Additional Value of Screening for Minor Genes and Copy Number Variants in Hypertrophic Cardiomyopathy

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2017 Aug 4

PMID 28771489

Citations 21

Authors

Irene Mademont-Soler

Jesus Mates

Raquel Yotti

Maria Angeles Espinosa

Alexandra Perez-Serra

Ana Isabel Fernandez-Avila

Monica Coll

Irene Mendez

Anna Iglesias

Bernat Del Olmo

Helena Riuro

Sofia Cuenca

Catarina Allegue

Oscar Campuzano

Ferran Pico

Carles Ferrer-Costa

Patricia Alvarez

Sergio Castillo

Pablo Garcia-Pavia

Esther Gonzalez-Lopez

Laura Padron-Barthe

Aranzazu Diaz de Bustamante

Maria Teresa Darnaude

Jose Ignacio Gonzalez-Hevia

Josep Brugada

Francisco Fernandez-Aviles

Ramon Brugada

Affiliations

Soon will be listed here.

Abstract

Introduction: Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited heart disease. Next-generation sequencing (NGS) is the preferred genetic test, but the diagnostic value of screening for minor and candidate genes, and the role of copy number variants (CNVs) deserves further evaluation.

Methods: Three hundred and eighty-seven consecutive unrelated patients with HCM were screened for genetic variants in the 5 most frequent genes (MYBPC3, MYH7, TNNT2, TNNI3 and TPM1) using Sanger sequencing (N = 84) or NGS (N = 303). In the NGS cohort we analyzed 20 additional minor or candidate genes, and applied a proprietary bioinformatics algorithm for detecting CNVs. Additionally, the rate and classification of TTN variants in HCM were compared with 427 patients without structural heart disease.

Results: The percentage of patients with pathogenic/likely pathogenic (P/LP) variants in the main genes was 33.3%, without significant differences between the Sanger sequencing and NGS cohorts. The screening for 20 additional genes revealed LP variants in ACTC1, MYL2, MYL3, TNNC1, GLA and PRKAG2 in 12 patients. This approach resulted in more inconclusive tests (36.0% vs. 9.6%, p<0.001), mostly due to variants of unknown significance (VUS) in TTN. The detection rate of rare variants in TTN was not significantly different to that found in the group of patients without structural heart disease. In the NGS cohort, 4 patients (1.3%) had pathogenic CNVs: 2 deletions in MYBPC3 and 2 deletions involving the complete coding region of PLN.

Conclusions: A small percentage of HCM cases without point mutations in the 5 main genes are explained by P/LP variants in minor or candidate genes and CNVs. Screening for variants in TTN in HCM patients drastically increases the number of inconclusive tests, and shows a rate of VUS that is similar to patients without structural heart disease, suggesting that this gene should not be analyzed for clinical purposes in HCM.

Citing Articles

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Fadoni J, Santos A, Amorim A, Caine L Diagnostics (Basel). 2025; 15(4).

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Novel Copy Number Deletion Involving Associated With Epilepsy, Tremor, and Intellectual Disability.

Hsu J, Ibrahim D, Ali R, Marchi E, Gavin M, Amble K Clin Case Rep. 2025; 13(1):e70022.

PMID: 39780902 PMC: 11710847. DOI: 10.1002/ccr3.70022.

Generation of Isogenic iPSC Lines for Studying the Effect of the p.N515del (c.1543_1545delAAC) Variant on MYBPC3 Function and Hypertrophic Cardiomyopathy Pathogenesis.

Pavlova S, Shulgina A, Minina J, Zakian S, Dementyeva E Int J Mol Sci. 2024; 25(23).

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Hypertrophic cardiomyopathy due to truncating variants in myosin binding protein C: a Spanish cohort.

Melendo-Viu M, Salguero-Bodes R, Valverde-Gomez M, Larranaga-Moreira J, Barriales R, Diez-Lopez C Open Heart. 2024; 11(2).

PMID: 39581692 PMC: 11590831. DOI: 10.1136/openhrt-2024-002891.

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