Genotype-phenotype correlations in recessive titinopathies

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 cl...

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Authors: 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
Format: article
Status:Published version
Publication Date:2020
Country:España
Institution:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repository:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p1400
Online Access:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=1400
Access Level:Open access
Keyword:titin
skeletal muscle disorders
cardiomyopathy
congenital myopathy
arthrogryposis
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network_name_str España
repository_id_str
spelling Genotype-phenotype correlations in recessive titinopathiesSavarese, MVihola, AOates, ECBarresi, RFiorillo, CTasca, GJokela, MSarkozy, ALuo, SSDiaz-Manera, JEhrstedt, CRojas-Garcia, RSaenz, AMuelas, NLonardo, FFodstad, HQureshi, TJohari, MValipakka, SLuque, HPetiot, Pde Munain, ALPane, MMercuri, ETorella, ANigro, VAstrea, GSantorelli, FMBruno, CKuntzer, TIlla, IVilchez, JJJulien, CFerreiro, AMalandrini, AZhao, CBCasar-Borota, ODavis, MMuntoni, FHackman, PUdd, Btitinskeletal muscle disorderscardiomyopathycongenital myopathyarthrogryposisPurpose 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.SPRINGERNATURE2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=1400GENETICS IN MEDICINEISSN: 10983600ISSNe: 15300366reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p14002026-06-14T12:41:47Z
dc.title.none.fl_str_mv Genotype-phenotype correlations in recessive titinopathies
title Genotype-phenotype correlations in recessive titinopathies
spellingShingle Genotype-phenotype correlations in recessive titinopathies
Savarese, M
titin
skeletal muscle disorders
cardiomyopathy
congenital myopathy
arthrogryposis
title_short Genotype-phenotype correlations in recessive titinopathies
title_full Genotype-phenotype correlations in recessive titinopathies
title_fullStr Genotype-phenotype correlations in recessive titinopathies
title_full_unstemmed Genotype-phenotype correlations in recessive titinopathies
title_sort Genotype-phenotype correlations in recessive titinopathies
dc.creator.none.fl_str_mv 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
author Savarese, M
author_facet 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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv titin
skeletal muscle disorders
cardiomyopathy
congenital myopathy
arthrogryposis
topic titin
skeletal muscle disorders
cardiomyopathy
congenital myopathy
arthrogryposis
description 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.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=1400
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=1400
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv SPRINGERNATURE
publisher.none.fl_str_mv SPRINGERNATURE
dc.source.none.fl_str_mv GENETICS IN MEDICINE
ISSN: 10983600
ISSNe: 15300366
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869408067740762112
score 15,198674

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