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Genotype-phenotype correlations in recessive titinopathies

Marco Savarese 1 Anna Vihola 2, 3 Emily C. Oates 4 Rita Barresi 5 Chiara Fiorillo 6 Giorgio Tasca 7 Manu Jokela 8 Anna Sarkozy 9 Sushan Luo 10 Jordi Diaz-Manera 11 Christoffer Ehrstedt 12 Ricardo Rojas-Garcia 11 Amets Saenz 13 Nuria Muelas 11 Fortunato Lonardo Heidi Fodstad 14 Talha Qureshi 1 Mridul Johari 2 Salla Valipakka 2 Helena Luque 2 Philippe Petiot 15 Adolfo Lopez de Munain 13 Marika Pane 7 Eugenio Mercuri 7 Annalaura Torella 16 Vincenzo Nigro 16 Guja Astrea 17 Filippo Maria Santorelli 17 Claudio Bruno 6 Thierry Kuntzer 14 Isabel Illa 11 Juan J. Vilchez 11 Cedric Julien 18 Ana Ferreiro 19 Alessandro Malandrini 20 Chong-Bo Zhao 10 Olivera Casar-Borota 21 Mark Davis 22 Francesco Muntoni 9 Peter Hackman 2 Bjarne Udd 2 
Abstract : Purpose 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. Methods We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenicTTNvariants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families). Results 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 threeTTNexons (362-364). Conclusion Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.
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Submitted on : Tuesday, July 27, 2021 - 10:15:43 AM
Last modification on : Tuesday, November 22, 2022 - 2:32:29 PM

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Marco Savarese, Anna Vihola, Emily C. Oates, Rita Barresi, Chiara Fiorillo, et al.. Genotype-phenotype correlations in recessive titinopathies. Genetics in Medicine, 2020, 22 (12), pp.2029-2040. ⟨10.1038/s41436-020-0914-2⟩. ⟨hal-03300419⟩



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