Highlights
- •Mutations in MYBPC, MYH7 and TNNT2 cause hypertrophic cardiomyopathy (HCM).
- •MYBPC3 p.Val158Met was associated with severe left ventricular hypertrophy (LVH).
- •TNNT2 p.Lys263Arg was associated with severe LVH and increased septum thickness.
- •MYH7 p.Val320Met pathogenic variant was associated with early sudden cardiac death (SCD).
- •MYBPC, MYH7 and TNNT2 variants contribute to the risk of SCD and other HCM outcomes.
Abstract
Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular
hypertrophy (LVH) and is one of the major causes of sudden cardiac death (SCD). An
exon-targeted gene sequencing strategy was used to investigate the association of
functional variants in sarcomeric genes (MYBPC3, MYH7 and TNNT2) with severe LVH and other SCD-related risk factors in Brazilian HCM patients. Clinical
data of 55 HCM patients attending a Cardiology Hospital (Sao Paulo city, Brazil) were
recorded. Severe LVH, aborted SCD, family history of SCD, syncope, non-sustained ventricular
tachycardia and abnormal blood pressure in response to exercise were evaluated as
SCD risk factors. Blood samples were obtained for genomic DNA extraction and the exons
and untranslated regions of the MYH7, MYBPC3 and TNNT2 were sequenced using Nextera® and MiSEq® reagents. Variants were identified and annotated
using in silico tools, and further classified as pathogenic or benign according to the American College
of Medical Genetics and Genomics guidelines. Variants with functional effects were
identified in MYBPC3 (n = 9), MYH7 (n = 6) and TNNT2 (n = 4). The benign variants MYBPC3 p.Val158Met and TNNT2 p.Lys263Arg were associated with severe LVH (p < 0.05), and the MYH7 p.Val320Met (pathogenic) was associated with family history of SCD (p = 0.037). Increased
risk for severe LVH was found in carriers of MYBPC3 Met158 (c.472 A allele, OR = 13.5, 95% CI = 1.80–101.12, p = 0.011) or combined variants
(MYBPC3, MYH7 and TNNT2: OR = 12.39, 95% CI = 2.14–60.39, p = 0.004). Carriers of TNNT2 p.Lys263Arg and combined variants had higher values of septum thickness than non-carriers
(p < 0.05). Molecular modeling analysis showed that MYBPC3 158Met reduces the interaction of cardiac myosin-binding protein C (cMyBP-C) RASK
domain (amino acids Arg215-Ala216-Ser217-Lys218) with tropomyosin. In conclusion,
the variants MYBPC3 p.Val158Met, TNNT2 p.Lys263Arg and MYH7 p.Val320Met individually or combined contribute to the risk of sudden cardiac death
and other outcomes of hypertrophic cardiomyopathy.
Keywords
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Article info
Publication history
Published online: February 03, 2021
Accepted:
January 31,
2021
Received in revised form:
January 29,
2021
Received:
November 1,
2020
Identification
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© 2021 Elsevier B.V. All rights reserved.
