Hostname: page-component-76d6cb85b7-dqfph Total loading time: 0 Render date: 2026-07-17T04:23:13.381Z Has data issue: false hasContentIssue false
  • English
  • Français

Whole-exome sequencing identified compound heterozygous variants in the TTN gene causing Salih myopathy with dilated cardiomyopathy in an Iranian family

Part of: Basic Science

Published online by Cambridge University Press:  16 November 2021

Mohammad Mahdavi ,
Neda Mohsen-Pour ,
Majid Maleki ,
Mahshid Hesami ,
Niloofar Naderi ,
Golnaz Houshmand ,
Hamid R. Rasouli Jazi ,
Hossein Shahzadi  and
Samira Kalayinia Open the ORCID record for Samira Kalayinia [Opens in a new window]
Mohammad Mahdavi
Affiliation:
Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
Neda Mohsen-Pour
Affiliation:
Zanjan Pharmaceutical Biotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
Majid Maleki
Affiliation:
Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
Mahshid Hesami
Affiliation:
Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
Niloofar Naderi
Affiliation:
Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
Golnaz Houshmand
Affiliation:
Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
Hamid R. Rasouli Jazi
Affiliation:
Biotechnology Research Center, Malek Ashtar University of Technology, Tehran, Iran
Hossein Shahzadi
Affiliation:
Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
Samira Kalayinia*
Affiliation:
Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
*
Author for correspondence: S. Kalayinia, PhD, Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran. Tel: +98 (21) 23923148; Fax: +98 (21) 22663213. E-mail: samira.kalayi@yahoo.com
Get access Rights & Permissions [Opens in a new window]

Abstract

Background:

Salih myopathy, characterised by both congenital myopathy and fatal dilated cardiomyopathy, is an inherited muscle disorder that affects skeletal and cardiac muscles. TTN has been identified as the main cause of this myopathy, the enormous size of this gene poses a formidable challenge to molecular genetic diagnostics.

Method:

In the present study, whole-exome sequencing, cardiac MRI, and metabolic parameter assessment were performed to investigate the genetic causes of Salih myopathy in a consanguineous Iranian family who presented with titinopathy involving both skeletal and heart muscles in an autosomal recessive inheritance pattern.

Results:

Two missense variants of TTN gene (NM_001267550.2), namely c.61280A>C (p. Gln20427Pro) and c.54970G>A (p. Gly18324Ser), were detected and segregations were confirmed by polymerase chain reaction-based Sanger sequencing.

Conclusions:

The compound heterozygous variants, c.61280A>C, (p. Gln20427Pro) and c.54970G>A, (p. Gly18324Ser) in the TTN gene appear to be the cause of Salih myopathy and dilated cardiomyopathy in the family presented. Whole-exome sequencing is an effective molecular diagnostic tool to identify the causative genetic variants of large genes such as TTN.

Keywords

Dilated cardiomyopathySalih myopathytitinopathyTTNwhole-exome sequencingcompound heterozygous

Information

Type
Original Article
Information
Cardiology in the Young , Volume 32 , Issue 9 , September 2022 , pp. 1462 - 1467
Check for updates
Copyright
© The Author(s), 2021. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

Footnotes

Mohammad Mahdavi and Neda Mohsen-Pour are contributed equally to this work.

