CaseV-1: Male, 27 yrs onset, China, Asian

      CasePresentingHPOs: HP:0002875, HP:0001639, HP:0002027, HP:0001712, HP:0001671, HP:0032092, HP:0001645 (Exertional dyspnea, Hypertrophic cardiomyopathy, Abdominal pain, Left ventricular hypertrophy, Abnormal cardiac septum morphology, Left ventricular outflow tract obstruction, Sudden cardiac death)

      HPOsFreeText: N/A

      CaseNotHPOs: N/A

      NotHPOsFreeText: N/A

      CaseAddInfo: Family is consanguineous, The MYPBC3 variant was the only one to segregate with the disease, with the CACNB2 variant also being present in individuals with "severe" forms of the disease. CACNB2+ MYH7- individuals showed no symptoms of cardiomyopathy, supporting a modifying effect leading to the clinical heterogeneity of this family, MYBPC3 variant leads to a premature termination and a loss of 49 amino acids which is predicted to undergo NMD but is also associated with incomplete penetrance

      CasePreviousTesting: Marked hypertrophic septum (27  mm) and a left-ventricular outflow obstruction (LVOTO) of 32  mmHg, Clinical features in Table 1, No members showed Brugada syndrome phenotypes, Proband also has polymorphisms in TGFB1 and AKAP9 but no other affected family member contains them suggesting a benign pathogenicity

      CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. PCR amplification was performed and sanger sequencing was performed for MYH7 and MYPBC3 mutations. After positive confirmation of the MYBPC3 mutation, RAAS genes were genotyped for a possible modifying effect. Negative findings led to a targeted NGS for the index patient using all known 104 causing/closely related genes of cardiomyopathy and chanelopathy. These variants were then filtered and analyzed for pathogenicity and confirmed in family members via Sanger sequencing.

      Variant: NM_201597.3:c.1598C>T (p.Ser533Leu)

      ClinVar: 190730 https://www.ncbi.nlm.nih.gov/clinvar/variation/190730/

      gnomAD: 0.01004, https://gnomad.broadinstitute.org/variant/10-18828340-C-T

      MultipleGeneVariants

      MYBPC3 Variant

      Variant: NM_000256.3(MYBPC3):c.3624del (p.Lys1209fs)

      ClinVar: 42727 https://www.ncbi.nlm.nih.gov/clinvar/variation/42727/

      gnomAD: 0.00005140, https://gnomad.broadinstitute.org/variant/11-47354119-TG-T

      DSP Variant

      Variant: NM_004415.4(DSP):c.3923G>A (p.Arg1308Gln)

      ClinVar: 178028 https://www.ncbi.nlm.nih.gov/clinvar/variation/178028/

      gnomAD: 0.01680, https://gnomad.broadinstitute.org/variant/6-7580346-G-A

      Individual Variant GenotypingMethod CaseInfo inferred_gene_hgnc:7551 inferred_gene_source:RefSeq UNC Biocuration Core
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    ncbi.nlm.nih.gov/pmc/articles/PMC5478307/