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Genotype–phenotype correlations in recessive titinopathies



High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype–phenotype correlations in this cohort.


We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenic TTN variants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families).


Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final three TTN exons (362–364).


Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.

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Fig. 1: Clinical presentation and muscle magnetic resonance image (MRI) of patient 19.
Fig. 2: Reverse transcription polymerase chain reaction (RT-PCR) of intronic variants affecting the canonical splicing in patients 8, 9, and 14.
Fig. 3: Protein analysis.
Fig. 4: Positional effect of TTN M-band variants introducing premature termination codons.


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The authors thank all the patients and family members for their cooperation; all the clinicians for collecting patient data; Meharji Arumilli at Folkhälsan Research Center (FHR) and Francesco Musacchia at TIGEM for bioinformatic help; Merja Soininen and Anni Evilä at FHR, Sini Penttilä and Sara Lehtinen at Neuromuscular Research Center Tampere, Denise Cassandrini at Stella Maris, Claire Chauveau at Institut de Myologie, and Monica Traverso at Istituto Gaslini for sample and data acquisition; the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant reference 203141/Z/16/Z) for the generation and initial processing of the sequencing data. We also thank Magnus Ehrnrooth Foundation (M.S.), Päivikki ja Sakari Sohlbergin Säätiö (M.S. and Mridul Johari), Biomedicum Helsinki säätiö (Mridul Johari), Jane and Aatos Erkko Foundation (P.H.), Medicinska Understödsföreningen Liv och Hälsa rf (P.H.), Folkhälsan Research Foundation (B.U.), Erkko Foundation (B.U.), Juselius Foundation (B.U.), Finnish Academy (B.U.), Alfred Kordelin Foundation (S.V.), AFM-Telethon (grant number 22431 to CF), National Health and Medical Research Council (NHMRC) (GNT1090428 to ECO) for their support. N.M. and J.J.V. are funded by a project PI16/00316 supported by the Instituto de Salud Carlos III (ISCIII) Madrid: “Estudio de miopatías distales: diagnóstico mediante NGS, ampliación de estudios sobre su historia natural y exploración de factores patogénicos,” a grant by Fundación Isabel Gemio, and by the Generalitat Valenciana (grant PROMETEO/2019/075) to N.M. F.M. and Anna Sarkozy thank the European Community’s Seventh Framework Programme (FP7/2007–2013) funded grant “Integrated European –omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)” (grant agreement number 2012–305121); the Muscular Dystrophy UK Grant on Gene Identification to F.M.; the Highly Specialised Services for Congenital Myopathies and Congenital dystrophies in England, and the support of the MRC and BRC Neuromuscular Centre Biobank at UCL is also gratefully acknowledged. Figure 4 and Supplementary Fig. 3 were created with BioRender (

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Correspondence to Marco Savarese PhD.

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Savarese, M., Vihola, A., Oates, E.C. et al. Genotype–phenotype correlations in recessive titinopathies. Genet Med 22, 2029–2040 (2020).

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  • titin
  • skeletal muscle disorders
  • cardiomyopathy
  • congenital myopathy
  • arthrogryposis


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