References

Adam, MP, Ardinger, HH, Pagon, RA, et al. GeneReviews®[Internet] 1993.Google Scholar
Gigli, M, Begay, RL, Morea, G, et al. A review of the giant protein titin in clinical molecular diagnostics of cardiomyopathies. Front Cardiovasc Med 2016; 3: 21.CrossRefGoogle ScholarPubMed
Carmignac, V, Salih, MA, Quijano-Roy, S, et al. C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Ann Neurol 2007; 61: 340–351.CrossRefGoogle Scholar
Puchner, EM, Alexandrovich, A, Kho, AL, et al. Mechanoenzymatics of titin kinase. Proc Natl Acad Sci USA 2008; 105: 13385–13390.CrossRefGoogle ScholarPubMed
Krüger, M, Linke, WA. The giant protein titin: a regulatory node that integrates myocyte signaling pathways. J Biol Chem 2011; 286: 9905–9912.CrossRefGoogle ScholarPubMed
Kontrogianni-Konstantopoulos, A, Ackermann, MA, Bowman, AL, Yap, SV, Bloch, RJ. Muscle giants: molecular scaffolds in sarcomerogenesis. Physiol Rev 2009; 89: 1217–1267.CrossRefGoogle ScholarPubMed
Yu, M, Zhu, Y, Xie, Z, et al. Novel TTN mutations and muscle imaging characteristics in congenital titinopathy. Ann Clin Transl Neur 2019; 6: 1311–1318.CrossRefGoogle ScholarPubMed
Bang, M-L, Centner, T, Fornoff, F, et al. The complete gene sequence of titin, expression of an unusual≈ 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ Res 2001; 89: 1065–1072.CrossRefGoogle ScholarPubMed
Freiburg, A, Trombitas, K, Hell, W, et al. Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity. Circ Res 2000; 86: 1114–1121.CrossRefGoogle ScholarPubMed
Evilä, A, Palmio, J, Vihola, A, et al. Targeted next-generation sequencing reveals novel TTN mutations causing recessive distal titinopathy. Mol Neurobiol 2017; 54: 7212–7223.CrossRefGoogle ScholarPubMed
Pfeffer, G, Barresi, R, Wilson, IJ, et al. Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure. J Neurol Neurosurg Psychiatry 2014; 85: 331–338.CrossRefGoogle ScholarPubMed
Evila, A, Vihola, A, Sarparanta, J, et al, . P.3.11 Atypical phenotypes in titinopathies explained by second titin mutations and compound heterozygosity. Neuromuscular Disord 2013; 23: 758–759.CrossRefGoogle Scholar
Chauveau, C, Bonnemann, CG, Julien, C, et al. Recessive TTN truncating mutations define novel forms of core myopathy with heart disease. Hum Mol Genet 2014; 23: 980–991.CrossRefGoogle ScholarPubMed
Ceyhan-Birsoy, O, Agrawal, PB, Hidalgo, C, et al. Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Neurology 2013; 81: 1205–1214.CrossRefGoogle ScholarPubMed
Dabby, R, Sadeh, M, Hilton-Jones, D, et al. Adult onset limb-girdle muscular dystrophy—A recessive titinopathy masquerading as myositis. J Neurol Sci 2015; 351: 120–123.CrossRefGoogle ScholarPubMed
Savarese, M, Sarparanta, J, Vihola, A, Udd, B, Hackman, P. Increasing role of titin mutations in neuromuscular disorders. J Neuromuscul Dis 2016; 3: 293–308.CrossRefGoogle ScholarPubMed
Rees, M, Nikoopour, R, Fukuzawa, A, et al. Making sense of missense variants in TTN-related congenital myopathies. Acta Neuropathologica 2009; 89: 1–23.Google Scholar
Chauveau, C, Rowell, J, Ferreiro, A. A rising titan: TTN review and mutation update. Hum Mutat 2014; 35: 1046–1059.CrossRefGoogle ScholarPubMed
Li, H, Durbin, R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 2010; 26: 589–595.CrossRefGoogle ScholarPubMed
Wang, K, Li, M, Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010; 38: e164.CrossRefGoogle ScholarPubMed
Liu, X, Wu, C, Li, C, Boerwinkle, E. dbNSFP v3.0: a one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs. Hum Mutat 2016; 37: 235–241.CrossRefGoogle ScholarPubMed
Marchler-Bauer, A, Bo, Y, Han, L, et al. CDD/SPARCLE: functional classification of proteins via subfamily domain architectures. Nucleic Acids Res 2017; 45: D200–D203.CrossRefGoogle ScholarPubMed
Waterhouse, A, Bertoni, M, Bienert, S, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res 2018; 46: W296–W303.CrossRefGoogle ScholarPubMed
Capriotti, E, Fariselli, P, Casadio, R. I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res 2005; 33: W306–W310.CrossRefGoogle ScholarPubMed
Cheng, J, Randall, A, Baldi, P. Prediction of protein stability changes for single-site mutations using support vector machines. Proteins 2006; 62: 1125–1132.CrossRefGoogle ScholarPubMed
Pires, DE, Ascher, DB, Blundell, TL. DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res 2014; 42: W314–W319.CrossRefGoogle ScholarPubMed
Richards, S, Aziz, N, Bale, S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405–423.CrossRefGoogle ScholarPubMed
Kleinberger, J, Maloney, KA, Pollin, TI, Jeng, LJB. An openly available online tool for implementing the ACMG/AMP standards and guidelines for the interpretation of sequence variants. Genet Med 2016; 18: 1165–1165.CrossRefGoogle ScholarPubMed
Hackman, P, Savarese, M, Carmignac, V, Udd, B, Salih, MA. Salih Myopathy. University of Washington, Seattle, Seattle (WA), 1993.Google ScholarPubMed
Linke, WA, Hamdani, N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114: 1052–1068.CrossRefGoogle ScholarPubMed
Misaka, T, Yoshihisa, A, Takeishi, Y. Titin in muscular dystrophy and cardiomyopathy: urinary titin as a novel marker. Clin Chim Acta 2019; 495: 123–128.CrossRefGoogle ScholarPubMed
Neiva-Sousa, M, Almeida-Coelho, J, Falcao-Pires, I, Leite-Moreira, AF. Titin mutations: the fall of Goliath. Heart Fail Rev 2015; 20: 579–588.CrossRefGoogle ScholarPubMed
Younus, M, Ahmad, F, Malik, E, et al. SGCD homozygous nonsense mutation (p. Arg97∗) causing limb-girdle muscular dystrophy type 2F (LGMD2F) in a consanguineous family, a case report. Front Genet 2019; 9: 727.CrossRefGoogle Scholar
Yoskovitz, G, Peled, Y, Gramlich, M, et al. A novel titin mutation in adult-onset familial dilated cardiomyopathy. Am J Cardiol 2012; 109: 1644–1650.CrossRefGoogle ScholarPubMed
Herman, DS, Lam, L, Taylor, MR, et al. Truncations of titin causing dilated cardiomyopathy. New Engl J Med 2012; 366: 619–628.CrossRefGoogle ScholarPubMed
Izumi, R, Niihori, T, Aoki, Y, et al. Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure. J Hum Genet 2013; 58: 259–266.CrossRefGoogle Scholar
Charton, K, Daniele, N, Vihola, A, et al. Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies. Hum Mol Genet 2010; 19: 4608–4624.CrossRefGoogle Scholar
Liu, J-S, Fan, L-L, Zhang, H, et al. Whole-exome sequencing identifies two novel TTN mutations in Chinese families with dilated cardiomyopathy. Cardiology 2017; 136: 10–14.CrossRefGoogle ScholarPubMed