Inferring disease course from differential exon usage in the wide titinopathy spectrum
Di Feo, Maria Francesca (University of Genoa (Gènova, Itàlia))
Oghabian, Ali (University of Genoa (Gènova, Itàlia))
Nippala, Ella (Folkhälsan Research Center (Helsinki, Finland))
Gautel, Mathias (King's College London BHF Centre of Research Excellence)
Jungbluth, Heinz (Guy's and St Thomas' Hospitals NHS Trust (London, Regne Unit))
Forzano, Francesca (Guy's and St Thomas' Hospitals NHS Trust (London, Regne Unit))
Malfatti, Edoardo (Université Paris Est Créteil, INSERM, U955, IMRB, and Reference Center for Neuromuscular Disorders, APHP Henri Mondor University Hospital)
Castiglioni, Claudia (Clinica MEDS (Santiago de Chile, Xile))
Krey, Ilona (University of Leipzig Hospitals and Clinics)
Gómez-Andrés, David (Hospital Universitari Vall d'Hebron)
Brady, Angela F. (Northwick Park and St. Mark's Hospitals (Harrow, London))
Iascone, Maria (ASST Papa Giovanni XXIII (Bergamo, Itàlia))
Cereda, Anna (ASST Papa Giovanni XXIII (Bergamo, Itàlia))
Pezzani, Lidia (ASST Papa Giovanni XXIII (Bergamo, Itàlia))
Natera-de Benito, Daniel (Hospital Sant Joan de Déu (Esplugues de Llobregat, Catalunya))
Nascimiento Osorio, Andres (Hospital Sant Joan de Déu (Esplugues de Llobregat, Catalunya))
Estévez-Arias, Berta (Hospital Sant Joan de Déu (Esplugues de Llobregat, Catalunya))
Kurbatov, Sergei A. (Saratov State Medical University)
Attie-Bitach, Tania (Hôpital Necker-Enfants Malades (Paris, França))
Nampoothiri, Sheela (Amrita Institute of Medical Sciences & Research Centre (Kochi, Índia))
Ryan, Erin (GeneDx (Gaithersburg, Estats Units d'Amèrica))
Morrow, Michelle M. (GeneDx (Gaithersburg, Estats Units d'Amèrica))
Gorokhova, Svetlana (Aix-Marseille Université)
Chabrol, Brigitte (Marseille University Hospital)
Sinisalo, Juha (Helsinki University Central Hospital)
Tolppanen, Heli (Helsinki University Central Hospital)
Tolva, Johanna (University of Helsinki)
Munell Casadesus, Francina (Hospital Universitari Vall d'Hebron)
Camacho, Jessica (Hospital Universitari Vall d'Hebron)
Sanchez-Durán, Maria Angeles (Hospital Universitari Vall d'Hebron)
Johari, Mridul (University of Western Australia)
Tajsharghi, Homa (University of Skovde)
Hackman, Peter (Folkhälsan Research Center (Helsink, Finland))
Udd, Bjarne (Tampere University Hospital)
Savarese, Marco (Folkhälsan Research Center)
Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i de Medicina Preventiva i Salut Pública

Fecha:	2024
Resumen:	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.
Ayudas:	Instituto de Salud Carlos III AC19/00048
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	Annals of clinical and translational neurology, Vol. 11 (august 2024) , p. 2745-2755, ISSN 2328-9503

DOI: 10.1002/acn3.52189
PMID: 39198997

11 p, 734.6 KB

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