Novel Frameshift Variant of the MYBPC3 Gene Associated with Hypertrophic Cardiomyopathy Significantly Decreases the Level of This Gene’s Transcript in the Myocardium

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Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease with a prevalence of 1 : 200–1 : 500 in the general population. The majority of HCM-linked pathogenic (or likely pathogenic) variants is located in eight genes encoding proteins of sarcomere, the main contractile unit of cardiomyocytes; one of these genes, MYBPC3, is the most commonly affected and usually associated with the more benign clinical course of the disease compared to other HCM-related genes. Here, we describe a novel frame shift variant NM_000256.3:c.2781_2782insCACA of the MYBPC3 gene that causes familial HCM in the heterozygous state. The proband had a progressive heart failure despite the surgical removal of left ventricular tract obstruction. Evaluation of levels of transcripts produced from the mutant allele and wild-type allele of the MYBPC3 gene in proband myocardial tissue and comparison of their total levels with ones in the control samples from patients without HCM showed a significant allele-specific reduction of mutant transcript levels. Our results expand the spectrum of known genetic variants with a proven role in the development of HCM.

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About the authors

I. S. Kiselev

Chazov National Medical Research Centre of Cardiology

Email: kozinmax1992@gmail.com
Russian Federation, Moscow, 121552

M. S. Kozin

Chazov National Medical Research Centre of Cardiology

Author for correspondence.
Email: kozinmax1992@gmail.com
Russian Federation, Moscow, 121552

N. M. Baulina

Chazov National Medical Research Centre of Cardiology

Email: kozinmax1992@gmail.com
Russian Federation, Moscow, 121552

M. B. Sharipova

Regional Multidisciplinary Medical Сenter

Email: kozinmax1992@gmail.com
Uzbekistan, Bukhara, 200100

A. S. Zotov

Chazov National Medical Research Centre of Cardiology

Email: kozinmax1992@gmail.com
Russian Federation, Moscow, 121552

E. A. Stepanova

Russian Medical Academy of Continuous Professional Education

Email: kozinmax1992@gmail.com
Russian Federation, Moscow, 125993

E. V. Kurilina

Chazov National Medical Research Centre of Cardiology

Email: kozinmax1992@gmail.com
Russian Federation, Moscow, 121552

G. Zh. Abdullaeva

Republican Specialized Scientific and Practical Medical Center of Cardiology

Email: kozinmax1992@gmail.com
Uzbekistan, Tashkent, 100052

D. A. Zateyshchikov

Chazov National Medical Research Centre of Cardiology; City Clinical Hospital #17

Email: kozinmax1992@gmail.com
Russian Federation, Moscow, 121552; Moscow, 119620

O. O. Favorova

Chazov National Medical Research Centre of Cardiology

Email: kozinmax1992@gmail.com
Russian Federation, Moscow, 121552

O. S. Chumakova

Chazov National Medical Research Centre of Cardiology; City Clinical Hospital #17

Email: kozinmax1992@gmail.com
Russian Federation, Moscow, 121552; Moscow, 119620

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Supplementary files

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2. Fig. 1. Histological analysis of proband myocardial biopsy. a – cardiomyocyte hypertrophy and nuclear polymorphism, hematoxylin and eosin staining; b – disordered arrangement and hypertrophy of cardiomyocytes, hematoxylin and eosin staining; c – interstitial fibrosis: collagen fibers (purple-red), cardiomyocytes (yellow), Van Gieson staining.

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3. Fig. 2. Results of Sanger sequencing of the MYBPC3 gene region in a patient with HCMP II.3 (proband), carrier of variant C.2781insCACA in a heterozygous state (electrophoregram a), and in patient III.2, which is not a carrier (electrophoregram b). On electrophoregram A, the green stripe shows the region in the 5’ region from the index variant, the blue stripe shows the insertion of TGTG, the orange stripe shows the “doubled sequence" in the 3’ region from the variant.

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4. Fig. 3. Relative transcript levels of the MYBPC3 gene in the tissue of the left ventricle of proband and 14 patients with aortic stenosis who made up the control group. For proband, the analysis was performed independently in three myocardial fragments (three technical repeats). The levels of the studied transcripts were calculated relative to the expression level of the GAPDH gene. The data is presented in the form of a scattering graph (the average value with a standard deviation).

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5. Fig. 4. Pedigree of a patient with HCMP II.3 (proband, shown by arrow), a carrier of the c.2781insCACA variant in the MYBPC3 gene. Symbols with a solid fill are carriers of the variant, in which the HCMP is confirmed; symbols with a vertical black stripe inside are asymptomatic carriers of the variant; N are relatives of the proband, who are not carriers of the variant; ? – the father of a proband with an unknown genotype and phenotype (presumably the carrier of a variant with the disease).

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