Genotype-phenotype correlations in recessive titinopathies

被引：46

作者：

Savarese, Marco ^{[1
,2
]}

Vihola, Anna ^{[1
,2
,3
,4
]}

Oates, Emily C. ^{[5
]}

Barresi, Rita ^{[6
,7
]}

Fiorillo, Chiara ^{[8
]}

Tasca, Giorgio ^{[9
]}

Jokela, Manu ^{[10
,11
]}

Sarkozy, Anna ^{[12
]}

Luo, Sushan ^{[13
]}

Diaz-Manera, Jordi ^{[14
,15
,16
]}

Ehrstedt, Christoffer ^{[17
,18
]}

Rojas-Garcia, Ricardo ^{[14
,15
]}

Saenz, Amets ^{[19
]}

Muelas, Nuria ^{[15
,20
]}

Lonardo, Fortunato ^{[21
]}

Fodstad, Heidi ^{[22
]}

Qureshi, Talha ^{[1
,2
]}

Johari, Mridul ^{[1
,2
]}

Valipakka, Salla ^{[1
,2
]}

Luque, Helena ^{[1
,2
]}

Petiot, Philippe ^{[23
]}

de Munain, Adolfo Lopez ^{[19
]}

Pane, Marika ^{[24
]}

Mercuri, Eugenio ^{[24
]}

Torella, Annalaura ^{[25
]}

Nigro, Vincenzo ^{[25
]}

Astrea, Guja ^{[26
]}

Santorelli, Filippo Maria ^{[26
]}

Bruno, Claudio ^{[8
]}

Kuntzer, Thierry ^{[27
]}

Illa, Isabel ^{[14
,15
]}

Vilchez, Juan J. ^{[15
,20
]}

Julien, Cedric ^{[28
]}

Ferreiro, Ana ^{[28
,29
]}

Malandrini, Alessandro ^{[30
]}

Zhao, Chong-Bo ^{[13
]}

Casar-Borota, Olivera ^{[31
]}

Davis, Mark ^{[32
]}

Muntoni, Francesco ^{[12
,33
]}

Hackman, Peter ^{[1
,2
]}

Udd, Bjarne ^{[1
,2
,34
]}

机构：

[1] Folkhalsan Res Ctr, Helsinki, Finland

[2] Univ Helsinki, Dept Med Genet, Medicum, Helsinki, Finland

[3] Tampere Univ, Neuromuscular Res Ctr, Fimlab Labs, Tampere, Finland

[4] Univ Hosp, Tampere, Finland

[5] Univ New South Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia

[6] Univ Newcastle, Dent Hosp, Muscle Immunoanal Unit, Rare Dis Advisory Grp,Serv Neuromuscular Dis, Newcastle Upon Tyne, Tyne & Wear, England

[7] Univ Newcastle, John Walton Muscular Dystrophy Res Ctr, MRC Ctr Neuromuscular Dis, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England

[8] IRCCS Ist Giannina Gaslini, Paediat Neurol & Neuromuscular Disorders Unit, Genoa, Italy

[9] Fdn Policlin Univ A Gemelli IRCCS, Unita Operat Complessa Neurol, Rome, Italy

[10] Tampere Univ Hosp, Neuromuscular Res Ctr, Tampere, Finland

[11] Tampere Univ, Tampere, Finland

[12] UCL Great Ormond St Inst Child Hlth, Dubowitz Neuromuscular Ctr, MRC Ctr Neuromuscular Dis, London, England

[13] Fudan Univ, Dept Neurol, Huashan Hosp, Shanghai, Peoples R China

[14] Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Neurol Dept, Neuromuscular Disorders Unit, Barcelona, Spain

[15] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain

[16] Univ Newcastle, John Walton Muscular Dystrophy Res Ctr, Newcastle, England

[17] Uppsala Univ, Sect Paediat, Dept Women & Childrens Hlth, Uppsala, Sweden

[18] Uppsala Univ, Childrens Hosp, Uppsala, Sweden

[19] Biodonostia Hlth Res Inst, Grp Neuromuscular Dis, Neurosci Area, San Sebastian, Spain

[20] Hosp Univ & Politecn La Fe, Inst Invest Sanit La Fe, Neuromuscular & Ataxias Res Grp, Neurol Dept,Neuromuscular Dis Unit, Valencia, Spain

[21] AO Rummo, UOSD Genet Med, Benevento, Italy

[22] Lausanne Univ Hosp CHUV, Div Med Genet, Dept Lab Med & Pathol, Lausanne, Switzerland

