Fatal neonatal hypertrophic cardiomyopathy caused by compound heterozygous truncating MYBPC3 mutation

Alsters, Suzanne I. M.; Wong, Lok; Peferoen, Laura; Niessen, Hans W.M.; Bikker, Hennie; Elting, Mariet W.; Houweling, Arjan C.

doi:10.1007/s12471-019-1245-2

Cited by 5 publications

(3 citation statements)

References 5 publications

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“…In our cohort, the early and severe cardiomyopathy could be due to association of transmitted variants in cardiomyopathy dominant genes illustrated by compound heterozygous variants (allelic pathogenic variants in a same gene) in F1 and F2 and codominance of genes (F4). Compound heterozygous variants of MYBPC3 have also been involved in the literature in severe cardiomyopathies 24–26 . This association gene dose effect was also suggested in the literature as an explanation of severe cardiomyopathies, 27–29 presence of two pathogenic variants could affects the age at onset and severity of the disease in adult cohort and our data completed theses information.…”

Section: Discussionsupporting

confidence: 82%

“…Compound heterozygous variants of MYBPC3 have also been involved in the literature in severe cardiomyopathies. [24][25][26] This association gene dose effect was also suggested in the literature as an explanation of severe cardiomyopathies, [27][28][29] presence of two pathogenic variants Note: For ACMG classification following criteria have been PS4, PM2 referred to population frequency, PS1, PVS1, PM5, and PM4 referred to prediction data, PS3 and PM1 referred to functional data, PP1 referred to segregation data, PS2 and PM6 to de novo variants, PM3 referred to allelic data and PP4 to correlation between gene and phenotype. PS4, PS1, PVS1, PS3, PP1, PS2 are considered as strong and very strong evidence for pathogenicity.…”

Section: Mutations In Dominant Genes and Gene Dose Effectmentioning

confidence: 99%

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Morphological and genetic causes of fetal cardiomyopathies

et al. 2023

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Cardiomyopathies are diseases of the heart muscle with variable clinical expressivity. Most of forms are inherited as dominant trait, and with incomplete penetrance until adulthood. Severe forms of cardiomyopathies were observed during the antenatal period with a pejorative issue leading to fetal death or medical interruption of pregnancy. Variable phenotypes and genetic heterogeneity make etiologic diagnosis difficult. We report 11 families (16 cases) whose unborn, newborn or infant with early onset cardiomyopathies. Detailed morphological and histological examinations of hearts were implemented, as well as genetic analysis on a cardiac targeted NGS panel. This strategy allowed the identification of the genetic cause of the cardiomyopathy in 8/11 families. Compound heterozygous mutations in dominant adulthood cardiomyopathy genes were found in two, pathogenic variants in co‐dominant genes in one, de novo mutations in 5 including a germline mosaicism in one family. Parental testing was systematically performed to detect mutation carriers, and to manage cardiological surveillance and propose a genetic counseling. This study highlights the great diagnostic value of the genetic testing of severe antenatal cardiomyopathy both for genetic counseling and to detect presymptomatic parents at higher risk of developing cardiomyopathy.

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Section: Discussionsupporting

confidence: 82%

Section: Mutations In Dominant Genes and Gene Dose Effectmentioning

confidence: 99%

Morphological and genetic causes of fetal cardiomyopathies

et al. 2023

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“…The identification of these pathogenic gene variants not only explains the incidence of childhood probands with hypertrophic cardiomyopathy but also allows screening of other adult relatives at risk of hypertrophic cardiomyopathy. 20 Identifying the genetic factors of the disease is of great significance for the early diagnosis of family members and is helpful for targeted early intervention and treatment of variant carriers. Therefore, members of families with hypertrophic cardiomyopathy and pathogenic gene variations can be informed of the potential risk.…”

Section: Discussionmentioning

confidence: 99%

Novel pathogenic variant of MYBPC3 responsible for hypertrophic cardiomyopathy

Yang

Wang

et al. 2021

Cardiol Young

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Objectives: This study aims to investigate the pathogenic gene variant in a family with hypertrophic cardiomyopathy by using whole-exome sequencing and to explore the relationship between the gene variant and clinical phenotype. Methods: Peripheral blood was collected from a family with hypertrophic cardiomyopathy, and deoxyribonucleic acid was extracted. The possible pathogenic genes were detected by whole-exome sequencing, and the variant was verified by Sanger sequencing. Functional change in the variant was predicted by bioinformatics software. Clinical data of the family members are analysed simultaneously. Results: The proband carries a novel heterozygous nonsense variant of MYBPC3:c.2731G > T (p.E911X). The analysis of amino acid conservation suggests that the variation is highly conserved. The three-dimensional protein structure shows that the variant in MYBPC3 results in the incompleteness of the fibronectintype-III2 (p872–967) domain and deletion of Ig-like C2-type 6 (p971–1065) and fibronectin type-III 3 and Ig-like C2-type 7 (p1181–1274) domains, in which p1253–1268 is predicted to have a transmembrane helix structure. Clinical data indicate that the phenotypes of variant carriers with hypertrophic cardiomyopathy are diverse, suggesting the functional damages to the protein of MYBPC3. Conclusion: The phenotypes of variant carriers with hypertrophic cardiomyopathy caused by the novel variant in MYBPC3: c.2731G > T (p.E911X) exhibit variable severity and clinical manifestations. Whole-exome sequencing can be used to comprehensive screen hypertrophic cardiomyopathy genes and provide a strong basis for early screening and accurate diagnosis and treatment of hypertrophic cardiomyopathy in children.

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Left Ventricular Noncompaction

Hoedemaekers¹,

Germans²

2020

Clinical Cardiogenetics

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Fatal neonatal hypertrophic cardiomyopathy caused by compound heterozygous truncating MYBPC3 mutation

Cited by 5 publications

References 5 publications

Morphological and genetic causes of fetal cardiomyopathies

Morphological and genetic causes of fetal cardiomyopathies

Novel pathogenic variant of MYBPC3 responsible for hypertrophic cardiomyopathy

Left Ventricular Noncompaction

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