Genotype-phenotype correlations in recessive titinopathies
Por:
Savarese, M, Vihola, A, Oates, EC, Barresi, R, Fiorillo, C, Tasca, G, Jokela, M, Sarkozy, A, Luo, SS, Diaz-Manera, J, Ehrstedt, C, Rojas-Garcia, R, Saenz, A, Muelas, N, Lonardo, F, Fodstad, H, Qureshi, T, Johari, M, Valipakka, S, Luque, H, Petiot, P, de Munain, AL, Pane, M, Mercuri, E, Torella, A, Nigro, V, Astrea, G, Santorelli, FM, Bruno, C, Kuntzer, T, Illa, I, Vilchez, JJ, Julien, C, Ferreiro, A, Malandrini, A, Zhao, CB, Casar-Borota, O, Davis, M, Muntoni, F, Hackman, P, Udd, B
Publicada:
1 dic 2020
Ahead of Print:
1 ago 2020
Resumen:
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.
Filiaciones:
Savarese, M:
Folkhalsan Res Ctr, Helsinki, Finland
Univ Helsinki, Dept Med Genet, Medicum, Helsinki, Finland
Vihola, A:
Folkhalsan Res Ctr, Helsinki, Finland
Univ Helsinki, Dept Med Genet, Medicum, Helsinki, Finland
Tampere Univ, Neuromuscular Res Ctr, Fimlab Labs, Tampere, Finland
Univ Hosp, Tampere, Finland
Oates, EC:
Univ New South Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia
Barresi, R:
Univ Newcastle, Dent Hosp, Muscle Immunoanal Unit, Rare Dis Advisory Grp,Serv Neuromuscular Dis, Newcastle Upon Tyne, Tyne & Wear, England
Univ Newcastle, John Walton Muscular Dystrophy Res Ctr, MRC Ctr Neuromuscular Dis, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Fiorillo, C:
IRCCS Ist Giannina Gaslini, Paediat Neurol & Neuromuscular Disorders Unit, Genoa, Italy
Tasca, G:
Fdn Policlin Univ A Gemelli IRCCS, Unita Operat Complessa Neurol, Rome, Italy
Jokela, M:
Tampere Univ Hosp, Neuromuscular Res Ctr, Tampere, Finland
Tampere Univ, Tampere, Finland
Sarkozy, A:
UCL Great Ormond St Inst Child Hlth, Dubowitz Neuromuscular Ctr, MRC Ctr Neuromuscular Dis, London, England
Luo, SS:
Fudan Univ, Dept Neurol, Huashan Hosp, Shanghai, Peoples R China
Diaz-Manera, J:
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Neurol Dept, Neuromuscular Disorders Unit, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain
Univ Newcastle, John Walton Muscular Dystrophy Res Ctr, Newcastle, England
Ehrstedt, C:
Uppsala Univ, Sect Paediat, Dept Women & Childrens Hlth, Uppsala, Sweden
Uppsala Univ, Childrens Hosp, Uppsala, Sweden
Rojas-Garcia, R:
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Neurol Dept, Neuromuscular Disorders Unit, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain
Saenz, A:
Biodonostia Hlth Res Inst, Grp Neuromuscular Dis, Neurosci Area, San Sebastian, Spain
Muelas, N:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain
Hosp Univ & Politecn La Fe, Inst Invest Sanit La Fe, Neuromuscular & Ataxias Res Grp, Neurol Dept,Neuromuscular Dis Unit, Valencia, Spain
Lonardo, F:
AO Rummo, UOSD Genet Med, Benevento, Italy
Fodstad, H:
Lausanne Univ Hosp CHUV, Div Med Genet, Dept Lab Med & Pathol, Lausanne, Switzerland
Qureshi, T:
Folkhalsan Res Ctr, Helsinki, Finland
