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

Samantha 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 VissingKristl 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

Research output: Contribution to journalArticle

Abstract

We 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 that 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate ≥66%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). 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.

Original languageEnglish (US)
Pages (from-to)403-411
Number of pages9
JournalHuman mutation
Volume41
Issue number2
DOIs
StatePublished - Feb 1 2020

Keywords

  • TTN metatranscript-only
  • alternative splicing
  • arthrogryposis
  • congenital titinopathies
  • intronic splice variant

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Bryen, S. J., Ewans, L. J., 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., Grosmann, C., Malicki, D. M., Doyle, H., Witting, N., ... Cooper, S. T. (2020). Recurrent TTN metatranscript-only c.39974–11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy. Human mutation, 41(2), 403-411. https://doi.org/10.1002/humu.23938