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

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dc.contributor.authorBryen, S.J.
dc.contributor.authorEwans, L.
dc.contributor.authorPinner, J.
dc.contributor.authorMacLennan, S.C.
dc.contributor.authorDonkervoort, S.
dc.contributor.authorCastro, D.
dc.contributor.authorTöpf, A.
dc.contributor.authorO'Grady, G.
dc.contributor.authorCummings, B.
dc.contributor.authorChao, K.R.
dc.contributor.authorWeisburd, B.
dc.contributor.authorFrancioli, L.
dc.contributor.authorFaiz, F.
dc.contributor.authorBournazos, A.M.
dc.contributor.authorHu, Y.
dc.contributor.authorMalicki, D.M.
dc.contributor.authorDoyle, H.
dc.contributor.authorWitting, N.
dc.contributor.authorVissing, J.
dc.contributor.authorClaeys, K.G.
dc.contributor.authoret al.
dc.date.issued2020
dc.descriptionFirst published 29 October 2019
dc.description.abstractWe present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3' splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNA-sequencing from 365 adult human gastrocnemius samples revealed 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate ≥ 66%). Further, RNA-sequencing of five fetal muscle samples confirms 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). Importantly, contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons. This article is protected by copyright. All rights reserved.
dc.description.statementofresponsibilitySamantha J. Bryen, Lisa J. Ewans, Jason Pinner, Suzanna C. MacLennan, Sandra Donkervoort, Diana Castro, Ana Töpf, Gina O’Grady, Beryl Cummings, Katherine R. Chao, Ben Weisburd, Laurent Francioli, Fathimath Faiz, Adam M. Bournazos, Ying Hu, Carla Grosmann, Denise M. Malicki, Helen Doyle, Nanna Witting, John Vissing, Kristl G. Claeys, Kathryn Urankar, Ana Beleza-Meireles, Julia Baptista, Sian Ellard, Marco Savarese, Mridul Johari, Anna Vihola, Bjarne Udd, Anirban Majumdar, Volker Straub, Carsten G. Bönnemann, Daniel G. MacArthur, Mark R. Davis, Sandra T. Cooper
dc.identifier.citationHuman Mutation, 2020; 41(2):403-411
dc.identifier.doi10.1002/humu.23938
dc.identifier.issn1059-7794
dc.identifier.issn1098-1004
dc.identifier.orcidMacLennan, S.C. [0000-0003-0327-7155]
dc.identifier.urihttp://hdl.handle.net/2440/122660
dc.language.isoen
dc.publisherWiley
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1048816
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1136197
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1080587
dc.rights© 2019 Wiley Periodicals, Inc.
dc.source.urihttps://doi.org/10.1002/humu.23938
dc.subjectAlternative splicing; arthrogryposis; congenital titinopathies; intronic splice variant; TTN metatranscript‐only
dc.titleRecurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy
dc.typeJournal article
pubs.publication-statusPublished

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