[23] Hop Croix Rousse, Hosp Civils Lyon, Explorat Fonct Neurol, Lyon, France

[24] Univ Cattolica Sacro Cuore, Pediat Neurol & Nemo Clin Ctr, Fdn Policlin Univ A Gemelli IRCSS, Rome, Italy

[25] Univ Campania Luigi Vanvitel Naples Italy, Dept Biochem Biophys & Gen Pathol, Med Genet, Caserta, Italy

[26] IRCCS Fdn Stella Maris, Mol Med, Pisa, Italy

[27] Lausanne Univ Hosp CHUV, Nerve Muscle Unit, Dept Neurosci, CH-1011 Lausanne, Switzerland

[28] GH Pitie Salpetriere, APHP, Inst Myol, Ctr Reference Pathol Neuromusculaire Nord Est Ile, Paris, France

[29] Univ Paris, Basic & Translat Myol Lab, CNRS, BFA,UMR8251, Paris, France

[30] Univ Siena, Dept Med Surg & Neurosci, Neurol & Neurometabol Unit, Siena, Italy

[31] Uppsala Univ Hosp, Dept Clin Pathol, Uppsala, Sweden

[32] QEII Med Ctr, Dept Hlth, PathWest Lab Med, Dept Diagnost Genom, Nedlands, WA, Australia

[33] NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England

[34] Vaasa Cent Hosp, Dept Neurol, Vaasa, Finland

来源：

GENETICS IN MEDICINE | 2020年 / 22卷 / 12期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

titin; skeletal muscle disorders; cardiomyopathy; congenital myopathy; arthrogryposis; TIBIAL MUSCULAR-DYSTROPHY; C-TERMINAL TITIN; TRUNCATING MUTATIONS; TTN; GENE; MYOPATHY; VARIANT; LINE; EXPRESSION; SEQUENCE;

D O I：

10.1038/s41436-020-0914-2

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：2029 / 2040

页数：12

共 40 条

[1] Loss of Sarcomeric Scaffolding as a Common Baseline Histopathologic Lesion in Titin-Related Myopathies [J].

Avila-Polo, Rainiero ;

Malfatti, Edoardo ;

Lornage, Xaviere ;

Cheraud, Chrystel ;

Nelson, Isabelle ;

Nectoux, Juliette ;

Bohm, Johann ;

Schneider, Raphael ;

Hedberg-Oldfors, Carola ;

Eymard, Bruno ;

Monges, Soledad ;

Lubieniecki, Fabiana ;

Brochier, Guy ;

Bui, Mai Thao ;

Madelaine, Angeline ;

Labasse, Clemence ;

Beuvin, Maud ;

Lacene, Emmanuelle ;

Boland, Anne ;

Deleuze, Jean-Francois ;

Thompson, Julie ;

Richard, Isabelle ;

Taratuto, Ana Lia ;

Udd, Bjarne ;

Leturcq, France ;

Bonne, Gisele ;

Oldfors, Anders ;

Laporte, Jocelyn ;

Romero, Norma Beatriz .

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 2018, 77 (12) :1101-1114

[2] The complete gene sequence of titin, expression of an unusual ≈700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system [J].

Bang, ML ;

Centner, T ;

Fornoff, F ;

Geach, AJ ;

Gotthardt, M ;

McNabb, M ;

Witt, CC ;

Labeit, D ;

Gregorio, CC ;

Granzier, H ;

Labeit, S .

CIRCULATION RESEARCH, 2001, 89 (11) :1065-1072

[3] Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy [J].

Bryen, Samantha J. ;

Ewans, Lisa J. ;

Pinner, Jason ;

MacLennan, Suzanna C. ;

Donkervoort, Sandra ;

Castro, Diana ;

Topf, Ana ;

O'Grady, Gina ;

Cummings, Beryl ;

Chao, Katherine R. ;

Weisburd, Ben ;

Francioli, Laurent ;

Faiz, Fathimath ;

Bournazos, Adam M. ;

Hu, Ying ;

Grosmann, Carla ;

Malicki, Denise M. ;

Doyle, Helen ;

Witting, Nanna ;

Vissing, John ;

Claeys, Kristl G. ;

Urankar, Kathryn ;

Beleza-Meireles, Ana ;

Baptista, Julia ;

Ellard, Sian ;

Savarese, Marco ;

Johari, Mridul ;

Vihola, Anna ;

Udd, Bjarne ;

Majumdar, Anirban ;

Straub, Volker ;

Bonnemann, Carsten G. ;

MacArthur, Daniel G. ;

Davis, Mark R. ;

Cooper, Sandra T. .

