Inferring disease course from differential exon usage in the wide titinopathy spectrum.
Journal
Annals of clinical and translational neurology
ISSN: 2328-9503
Titre abrégé: Ann Clin Transl Neurol
Pays: United States
ID NLM: 101623278
Informations de publication
Date de publication:
28 Aug 2024
28 Aug 2024
Historique:
received:
23
07
2024
accepted:
07
08
2024
medline:
31
8
2024
pubmed:
31
8
2024
entrez:
29
8
2024
Statut:
aheadofprint
Résumé
Biallelic titin truncating variants (TTNtv) have been associated with a wide phenotypic spectrum, ranging from complex prenatal muscle diseases with dysmorphic features to adult-onset limb-girdle muscular dystrophy, with or without cardiac involvement. Given the size and complexity of TTN, reaching an unequivocal molecular diagnosis and precise disease prognosis remains challenging. In this case series, 12 unpublished cases and one already published case with biallelic TTNtv were collected from multiple international medical centers between November 2022 and September 2023. TTN mutations were detected through exome or genome sequencing. Information about familial and personal clinical history was collected in a standardized form. RNA-sequencing and analysis of TTN exon usage were performed on an internal sample cohort including postnatal skeletal muscles, fetal skeletal muscles, postnatal heart muscles, and fetal heart muscles. In addition, publicly available RNA-sequencing data was retrieved from ENCODE. We generated new RNA-seq data on TTN exons and identified genotype-phenotype correlations with prognostic implications for each titinopathy patient (whether worsening or improving in prenatal and postnatal life) using percentage spliced in (PSI) data for the involved exons. Interestingly, thanks to exon usage, we were also able to rule out a titinopathy diagnosis in one prenatal case. This study demonstrates that exon usage provides valuable insights for a more exhaustive clinical interpretation of TTNtv; additionally, it may serve as a model for implementing personalized medicine in many other genetic diseases, since most genes undergo alternative splicing.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Samfundet Folkhälsan i Svenska Finland
Organisme : French Muscular Dystrophy Association
ID : 23281
Organisme : Magnus Ehrnroothin Säätiö
Organisme : European Research Council
ID : European Joint Program on Rare Diseases (project I
Pays : International
Organisme : Instituto de Salud Carlos III
ID : AC19/00048
Organisme : Sydäntutkimussäätiö
Organisme : Research Council of Finland
ID : 339437
Organisme : Jane ja Aatos Erkon Säätiö
Organisme : Juselius Foundation
Informations de copyright
© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Références
Bang ML, Centner T, Fornoff F, et al. The complete gene sequence of titin, expression of an unusual approximately 700‐kDa titin isoform, and its interaction with obscurin identify a novel Z‐line to I‐band linking system. Circ Res. 2001;89(11):1065‐1072. doi:10.1161/HH2301.100981
Linke WA, Kulke M, Li H, et al. PEVK domain of titin: an entropic spring with actin‐binding properties. J Struct Biol. 2002;137(1–2):194‐205. doi:10.1006/jsbi.2002.4468
Savarese M, Sarparanta J, Vihola A, Udd B, Hackman P. Increasing role of titin mutations in neuromuscular disorders. J Neuromuscul Dis. 2016;3(3):293‐308. doi:10.3233/JND‐160158
Savarese M, Jonson PH, Huovinen S, et al. The complexity of titin splicing pattern in human adult skeletal muscles. Skelet Muscle. 2018;8(1):11. doi:10.1186/S13395‐018‐0156‐Z
