Genotype-phenotype correlations in recessive titinopathies.,Genetics in Medicine

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Genotype-phenotype correlations in recessive titinopathies.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-08-11 , DOI: 10.1038/s41436-020-0914-2
Marco Savarese _{1,

2} , Anna Vihola _{1,

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 Díaz-Manera _{11,

12,

13} , Christoffer Ehrstedt _{14,

15} , Ricardo Rojas-García _{11,

12} , Amets Sáenz ₁₆ , Nuria Muelas _{12,

17} , Fortunato Lonardo ₁₈ , Heidi Fodstad ₁₉ , Talha Qureshi _{1,

2} , Mridul Johari _{1,

2} , Salla Välipakka _{1,

2} , Helena Luque _{1,

2} , Philippe Petiot ₂₀ , Adolfo López de Munain ₁₆ , Marika Pane ₂₁ , Eugenio Mercuri ₂₁ , Annalaura Torella ₂₂ , Vincenzo Nigro ₂₂ , Guja Astrea ₂₃ , Filippo Maria Santorelli ₂₃ , Claudio Bruno ₆ , Thierry Kuntzer ₂₄ , Isabel Illa _{11,

12} , Juan J Vílchez _{12,

17} , Cedric Julien ₂₅ , Ana Ferreiro _{25,

26} , Alessandro Malandrini ₂₇ , Chong-Bo Zhao ₁₀ , Olivera Casar-Borota ₂₈ , Mark Davis ₂₉ , Francesco Muntoni _{9,

30} , Peter Hackman _{1,

2} , Bjarne Udd _{1,

2,

31}

Affiliation

Folkhälsan Research Center, Helsinki, Finland.
Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
Neuromuscular Research Center, Fimlab Laboratories, Tampere University and University Hospital, Tampere, Finland.
School of Biotechnology & Biomolecular Sciences, University of New South Wales, Sydney, Australia.
Rare Diseases Advisory Group Service for Neuromuscular Diseases, Muscle Immunoanalysis Unit, Dental Hospital, and The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Translational and Clinical Research Institute, University of Newcastle, Newcastle upon Tyne, UK.
Paediatric Neurology and Neuromuscular Disorders Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Unità Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
Neuromuscular Research Center, Tampere University Hospital and Tampere University, Tampere, Finland.
Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, UK.
Department of Neurology, Huashan Hospital Fudan University, Shanghai, China.
Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu I Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
John Walton Muscular Dystrophy Research Center, University of Newcastle, Newcastle, UK.
Department of Women and Childrens Health, Section for Paediatrics, Uppsala University, Uppsala, Sweden.
Uppsala University Childrens Hospital, Uppsala, Sweden.
Group of Neuromuscular Diseases, Neurosciences Area, Biodonostia Health Research Institute, San Sebastián, Spain.
Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
UOSD Genetica Medica, AO Rummo, Benevento, Italy.
Department of Laboratory Medicine and Pathology, Division of Genetic Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
Hospices Civils de Lyon, Explorations Fonctionnelles Neurologiques, Hôpital de la Croix Rousse, Lyon, France.
Pediatric Neurology and Nemo Clinical Centre, Fondazione Policlinico Universitario A. Gemelli IRCSS, Università Cattolica del Sacro Cuore, Roma, Italy.
Medical Genetics, Department of Biochemistry, Biophysics and General Pathology University of Campania 'Luigi Vanvitelli' Naples Italy, Caserta, Italy.
Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy.
Department of Neurosciences, Nerve-Muscle Unit, Lausanne University Hospital (CHUV), 1011, Lausanne, Switzerland.
Centre de Référence de Pathologie Neuromusculaire Nord/Est/Ile-de-France (APHP), Institut de Myologie, GH Pitié-Salpêtrière, Paris, France.
Basic and Translational Myology Lab, UMR8251 BFA, Université de Paris/CNRS, Paris, France.
Neurology and Neurometabolic Unit, Department of Medicine, Surgery, and Neurosciences, University of Siena, Siena, Italy.
Department of Clinical Pathology, Uppsala University Hospital, Uppsala, Sweden.
Department of Diagnostic Genomics, Department of Health, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia.
NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK.
Department of Neurology, Vaasa Central Hospital, Vaasa, Finland.

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 pathogenic TTN variants. 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 three TTN exons (362–364).

Conclusion

Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.

中文翻译：

隐性肌动蛋白病中的基因型-表型相关性。

目的

高通量测序分析促进了整个titin ( TTN ) 编码序列的快速分析。这导致识别出越来越多的隐性肌腱病患者。本研究的目的是 (1) 描述迄今为止报道的最大的隐性肌腱病患者队列的致病基因变异和临床特征，以及 (2) 评估该队列中的基因型 - 表型相关性。

方法

我们分析了一组具有双等位基因致病性或可能致病性TTN变异的患者的临床和遗传数据。该队列包括先前报告的病例（来自 81 个无关家庭的 100 名患者）和未报告的病例（来自 20 个无关家庭的 23 名患者）。

结果

总体而言，在队列成员中发现了 132 个致病变异。超过一半的病例在出生时出现肌张力减退或肌肉无力，并且在生命的前 12 个月内出现运动发育迟缓（先天性肌病），致病变异位于整个基因上。其余患者具有远端或近端表型和儿童期或更晚（非先天性）发病。所有非先天性病例在最后三个TTN外显子之一中至少有一个致病性变异(362-364)。