Genetic Spectrum of Idiopathic Restrictive Cardiomyopathy Uncovered by Next-Generation Sequencing.
BACKGROUND
Cardiomyopathies represent a rare group of disorders often of genetic origin. While approximately 50% of genetic causes are known for other types of cardiomyopathies, the genetic spectrum of restrictive cardiomyopathy (RCM) is largely unknown. The aim of the present study was to identify the genetic background of idiopathic RCM and to compile the obtained genetic variants to the novel signalling pathways using in silico protein network analysis.


METHODS
We used Illumina MiSeq setup to screen for 108 cardiomyopathy and arrhythmia-associated genes in 24 patients with idiopathic RCM. Pathogenicity of genetic variants was classified according to American College of Medical Genetics and Genomics classification.


RESULTS
Pathogenic and likely-pathogenic variants were detected in 13 of 24 patients resulting in an overall genotype-positive rate of 54%. Half of the genotype-positive patients carried a combination of pathogenic, likely-pathogenic variants and variants of unknown significance. The most frequent combination included mutations in sarcomeric and cytoskeletal genes (38%). A bioinformatics approach underlined the mechanotransducing protein networks important for RCM pathogenesis.


CONCLUSIONS
Multiple gene mutations were detected in half of the RCM cases, with a combination of sarcomeric and cytoskeletal gene mutations being the most common. Mutations of genes encoding sarcomeric, cytoskeletal, and Z-line-associated proteins appear to have a predominant role in the development of RCM.
Almazov Federal Medical Research Centre, St. Petersburg, 197341, Russia.|Department of Women's and Children's Health and Centre for Molecular Medicine, Karolinska Institute, Stockholm, 17176, Sweden.|ITMO University, Institute of Translational Medicine, St. Petersburg, 197101, Russia.
Anna
A
Kostareva
Almazov Federal Medical Research Centre, St. Petersburg, 197341, Russia.
Artem
A
Kiselev
Almazov Federal Medical Research Centre, St. Petersburg, 197341, Russia.|Department of Faculty Therapy, Pavlov Medical University, St. Petersburg, 197022, Russia.
Alexandra
A
Gudkova
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany.
Goar
G
Frishman
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany.
Andreas
A
Ruepp
St. Petersburg State Polytechnical University, St. Petersburg, 195251, Russia.|Department of BioinformRatics, Wissenschaftszentrum Weihenstephan, Technische Universität München, 85354, Freising, Germany.|Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany.
Dmitrij
D
Frishman
Almazov Federal Medical Research Centre, St. Petersburg, 197341, Russia.|Department of Women's and Children's Health and Centre for Molecular Medicine, Karolinska Institute, Stockholm, 17176, Sweden.
Natalia
N
Smolina
St. Petersburg State Polytechnical University, St. Petersburg, 195251, Russia.
Svetlana
S
Tarnovskaya
Institutite of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, 17176, Sweden.
Daniel
D
Nilsson
Almazov Federal Medical Research Centre, St. Petersburg, 197341, Russia.
Anna
A
Zlotina
Almazov Federal Medical Research Centre, St. Petersburg, 197341, Russia.|ITMO University, Institute of Translational Medicine, St. Petersburg, 197101, Russia.
Tatiana
T
Khodyuchenko
Almazov Federal Medical Research Centre, St. Petersburg, 197341, Russia.
Tatiana
T
Vershinina
Almazov Federal Medical Research Centre, St. Petersburg, 197341, Russia.
Tatiana
T
Pervunina
Almazov Federal Medical Research Centre, St. Petersburg, 197341, Russia.
Alexandra
A
Klyushina
Almazov Federal Medical Research Centre, St. Petersburg, 197341, Russia.
Andrey
A
Kozlenok
Department of Women's and Children's Health and Centre for Molecular Medicine, Karolinska Institute, Stockholm, 17176, Sweden.
Gunnar
G
Sjoberg
ITMO University, Institute of Translational Medicine, St. Petersburg, 197101, Russia.|National Institute for Health Development, Tallinn, Estonia.
Irina
I
Golovljova
Department of Women's and Children's Health and Centre for Molecular Medicine, Karolinska Institute, Stockholm, 17176, Sweden.
Thomas
T
Sejersen
Almazov Federal Medical Research Centre, St. Petersburg, 197341, Russia.
Eugeniy
E
Shlyakhto
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