Greaser ML, Guo W, Bharmal SJ, Esbona K. Titin diversity—alternative splicing gone wild. J Biomed Biotechnol. 2010;2010:753675. doi:10.1155/2010/753675
Prado LG, Makarenko I, Andresen C, Krüger M, Opitz CA, Linke WA. Isoform diversity of giant proteins in relation to passive and active contractile properties of rabbit skeletal muscles. J Gen Physiol. 2005;126(5):461‐480. doi:10.1085/jgp.200509364
Trinick J, Tskhovrebova L. Roles of titin in the structure and elasticity of the sarcomere. J Biomed Biotechnol. 2010;2010:612482. doi:10.1155/2010/612482
Ware JS, Li J, Mazaika E, et al. Shared genetic predisposition in peripartum and dilated cardiomyopathies. N Engl J Med. 2016;374(3):233‐241. doi:10.1056/NEJMOA1505517
Gerull B, Gramlich M, Atherton J, et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet. 2002;30(2):201‐204. doi:10.1038/NG815
Ware JS, Cook SA. Role of titin in cardiomyopathy: from DNA variants to patient stratification. Nat Rev Cardiol. 2018;15(4):241‐252. doi:10.1038/nrcardio.2017.190
Hackman P, Vihola A, Haravuori H, et al. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal‐muscle protein titin. Am J Hum Genet. 2002;71(3):492‐500. doi:10.1086/342380
Lillback V, Savarese M, Sandholm N, Hackman P, Udd B. Long‐term favorable prognosis in late onset dominant distal titinopathy: tibial muscular dystrophy. Eur J Neurol. 2023;30(4):1080‐1088. doi:10.1111/ene.15688
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(4):980‐991. doi:10.1093/hmg/ddt494
Tasca G, Udd B. Hereditary myopathy with early respiratory failure (HMERF): still rare, but common enough. Neuromuscul Disord. 2018;28(3):268‐276. doi:10.1016/J.NMD.2017.12.002
Savarese M, Vihola A, Oates EC, et al. Genotype‐phenotype correlations in recessive titinopathies. Genet Med. 2020;22(12):2029‐2040. doi:10.1038/S41436‐020‐0914‐2
Averdunk L, Donkervoort S, Horn D, et al. Recognizable pattern of arthrogryposis and congenital myopathy caused by the recurrent TTN metatranscript‐only c39974‐11T>G splice variant. Neuropediatrics. 2022;53(5):309‐320. doi:10.1055/a‐1859‐0800
Bryen SJ, Ewans L, Pinner J, et al. Recurrent TTN metatranscript‐only c.39974‐11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy. Hum Mutat. 2020;41:403‐411.
Oates EC, Jones KJ, Donkervoort S, et al. Congenital Titinopathy: comprehensive characterization and pathogenic insights. Ann Neurol. 2018;83(6):1105‐1124. doi:10.1002/ANA.25241
Di Feo MF, Lillback V, Jokela M, et al. The crucial role of titin in fetal development: recurrent miscarriages and bone, heart and muscle anomalies characterise the severe end of titinopathies spectrum. J Med Genet. 2023;60(9):866‐873. doi:10.1136/jmg‐2022‐109018
Chervinsky E, Khayat M, Soltsman S, Habiballa H, Elpeleg O, Shalev S. A homozygous TTN gene variant associated with lethal congenital contracture syndrome. Am J Med Genet A. 2018;176(4):1001‐1005. doi:10.1002/ajmg.a.38639
Balasundaram P, Avulakunta ID, Delfiner L, Levy P, Forman KR. Novel TTN mutation causing severe congenital myopathy and uncertain association with infantile hydrocephalus. Case Rep Genet. 2023;2023:5535083. doi:10.1155/2023/5535083
Laquerriere A, Jaber D, Abiusi E, et al. Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita. J Med Genet. 2022;59(6):559‐567. doi:10.1136/JMEDGENET‐2020‐107595
