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Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited heart disease. Nextgeneration 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

PLoS One, 2017, vol. 12, núm. 8, p. e0181465

Public Library of Science (PLoS)

Author: Mademont Soler, Irene
Matés Ramírez, Jesús
Yotti, Raquel
Espinosa, Maria Angeles
Pérez Serra, Alexandra
Fernandez Avila, Ana Isabel
Coll, Monica
Méndez, Irene
Iglesias, Anna
Olmo, Bernat del
Riuró Cáceres, Helena
Cuenca, Sofía
Allegue, Catarina
Campuzano Larrea, Oscar
Picó, Ferran
Ferrer Costa, Carles
Álvarez, Patricia
Castillo, Sergio
García Pavía, Pablo
González López, Esther
Padron Barthe, Laura
Díaz de Bustamante, Aranzazu
Darnaude, María Teresa
González Hevia, José Ignacio
Brugada Terradellas, Josep
Fernández Avilés, Francisco
Brugada, Ramon
Date: 2017 August 3
Abstract: Introduction: Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited heart disease. Nextgeneration 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
Format: application/pdf
Citation: https://doi.org/10.1371/journal.pone.0181465
ISSN: 1932-6203
Document access: http://hdl.handle.net/10256/14363
Language: eng
Publisher: Public Library of Science (PLoS)
Collection: Reproducció digital del document publicat a: https://doi.org/10.1371/journal.pone.0181465
Articles publicats (D-CM)
Is part of: PLoS One, 2017, vol. 12, núm. 8, p. e0181465
Rights: Attribution 4.0 Spain
Rights URI: http://creativecommons.org/licenses/by/4.0/es/
Subject: Miocardi -- Malalties
Myocardium -- Diseases
Cardiopatia congènita
Congenital heart disease
Cor -- Malalties -- Aspectes genètics
Heart -- Diseases -- Genetic aspects
Title: Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy
Type: info:eu-repo/semantics/article
Repository: DUGiDocs

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