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22.01.2020 | Original articles

Multiallelic rare variants support an oligogenic origin of sudden cardiac death in the young

verfasst von: Hager Jaouadi, Yosra Bouyacoub, Sonia Chabrak, Lilia Kraoua, Amira Zaroui, Sahar Elouej, Majdi Nagara, Hamza Dallali, Valérie Delague, Nicolas Levy, Rym Benkhalifa, Rachid Mechmeche, Stéphane Zaffran, Sonia Abdelhak

Erschienen in: Herz | Sonderheft 1/2021

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Abstract

Unexplained sudden death in the young is cardiovascular in most cases. Structural and conduction defects in cardiac-related genes can conspire to underlie sudden cardiac death. Here we report a clinical investigation and an extensive genetic assessment of a Tunisian family with sudden cardiac death in young members. In order to identify the family-genetic basis of sudden cardiac death, we performed Whole Exome Sequencing (WES), read depth copy-number-variation (CNV) screening and segregation analysis. We identify 6 ultra-rare pathogenic heterozygous variants in OBSCN, RYR2, DSC2, AKAP9, CACNA1C and RBM20 genes, and one homozygous splicing variant in TECRL gene consistent with an oligogenic model of inheritance. CNV analysis did not reveal any causative CNV consistent with the family phenotype. Overall, our results are highly suggestive for a cumulative effect of heterozygous missense variants as disease causation and to account for a greater disease severity among offspring. Our study further confirms the complexity of the inheritance of sudden cardiac death and highlights the utility of family-based WES and segregation analysis in the identification of family specific mutations within different cardiac genes pathways.

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Titel: Multiallelic rare variants support an oligogenic origin of sudden cardiac death in the young
verfasst von: Hager Jaouadi
Yosra Bouyacoub
Sonia Chabrak
Lilia Kraoua
Amira Zaroui
Sahar Elouej
Majdi Nagara
Hamza Dallali
Valérie Delague
Nicolas Levy
Rym Benkhalifa
Rachid Mechmeche
Stéphane Zaffran
Sonia Abdelhak
Publikationsdatum: 22.01.2020
Verlag: Springer Medizin
Erschienen in: Herz / Ausgabe Sonderheft 1/2021
Print ISSN: 0340-9937
Elektronische ISSN: 1615-6692
DOI: https://doi.org/10.1007/s00059-019-04883-1

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