Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients

Julie Hathaway ,Massimiliano Gentile ,Pertteli Salmenperä ,Tero-Pekka Alastalo ,Jussi Paananen ,Eija H Seppälä ,Mikko Muona ,Krista Heliö ,Samuel Myllykangas ,Inka Saarinen ,Jennifer Schleit ,Ville Kytölä ,Hannu Turpeinen ,Tiia Kangas‐Kontio ,Sari Tuupanen ,Johanna Sistonen ,Miko Valori ,Johanna Tommiska ,Tiina Heliö ,Jonna Tallila ,Juha Koskenvuo

doi:10.1186/s12872-021-01927-5

Abstract

BackgroundGenetic testing in hypertrophic cardiomyopathy (HCM) is a published guideline-based recommendation. The diagnostic yield of genetic testing and corresponding HCM-associated genes have been largely documented by single center studies and carefully selected patient cohorts. Our goal was to evaluate the diagnostic yield of genetic testing in a heterogeneous cohort of patients with a clinical suspicion of HCM, referred for genetic testing from multiple centers around the world.MethodsA retrospective review of patients with a suspected clinical diagnosis of HCM referred for genetic testing at Blueprint Genetics was undertaken. The analysis included syndromic, myopathic and metabolic etiologies. Genetic test results and variant classifications were extracted from the database. Variants classified as pathogenic (P) or likely pathogenic (LP) were considered diagnostic.ResultsA total of 1376 samples were analyzed. Three hundred and sixty-nine tests were diagnostic (26.8%); 373 P or LP variants were identified. Only one copy number variant was identified. The majority of diagnostic variants involved genes encoding the sarcomere (85.0%) followed by 4.3% of diagnostic variants identified in the RASopathy genes. Two percent of diagnostic variants were in genes associated with a cardiomyopathy other than HCM or an inherited arrhythmia. Clinical variables that increased the likelihood of identifying a diagnostic variant included: an earlier age at diagnosis (p < 0.0001), a higher maximum wall thickness (MWT) (p < 0.0001), a positive family history (p < 0.0001), the absence of hypertension (p = 0.0002), and the presence of an implantable cardioverter-defibrillator (ICD) (p = 0.0004).ConclusionThe diagnostic yield of genetic testing in this heterogeneous cohort of patients with a clinical suspicion of HCM is lower than what has been reported in well-characterized patient cohorts. We report the highest yield of diagnostic variants in the RASopathy genes identified in a laboratory cohort of HCM patients to date. The spectrum of genes implicated in this unselected cohort highlights the importance of pre-and post-test counseling when offering genetic testing to the broad HCM population.

Highlights

Genetic testing in hypertrophic cardiomyopathy (HCM) is a published guideline-based recommen‐ dation
The aim of this study is to report on the diagnostic yield of genetic testing, outline the genes in which diagnostic variants were identified, by applying a systematic American College of Medical Genetics and Genomics (ACMG)/ Associa‐ tion for Molecular Pathology (AMP)-compatible variant classification scheme and determine which clinical variables influence the likelihood of a diagnostic test result in a heterogeneous HCM cohort evaluated over a 5-year period
The majority of likely pathogenic (LP)/P variants were in genes that are definitively associated with HCM [18]

Summary

Introduction

Genetic testing in hypertrophic cardiomyopathy (HCM) is a published guideline-based recommen‐ dation. The diagnostic yield of genetic testing and corresponding HCM-associated genes have been largely docu‐ mented by single center studies and carefully selected patient cohorts. Our goal was to evaluate the diagnostic yield of genetic testing in a heterogeneous cohort of patients with a clinical suspicion of HCM, referred for genetic testing from multiple centers around the world. Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder that is defined by the presence of increased left ventricular (LV) wall thickness that is not Hathaway et al BMC Cardiovasc Disord (2021) 21:126 solely explained by loading conditions [1]. Classic HCM is primarily caused by variants in the genes encoding proteins of the cardiac sarcomere [4] and follows an autosomal dominant pattern of inheritance. Obtaining a correct diagnosis is of utmost importance for medical management purposes, and for the identification of at-risk family members who require ongoing screening

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