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

Research output: Contribution to journalJournal articleResearchpeer-review

  • 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
  • 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

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
JournalHuman Mutation
Issue number2
Pages (from-to)403-411
Number of pages9
Publication statusPublished - 29 Oct 2020

ID: 236015844