Bryen, S.J.Ewans, L.Pinner, J.MacLennan, S.C.Donkervoort, S.Castro, D.Töpf, A.O'Grady, G.Cummings, B.Chao, K.R.Weisburd, B.Francioli, L.Faiz, F.Bournazos, A.M.Hu, Y.Malicki, D.M.Doyle, H.Witting, N.Vissing, J.Claeys, K.G.et al.2020-01-132020-01-132020Human Mutation, 2020; 41(2):403-4111059-77941098-1004http://hdl.handle.net/2440/122660First published 29 October 2019We 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.en© 2019 Wiley Periodicals, Inc.Alternative splicing; arthrogryposis; congenital titinopathies; intronic splice variant; TTN metatranscript‐onlyJournal article100000380310.1002/humu.23938000500154700001502875MacLennan, S.C. [0000-0003-0327-7155]