Inferring disease course from differential exon usage in the wide titinopathy spectrum
Por:
Di Feo MF, Oghabian A, Nippala E, Gautel M, Jungbluth H, Forzano F, Malfatti E, Castiglioni C, Krey I, Gomez Andres D, Brady AF, Iascone M, Cereda A, Pezzani L, Natera-de Benito D, Nascimento-Osorio A, Estévez-Arias B, Kurbatov SA, Attie-Bitach T, Nampoothiri S, Ryan E, Morrow M, Gorokhova S, Chabrol B, Sinisalo J, Tolppanen H, Tolva J, Munell F, Camacho Soriano J, Sanchez Duran MA, Johari M, Tajsharghi H, Hackman P, Udd B and Savarese M
Publicada:
1 oct 2024
Ahead of Print:
1 ago 2024
Resumen:
ObjectiveBiallelic 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an unequivocal molecular diagnosis and precise disease prognosis remains challenging.MethodsIn this case series, 12 unpublished cases and one already published case with biallelic TTNtv were collected from multiple international medical centers between November 2022 and September 2023.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.ResultsWe 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.InterpretationThis 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.
Filiaciones:
Di Feo MF:
Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy
Folkhälsan Research Center, Helsinki, Uusimaa, Finland
Oghabian A:
Folkhälsan Research Center, Helsinki, Uusimaa, Finland
Nippala E:
Folkhälsan Research Center, Helsinki, Uusimaa, Finland
Gautel M:
Randall Division of Cell and Molecular Biophysics and Cardiovascular Division, King's College London BHF Centre of Research Excellence, London, UK
Jungbluth H:
Randall Division of Cell and Molecular Biophysics and Cardiovascular Division, King's College London BHF Centre of Research Excellence, London, UK
Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's and St Thomas' Hospitals NHS Trust, London, UK
Forzano F:
Clinical Genetics Department, Guy's and St Thomas NHS Foundation Trust, London, SE1 9RT, UK
Malfatti E:
Université Paris Est Créteil, INSERM, U955, IMRB, and Reference Center for Neuromuscular Disorders, APHP Henri Mondor University Hospital, Créteil, France
Castiglioni C:
Clinica MEDS, Santiago de Chile, Chile
Krey I:
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, 4275, Germany
Gomez Andres D:
Child Neurology Unit. Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
Brady AF:
North West Thames Regional Service, Northwick Park and St. Mark's Hospitals, Harrow, London, UK
Iascone M:
Medical Genetics Laboratory, ASST Papa Giovanni XXIII, Bergamo, Italy
Cereda A:
Clinical Genetics Service, Pediatria 1-ASST Papa Giovanni XXIII, Bergamo, Italy
Pezzani L:
Clinical Genetics Service, Pediatria 1-ASST Papa Giovanni XXIII, Bergamo, Italy
Natera-de Benito D:
Neuropaediatrics Department, Hospital Sant Joan De Déu, Institut De Recerca Sant Joan De Déu, Barcelona, 08950, Spain
Nascimento-Osorio A:
Neuropaediatrics Department, Hospital Sant Joan De Déu, Institut De Recerca Sant Joan De Déu, Barcelona, 08950, Spain
Estévez-Arias B:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Kurbatov SA:
Voronezh NN Burdenko State Medical University, Voronezh, 394036, Russia
Saratov State Medical University, Saratov, 410012, Russia
Attie-Bitach T:
Unité D'embryofoetopathologie, Service D'histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, Paris, France
Nampoothiri S:
Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Kochi, Kerala, India
Ryan E:
GeneDx, Gaithersburg, Maryland, USA
Morrow M:
GeneDx, Gaithersburg, Maryland, USA
Gorokhova S:
Marseille Medical Genetics, Aix Marseille Université, Faculté Des Sciences Médicales Et Paramédicales, Marseille, France
Chabrol B:
Reference Center for Inherited Metabolic Diseases, Marseille University Hospital, Marseille, France
Sinisalo J:
Helsinki University Central Hospital, Helsinki, Finland
Tolppanen H:
Helsinki University Central Hospital, Helsinki, Finland
Tolva J:
Transplantation Laboratory, Department of Pathology, University of Helsinki, Helsinki, Finland
Munell F:
Unitat De Malalties Neuromusculars Pediàtriques, Hospital Universitari Vall D'Hebron, Barcelona, Spain
Camacho Soriano J:
Histology Department, Vall D'Hebron University Hospital, Barcelona, Spain
Sanchez Duran MA:
Maternal Fetal Medicine Unit, Department of Obstetrics, Universitat Autònoma de Barcelona, Hospital Vall D'Hebron, Barcelona, Spain
Johari M:
Folkhälsan Research Center, Helsinki, Uusimaa, Finland
Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia
Tajsharghi H:
Division of Biomedicine, School of Health Sciences, University of Skovde, Skovde, Sweden
Hackman P:
Folkhälsan Research Center, Helsinki, Uusimaa, Finland
Udd B:
Folkhälsan Research Center, Helsinki, Uusimaa, Finland
Department of Musculoskeletal Diseases, Tampere University Hospital, Tampere, Pirkanmaa, Finland
Savarese M:
Folkhälsan Research Center, Helsinki, Uusimaa, Finland
Green Submitted, gold
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