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A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans–A cohort study

Founder variants in sarcomere protein genes account for a significant proportion of disease-causing variants in patients with hypertrophic cardiomyopathy (HCM). However, information on founder variants in non-sarcomeric protein genes, such as FHOD3, which have only recently been associated with HCM,...

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Autores principales: Vodnjov, Nina, Toplišek, Janez, Maver, Aleš, Čuturilo, Goran, Jaklič, Helena, Teran, Nataša, Višnjar, Tanja, Škrjanec Pušenjak, Maruša, Hodžić, Alenka, Miljanović, Olivera, Peterlin, Borut, Writzl, Karin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10697513/
http://dx.doi.org/10.1371/journal.pone.0294969
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author Vodnjov, Nina
Toplišek, Janez
Maver, Aleš
Čuturilo, Goran
Jaklič, Helena
Teran, Nataša
Višnjar, Tanja
Škrjanec Pušenjak, Maruša
Hodžić, Alenka
Miljanović, Olivera
Peterlin, Borut
Writzl, Karin
author_facet Vodnjov, Nina
Toplišek, Janez
Maver, Aleš
Čuturilo, Goran
Jaklič, Helena
Teran, Nataša
Višnjar, Tanja
Škrjanec Pušenjak, Maruša
Hodžić, Alenka
Miljanović, Olivera
Peterlin, Borut
Writzl, Karin
author_sort Vodnjov, Nina
collection PubMed
description Founder variants in sarcomere protein genes account for a significant proportion of disease-causing variants in patients with hypertrophic cardiomyopathy (HCM). However, information on founder variants in non-sarcomeric protein genes, such as FHOD3, which have only recently been associated with HCM, remains scarce. In this study, we conducted a retrospective analysis of exome sequencing data of 134 probands with HCM for recurrent pathogenic variants. We discovered a novel likely pathogenic variant c.1646+2T>C in FHOD3 in heterozygous state in eight probands with HCM and confirmed its presence in seven additional relatives. Individuals with this variant had a wide range of ages at onset of the disease (4–63 years). No adverse cardiac events were observed. Haplotype analysis revealed that the individuals with this variant shared a genomic region of approximately 5 Mbp surrounding the variant, confirming the founder effect of the variant. FHOD3 c.1646+2T>C is estimated to have arisen 58 generations ago (95% CI: 45–81) in a common ancestor living on the Balkans. A founder FHOD3 c.1646+2T>C variant is the second most common genetic variant in our cohort of patients with HCM, occurring in 16% of probands with a known genetic cause of HCM, which represents a substantially higher proportion than the currently estimated 0.5–2% for causal FHOD3 variants. Our study broadens the understanding of the genetic causes of HCM and may improve the diagnosis of this condition, particularly in patients from the Balkans.
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spelling pubmed-106975132023-12-06 A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans–A cohort study Vodnjov, Nina Toplišek, Janez Maver, Aleš Čuturilo, Goran Jaklič, Helena Teran, Nataša Višnjar, Tanja Škrjanec Pušenjak, Maruša Hodžić, Alenka Miljanović, Olivera Peterlin, Borut Writzl, Karin PLoS One Research Article Founder variants in sarcomere protein genes account for a significant proportion of disease-causing variants in patients with hypertrophic cardiomyopathy (HCM). However, information on founder variants in non-sarcomeric protein genes, such as FHOD3, which have only recently been associated with HCM, remains scarce. In this study, we conducted a retrospective analysis of exome sequencing data of 134 probands with HCM for recurrent pathogenic variants. We discovered a novel likely pathogenic variant c.1646+2T>C in FHOD3 in heterozygous state in eight probands with HCM and confirmed its presence in seven additional relatives. Individuals with this variant had a wide range of ages at onset of the disease (4–63 years). No adverse cardiac events were observed. Haplotype analysis revealed that the individuals with this variant shared a genomic region of approximately 5 Mbp surrounding the variant, confirming the founder effect of the variant. FHOD3 c.1646+2T>C is estimated to have arisen 58 generations ago (95% CI: 45–81) in a common ancestor living on the Balkans. A founder FHOD3 c.1646+2T>C variant is the second most common genetic variant in our cohort of patients with HCM, occurring in 16% of probands with a known genetic cause of HCM, which represents a substantially higher proportion than the currently estimated 0.5–2% for causal FHOD3 variants. Our study broadens the understanding of the genetic causes of HCM and may improve the diagnosis of this condition, particularly in patients from the Balkans. Public Library of Science 2023-12-05 /pmc/articles/PMC10697513/ http://dx.doi.org/10.1371/journal.pone.0294969 Text en © 2023 Vodnjov et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Vodnjov, Nina
Toplišek, Janez
Maver, Aleš
Čuturilo, Goran
Jaklič, Helena
Teran, Nataša
Višnjar, Tanja
Škrjanec Pušenjak, Maruša
Hodžić, Alenka
Miljanović, Olivera
Peterlin, Borut
Writzl, Karin
A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans–A cohort study
title A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans–A cohort study
title_full A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans–A cohort study
title_fullStr A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans–A cohort study
title_full_unstemmed A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans–A cohort study
title_short A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans–A cohort study
title_sort novel splice-site fhod3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the balkans–a cohort study
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10697513/
http://dx.doi.org/10.1371/journal.pone.0294969
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