Phenotypic variations in carriers of predicted protein-truncating genetic variants in MYBPC3: an autopsy-based case series

Nori Williams, Robert W. Marion, Thomas V. McDonald, Dawei Wang, Bo Zhou, Lucy S. Eng, Sung Yon Um, Ying Lin, Kevin Ruiter, Lisa Rojas, Barbara A. Sampson, Yingying Tang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Our aim is to characterize predicted protein-truncating variants (PTVs) in MYBPC3, the gene most commonly associated with hypertrophic cardiomyopathy (HCM), found in a series of autopsied HCM cases after sudden unexpected cardiac death. All cases underwent death scene investigation, gross and microscopic autopsies, toxicological testing, a review of medical records, and a molecular analysis of 95 cardiac genes. We found four pathogenic PTVs in MYBPC3 among male decedents. All variants were previously submitted to ClinVar without phenotype details. Two PTVs were located in the cardiac-specific myosin S2-binding (M) motif at the N-terminus of the MYBPC3-encoded cMyBP-C protein, and two PTVs were in the non-cardiac-specific C-terminus of the protein. The carriers of two cardiac-specific M-motif PTVs died at age 38 years; their heart weight (HW, g) and body mass index (BMI, kg/m2) ratio were 34.90 (890/25.5) and 23.56 (980/41.6), respectively. In contrast, the carriers of two non-cardiac-specific C-terminal PTVs died at age 57 and 67 years, respectively; their HW and BMI ratio were 14.71 (450/30.6) and 13.98 (600/42.9), respectively. A detailed three-generation family study was conducted in one case. This study showed age-at-death variations among MYBPC3 PTVs carriers in adult males.

Original languageEnglish (US)
Pages (from-to)30-33
Number of pages4
JournalCardiovascular Pathology
Volume37
DOIs
StatePublished - Nov 1 2018

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Autopsy
Carrier Proteins
Protein C
Hypertrophic Cardiomyopathy
Proteins
Cardiac Myosins
Amino Acid Motifs
Sudden Cardiac Death
Toxicology
Genes
Medical Records
Body Mass Index
Phenotype
Weights and Measures

Keywords

  • Hypertrophic cardiomyopathy
  • MYBPC3
  • Sudden death
  • Truncating variants

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Phenotypic variations in carriers of predicted protein-truncating genetic variants in MYBPC3 : an autopsy-based case series. / Williams, Nori; Marion, Robert W.; McDonald, Thomas V.; Wang, Dawei; Zhou, Bo; Eng, Lucy S.; Um, Sung Yon; Lin, Ying; Ruiter, Kevin; Rojas, Lisa; Sampson, Barbara A.; Tang, Yingying.

In: Cardiovascular Pathology, Vol. 37, 01.11.2018, p. 30-33.

Research output: Contribution to journalArticle

Williams, N, Marion, RW, McDonald, TV, Wang, D, Zhou, B, Eng, LS, Um, SY, Lin, Y, Ruiter, K, Rojas, L, Sampson, BA & Tang, Y 2018, 'Phenotypic variations in carriers of predicted protein-truncating genetic variants in MYBPC3: an autopsy-based case series', Cardiovascular Pathology, vol. 37, pp. 30-33. https://doi.org/10.1016/j.carpath.2018.09.001
Williams, Nori ; Marion, Robert W. ; McDonald, Thomas V. ; Wang, Dawei ; Zhou, Bo ; Eng, Lucy S. ; Um, Sung Yon ; Lin, Ying ; Ruiter, Kevin ; Rojas, Lisa ; Sampson, Barbara A. ; Tang, Yingying. / Phenotypic variations in carriers of predicted protein-truncating genetic variants in MYBPC3 : an autopsy-based case series. In: Cardiovascular Pathology. 2018 ; Vol. 37. pp. 30-33.
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T2 - an autopsy-based case series

AU - Williams, Nori

AU - Marion, Robert W.

AU - McDonald, Thomas V.

AU - Wang, Dawei

AU - Zhou, Bo

AU - Eng, Lucy S.

AU - Um, Sung Yon

AU - Lin, Ying

AU - Ruiter, Kevin

AU - Rojas, Lisa

AU - Sampson, Barbara A.

AU - Tang, Yingying

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N2 - Our aim is to characterize predicted protein-truncating variants (PTVs) in MYBPC3, the gene most commonly associated with hypertrophic cardiomyopathy (HCM), found in a series of autopsied HCM cases after sudden unexpected cardiac death. All cases underwent death scene investigation, gross and microscopic autopsies, toxicological testing, a review of medical records, and a molecular analysis of 95 cardiac genes. We found four pathogenic PTVs in MYBPC3 among male decedents. All variants were previously submitted to ClinVar without phenotype details. Two PTVs were located in the cardiac-specific myosin S2-binding (M) motif at the N-terminus of the MYBPC3-encoded cMyBP-C protein, and two PTVs were in the non-cardiac-specific C-terminus of the protein. The carriers of two cardiac-specific M-motif PTVs died at age 38 years; their heart weight (HW, g) and body mass index (BMI, kg/m2) ratio were 34.90 (890/25.5) and 23.56 (980/41.6), respectively. In contrast, the carriers of two non-cardiac-specific C-terminal PTVs died at age 57 and 67 years, respectively; their HW and BMI ratio were 14.71 (450/30.6) and 13.98 (600/42.9), respectively. A detailed three-generation family study was conducted in one case. This study showed age-at-death variations among MYBPC3 PTVs carriers in adult males.

AB - Our aim is to characterize predicted protein-truncating variants (PTVs) in MYBPC3, the gene most commonly associated with hypertrophic cardiomyopathy (HCM), found in a series of autopsied HCM cases after sudden unexpected cardiac death. All cases underwent death scene investigation, gross and microscopic autopsies, toxicological testing, a review of medical records, and a molecular analysis of 95 cardiac genes. We found four pathogenic PTVs in MYBPC3 among male decedents. All variants were previously submitted to ClinVar without phenotype details. Two PTVs were located in the cardiac-specific myosin S2-binding (M) motif at the N-terminus of the MYBPC3-encoded cMyBP-C protein, and two PTVs were in the non-cardiac-specific C-terminus of the protein. The carriers of two cardiac-specific M-motif PTVs died at age 38 years; their heart weight (HW, g) and body mass index (BMI, kg/m2) ratio were 34.90 (890/25.5) and 23.56 (980/41.6), respectively. In contrast, the carriers of two non-cardiac-specific C-terminal PTVs died at age 57 and 67 years, respectively; their HW and BMI ratio were 14.71 (450/30.6) and 13.98 (600/42.9), respectively. A detailed three-generation family study was conducted in one case. This study showed age-at-death variations among MYBPC3 PTVs carriers in adult males.

KW - Hypertrophic cardiomyopathy

KW - MYBPC3

KW - Sudden death

KW - Truncating variants

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