Univ Helsinki, Dept Med Genet, Medicum, Helsinki, Finland
Johari, M:
Folkhalsan Res Ctr, Helsinki, Finland
Univ Helsinki, Dept Med Genet, Medicum, Helsinki, Finland
Valipakka, S:
Folkhalsan Res Ctr, Helsinki, Finland
Univ Helsinki, Dept Med Genet, Medicum, Helsinki, Finland
Luque, H:
Folkhalsan Res Ctr, Helsinki, Finland
Univ Helsinki, Dept Med Genet, Medicum, Helsinki, Finland
Petiot, P:
Hop Croix Rousse, Hosp Civils Lyon, Explorat Fonct Neurol, Lyon, France
de Munain, AL:
Biodonostia Hlth Res Inst, Grp Neuromuscular Dis, Neurosci Area, San Sebastian, Spain
Pane, M:
Univ Cattolica Sacro Cuore, Pediat Neurol & Nemo Clin Ctr, Fdn Policlin Univ A Gemelli IRCSS, Rome, Italy
Mercuri, E:
Univ Cattolica Sacro Cuore, Pediat Neurol & Nemo Clin Ctr, Fdn Policlin Univ A Gemelli IRCSS, Rome, Italy
Torella, A:
Univ Campania Luigi Vanvitel Naples Italy, Dept Biochem Biophys & Gen Pathol, Med Genet, Caserta, Italy
Nigro, V:
Univ Campania Luigi Vanvitel Naples Italy, Dept Biochem Biophys & Gen Pathol, Med Genet, Caserta, Italy
Astrea, G:
IRCCS Fdn Stella Maris, Mol Med, Pisa, Italy
Santorelli, FM:
IRCCS Fdn Stella Maris, Mol Med, Pisa, Italy
Bruno, C:
IRCCS Ist Giannina Gaslini, Paediat Neurol & Neuromuscular Disorders Unit, Genoa, Italy
Kuntzer, T:
Lausanne Univ Hosp CHUV, Nerve Muscle Unit, Dept Neurosci, CH-1011 Lausanne, Switzerland
Illa, I:
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Neurol Dept, Neuromuscular Disorders Unit, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain
Vilchez, JJ:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain
Hosp Univ & Politecn La Fe, Inst Invest Sanit La Fe, Neuromuscular & Ataxias Res Grp, Neurol Dept,Neuromuscular Dis Unit, Valencia, Spain
Julien, C:
GH Pitie Salpetriere, APHP, Inst Myol, Ctr Reference Pathol Neuromusculaire Nord Est Ile, Paris, France
Ferreiro, A:
GH Pitie Salpetriere, APHP, Inst Myol, Ctr Reference Pathol Neuromusculaire Nord Est Ile, Paris, France
Univ Paris, Basic & Translat Myol Lab, CNRS, BFA,UMR8251, Paris, France
Malandrini, A:
Univ Siena, Dept Med Surg & Neurosci, Neurol & Neurometabol Unit, Siena, Italy
Zhao, CB:
Fudan Univ, Dept Neurol, Huashan Hosp, Shanghai, Peoples R China
Casar-Borota, O:
Uppsala Univ Hosp, Dept Clin Pathol, Uppsala, Sweden
Davis, M:
QEII Med Ctr, Dept Hlth, PathWest Lab Med, Dept Diagnost Genom, Nedlands, WA, Australia
Muntoni, F:
UCL Great Ormond St Inst Child Hlth, Dubowitz Neuromuscular Ctr, MRC Ctr Neuromuscular Dis, London, England
NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England
Hackman, P:
Folkhalsan Res Ctr, Helsinki, Finland
Univ Helsinki, Dept Med Genet, Medicum, Helsinki, Finland
Udd, B:
Folkhalsan Res Ctr, Helsinki, Finland
Univ Helsinki, Dept Med Genet, Medicum, Helsinki, Finland
Vaasa Cent Hosp, Dept Neurol, Vaasa, Finland
Green Published
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