Cardone N, Moula M, Baelde RJ, et al. Clinical and functional characterization of a long survivor congenital titinopathy patient with a novel metatranscript‐only titin variant. Acta Neuropathol Commun. 2023;11(1):1‐10. doi:10.1186/S40478‐023‐01539‐4/FIGURES/5
Savarese M, Maggi L, Vihola A, et al. Interpreting genetic variants in titin in patients with muscle disorders. JAMA Neurol. 2018;75(5):557‐565. doi:10.1001/JAMANEUROL.2017.4899
Dobin A, Davis CA, Schlesinger F, et al. STAR: Ultrafast universal RNA‐seq aligner. Bioinformatics. 2013;29(1):15‐21. doi:10.1093/bioinformatics/bts635
Oghabian A, Greco D, Frilander MJ. IntEREst: Intron‐exon retention estimator. BMC Bioinformatics. 2018;19(1):1‐10. doi:10.1186/S12859‐018‐2122‐5/FIGURES/4
Tardaguila M, De La Fuente L, Marti C, et al. SQANTI: extensive characterization of long‐read transcript sequences for quality control in full‐length transcriptome identification and quantification. Genome Res. 2018;28(3):396‐411. doi:10.1101/gr.222976.117
Zou P, Pinotsis N, Lange S, et al. Palindromic assembly of the giant muscle protein titin in the sarcomeric Z‐disk. Nature. 2006;439(7073):229‐233. doi:10.1038/nature04343
Luther PK. The vertebrate muscle Z‐disc: sarcomere anchor for structure and signalling. J Muscle Res Cell Motil. 2009;30(5–6):171‐185. doi:10.1007/s10974‐009‐9189‐6
Perrin A, Juntas Morales R, Rivier F, et al. The importance of an integrated genotype‐phenotype strategy to unravel the molecular bases of titinopathies. Neuromuscul Disord. 2020;30(11):877‐887. doi:10.1016/j.nmd.2020.09.032
Fernández‐Marmiesse A, Carrascosa‐Romero MC, Alfaro Ponce B, et al. Homozygous truncating mutation in prenatally expressed skeletal isoform of TTN gene results in arthrogryposis multiplex congenita and myopathy without cardiac involvement. Neuromuscul Disord. 2017;27(2):188‐192. doi:10.1016/j.nmd.2016.11.002
Kasinathan A, Sankhyan N, Singhi P. Novel TTN mutation causing congenital myopathy. J Clin Neuromuscul Dis. 2018;19(4):232. doi:10.1097/CND.0000000000000167
Rees M, Nikoopour R, Fukuzawa A, et al. Making sense of missense variants in TTN‐related congenital myopathies. Acta Neuropathol. 2021;141(3):431‐453. doi:10.1007/s00401‐020‐02257‐0
Töpf A, Cox D, Zaharieva IT, et al. Digenic inheritance involving a muscle‐specific protein kinase and the giant titin protein causes a skeletal muscle myopathy. Nat Genet. 2024;56:395‐407. doi:10.1038/s41588‐023‐01651‐0
Van Den Hoogenhof MMG, Beqqali A, Amin AS, et al. RBM20 mutations induce an arrhythmogenic dilated cardiomyopathy related to disturbed calcium handling. Circulation. 2018;138(13):1330‐1342. doi:10.1161/CIRCULATIONAHA.117.031947
Savarese M, Johari M, Johnson K, et al. Improved criteria for the classification of titin variants in inherited skeletal myopathies. J Neuromuscul Dis. 2020;7(2):153‐166. doi:10.3233/JND‐190423
Schoch K, K‐G Tan Q, Stong N, et al. Alternative transcripts in variant interpretation: the potential for missed diagnoses and misdiagnoses. Genet Med. 2020;22(7):1269‐1275. doi:10.1038/s41436
Chauveau C, Rowell J, Ferreiro A. A rising titan: TTN review and mutation update. Hum Mutat. 2014;35(9):1046‐1059. doi:10.1002/HUMU.22611
Schafer S, De Marvao A, Adami E, et al. Titin‐truncating variants affect heart function in disease cohorts and the general population. Nat Genet. 2017;49(1):46‐53. doi:10.1038/NG.3719
Reese F, Williams B, Balderrama‐Gutierrez G, et al. The ENCODE4 long‐read RNA‐seq collection reveals distinct classes of transcript structure diversity. bioRxiv. 2023:2023.05.15.540865. doi:10.1101/2023.05.15.540865