Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients

Krista Heliö; Marcos Cicerchia; Julie Hathaway; Johanna Tommiska; Johanna Huusko; Inka Saarinen; Lotta Koskinen; Mikko Muona; Ville Kytölä; Janica Djupsjöbacka; Massimiliano Gentile; Pertteli Salmenperä; Tero-Pekka Alastalo; Christian Steinberg; Tiina Heliö; Jussi Paananen; Samuel Myllykangas; Juha Koskenvuo

doi:10.3389/fcvm.2023.1254272

Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients

Front Cardiovasc Med. 2023 Sep 19:10:1254272. doi: 10.3389/fcvm.2023.1254272. eCollection 2023.

Authors

Krista Heliö¹, Marcos Cicerchia², Julie Hathaway³, Johanna Tommiska², Johanna Huusko², Inka Saarinen², Lotta Koskinen², Mikko Muona², Ville Kytölä², Janica Djupsjöbacka², Massimiliano Gentile², Pertteli Salmenperä², Tero-Pekka Alastalo³, Christian Steinberg⁴, Tiina Heliö¹, Jussi Paananen², Samuel Myllykangas², Juha Koskenvuo²

Affiliations

¹ Heart and Lung Center, ERN GUARD-Heart Center, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
² Blueprint Genetics, A Quest Diagnostics Company, Espoo, Finland.
³ Blueprint Genetics, A Quest Diagnostics Company, Seattle, USA.
⁴ Quebec Heart and Lung Institute, Laval University, Quebec, Canada.

Abstract

Background: Familial dilated cardiomyopathy (DCM) causes heart failure and may lead to heart transplantation. DCM is typically a monogenic disorder with autosomal dominant inheritance. Currently disease-causing variants have been reported in over 60 genes that encode proteins in sarcomeres, nuclear lamina, desmosomes, cytoskeleton, and mitochondria. Over half of the patients undergoing comprehensive genetic testing are left without a molecular diagnosis even when patient selection follows strict DCM criteria.

Methods and results: This study was a retrospective review of patients referred for genetic testing at Blueprint Genetics due to suspected inherited DCM. Next generation sequencing panels included 23-316 genes associated with cardiomyopathies and other monogenic cardiac diseases. Variants were considered diagnostic if classified as pathogenic (P) or likely pathogenic (LP). Of the 2,088 patients 514 (24.6%) obtained a molecular diagnosis; 534 LP/P variants were observed across 45 genes, 2.7% (14/514) had two diagnostic variants in dominant genes. Nine copy number variants were identified: two multigene and seven intragenic. Diagnostic variants were observed most often in TTN (45.3%), DSP (6.7%), LMNA (6.7%), and MYH7 (5.2%). Clinical characteristics independently associated with molecular diagnosis were: a lower age at diagnosis, family history of DCM, paroxysmal atrial fibrillation, absence of left bundle branch block, and the presence of an implantable cardioverter-defibrillator.

Conclusions: Panel testing provides good diagnostic yield in patients with clinically suspected DCM. Causative variants were identified in 45 genes. In minority, two diagnostic variants were observed in dominant genes. Our results support the use of genetic panels in clinical settings in DCM patients with suspected genetic etiology.

Keywords: cardiomyopathy; diagnostic yield; dilated cardiomyopathy; genetic testing; next generation sequencing.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article.