HUMAN MUTATION, 2020, 41 (02) :403-411

[4] Downsizing the molecular spring of the giant protein titin reveals that skeletal muscle titin determines passive stiffness and drives longitudinal hypertrophy [J].

Brynnel, Ambjorn ;

Hernandez, Yaeren ;

Kiss, Balazs ;

Lindqvist, Johan ;

Adler, Maya ;

Kolb, Justin ;

Van der Pijl, Robbert ;

Gohlke, Jochen ;

Strom, Joshua ;

Smith, John ;

Ottenheim, Coen ;

Granzier, Henk L. .

ELIFE, 2018, 7

[5] Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy [J].

Ceyhan-Birsoy, Ozge ;

Agrawal, Pankaj B. ;

Hidalgo, Carlos ;

Schmitz-Abe, Klaus ;

DeChene, Elizabeth T. ;

Swanson, Lindsay C. ;

Soemedi, Rachel ;

Vasli, Nasim ;

Iannaccone, Susan T. ;

Shieh, Perry B. ;

Shur, Natasha ;

Dennison, Jane M. ;

Lawlor, Michael W. ;

Laporte, Jocelyn ;

Markianos, Kyriacos ;

Fairbrother, William G. ;

Granzier, Henk ;

Beggs, Alan H. .

NEUROLOGY, 2013, 81 (14) :1205-1214

[6] CAPN3-mediated processing of C-terminal titin replaced by pathological cleavage in titinopathy [J].

Charton, Karine ;

Sarparanta, Jaakko ;

Vihola, Anna ;

Milic, Astrid ;

Jonson, Per Harald ;

Suel, Laurence ;

Luque, Helena ;

Boumela, Imene ;

Richard, Isabelle ;

Udd, Bjarne .

HUMAN MOLECULAR GENETICS, 2015, 24 (13) :3718-3731

[7] Recessive TTN truncating mutations define novel forms of core myopathy with heart disease [J].

Chauveau, Claire ;

Bonnemann, Carsten G. ;

Julien, Cedric ;

Kho, Ay Lin ;

Marks, Harold ;

Talim, Beril ;

Maury, Philippe ;

Arne-Bes, Marie Christine ;

Uro-Coste, Emmanuelle ;

Alexandrovich, Alexander ;

Vihola, Anna ;

Schafer, Sebastian ;

Kaufmann, Beth ;

Medne, Livija ;

Huebner, Norbert ;

Foley, A. Reghan ;

Santi, Mariarita ;

Udd, Bjarne ;

Topaloglu, Haluk ;

Moore, Steven A. ;

Gotthardt, Michael ;

Samuels, Mark E. ;

Gautel, Mathias ;

Ferreiro, Ana .

HUMAN MOLECULAR GENETICS, 2014, 23 (04) :980-991

[8] A homozygous TTN gene variant associated with lethal congenital contracture syndrome [J].

Chervinsky, Elena ;

Khayat, Morad ;

Soltsman, Sofia ;

Habiballa, Hatem ;

Elpeleg, Orly ;

Shalev, Stavit .

AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2018, 176 (04) :1001-1005

[9] A new titinopathy Childhood-juvenile onset Emery-Dreifuss-like phenotype without cardiomyopathy [J].

De Cid, Rafael ;

Ben Yaou, Rabah ;

Roudaut, Carinne ;

Charton, Karine ;

Baulande, Sylvain ;

Leturcq, France ;

Romero, Norma Beatriz ;

Malfatti, Edoardo ;

Beuvin, Maud ;

Vihola, Anna ;

Criqui, Audrey ;

Nelson, Isabelle ;

Nectoux, Juliette ;

Ben Aim, Laurene ;

Caloustian, Christophe ;

Olaso, Robert ;

Udd, Bjarne ;

Bonne, Gisele ;

Eymard, Bruno ;

Richard, Isabelle .

NEUROLOGY, 2015, 85 (24) :2126-2135

[10] Human Splicing Finder: an online bioinformatics tool to predict splicing signals [J].

Desmet, Francois-Olivier ;

Hamroun, Dalil ;

Lalande, Marine ;

Collod-Beroud, Gwenaelle ;

Claustres, Mireille ;

Beroud, Christophe .

NUCLEIC ACIDS RESEARCH, 2009, 37 (09)

← 1 2 3 4 →