Yield of Rare Variants Detected by Targeted Next-Generation Sequencing in a Cohort of Romanian Index Patients with Hypertrophic Cardiomyopathy

Miruna Mihaela Micheu; Nicoleta-Monica Popa-Fotea; Nicoleta Oprescu; Stefan Bogdan; Monica Dan; Alexandru Deaconu; Lucian Dorobantu; Oana Gheorghe-Fronea; Maria Greavu; Corneliu Iorgulescu; Alexandru Scafa-Udriste; Razvan Ticulescu; Radu Gabriel Vatasescu; Maria Dorobanțu

doi:10.3390/diagnostics10121061

Yield of Rare Variants Detected by Targeted Next-Generation Sequencing in a Cohort of Romanian Index Patients with Hypertrophic Cardiomyopathy

Diagnostics (Basel). 2020 Dec 7;10(12):1061. doi: 10.3390/diagnostics10121061.

Authors

Miruna Mihaela Micheu¹, Nicoleta-Monica Popa-Fotea^{1

2}, Nicoleta Oprescu¹, Stefan Bogdan^{1

2}, Monica Dan¹, Alexandru Deaconu^{1

2}, Lucian Dorobantu^{1

3}, Oana Gheorghe-Fronea^{1

2}, Maria Greavu³, Corneliu Iorgulescu¹, Alexandru Scafa-Udriste^{1

2}, Razvan Ticulescu³, Radu Gabriel Vatasescu^{1

2}, Maria Dorobanțu^{1

2}

Affiliations

¹ Department of Cardiology, Clinical Emergency Hospital of Bucharest, Calea Floreasca 8, 014461 Bucharest, Romania.
² Department 4-Cardiothoracic Pathology, University of Medicine and Pharmacy Carol Davila, Eroii Sanitari Bvd. 8, 050474 Bucharest, Romania.
³ Monza Hospital, Tony Bulandra Street, No. 27, 021967 Bucharest, Romania.

Abstract

Background: The aim of this study was to explore the rare variants in a cohort of Romanian index cases with hypertrophic cardiomyopathy (HCM).

Methods: Forty-five unrelated probands with HCM were screened by targeted next generation sequencing (NGS) of 47 core and emerging genes connected with HCM.

Results: We identified 95 variants with allele frequency < 0.1% in population databases. MYBPC3 and TTN had the largest number of rare variants (17 variants each). A definite genetic etiology was found in 6 probands (13.3%), while inconclusive results due to either known or novel variants were established in 31 cases (68.9%). All disease-causing variants were detected in sarcomeric genes (MYBPC3 and MYH7 with two cases each, and one case in TNNI3 and TPM1 respectively). Multiple variants were detected in 27 subjects (60%), but no proband carried more than one causal variant. Of note, almost half of the rare variants were novel.

Conclusions: Herein we reported for the first time the rare variants identified in core and putative genes associated with HCM in a cohort of Romanian unrelated adult patients. The clinical significance of most detected variants is yet to be established, additional studies based on segregation analysis being required for definite classification.

Keywords: hypertrophic cardiomyopathy; next-generation sequencing; rare genetic variants.