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Personalized Interpretation and Clinical Translation of Genetic Variants Associated With Cardiomyopathies.

ABSTRACT: Cardiomyopathies are a heterogeneous group of inherited cardiac diseases characterized by progressive myocardium abnormalities associated with mechanical and/or electrical dysfunction. Massive genetic sequencing technologies allow a comprehensive genetic analysis to unravel the cause of disease. However, most identified genetic variants remain of unknown clinical significance due to incomplete penetrance and variable expressivity. Therefore, genetic interpretation of variants and translation into clinical practice remain a current challenge. We performed retrospective comprehensive clinical assessment and genetic analysis in six families, four diagnosed with arrhythmogenic cardiomyopathy, and two diagnosed with hypertrophic cardiomyopathy (HCM). Genetic testing identified three rare variants (two non-sense and one small indel inducing a frameshift), each present in two families. Although each variant is currently classified as pathogenic and the cause of the diagnosed cardiomyopathy, the onset and/or clinical course differed in each patient. New genetic technology allows comprehensive yet cost-effective genetic analysis, although genetic interpretation, and clinical translation of identified variants should be carefully done in each family in a personalized manner.

SUBMITTER: Campuzano O

PROVIDER: S-EPMC6529573 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Personalized Interpretation and Clinical Translation of Genetic Variants Associated With Cardiomyopathies.

Campuzano Oscar O Fernandez-Falgueras Anna A Sarquella-Brugada Georgia G Cesar Sergi S Arbelo Elena E García-Álvarez Ana A Jordà Paloma P Coll Monica M Fiol Victoria V Iglesias Anna A Perez-Serra Alexandra A Mates Jesus J Del Olmo Bernat B Ferrer Carles C Alcalde Mireia M Puigmulé Marta M Mademont-Soler Irene I Pico Ferran F Lopez Laura L Tiron Coloma C Brugada Josep J Brugada Ramon R

Frontiers in genetics 20190515

Cardiomyopathies are a heterogeneous group of inherited cardiac diseases characterized by progressive myocardium abnormalities associated with mechanical and/or electrical dysfunction. Massive genetic sequencing technologies allow a comprehensive genetic analysis to unravel the cause of disease. However, most identified genetic variants remain of unknown clinical significance due to incomplete penetrance and variable expressivity. Therefore, genetic interpretation of variants and translation int ...[more]

PMID: 31156706

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Project description:Clinical interpretation of DNA sequence variants is a critical step in reporting clinical genetic testing results. Application of next-generation sequencing technology in molecular genetic testing has facilitated diagnoses of genetic disorders in clinical practice. However, the large number of DNA sequence variants detected in clinical specimens, many of which have never been seen before, make clinical interpretation challenging. Recommendations by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) have been widely adopted by clinical laboratories around the world to guide clinical interpretation of sequence variants. The ClinGen Sequence Variant Interpretation Working Group and various disease-specific variant curation expert panels have also developed specifications for the ACMG/AMP recommendations. Despite these efforts to standardize variant interpretation in clinical practice, different laboratories may subjectively use professional judgment to determine which criteria are applicable when classifying a variant. In addition, clinicians and researchers who are not familiar with the variant interpretation process may have difficulty understanding clinical genetic reports and communicating the clinical significance of genetic testing results. Here we provide a step-by-step protocol for clinical interpretation of sequence variants, including practical examples. By following this protocol, clinical laboratory geneticists can interpret the clinical significance of sequence variants according to the ACMG/AMP recommendations and ClinGen framework. Furthermore, this article will help clinicians and researchers to understand variant classification in clinical genetic testing reports and evaluate the quality of the reports. © 2020 by John Wiley & Sons, Inc. Basic Protocol: Interpreting the clinical significance of sequence variants Support Protocol: Reevaluating the clinical significance of sequence variants.

Dataset Information

Personalized Interpretation and Clinical Translation of Genetic Variants Associated With Cardiomyopathies.

Publications

Personalized Interpretation and Clinical Translation of Genetic Variants Associated With Cardiomyopathies.

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