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

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  • Samantha J Bryen
  • Lisa Ewans
  • Jason Pinner
  • Suzanna C MacLennan
  • Sandra Donkervoort
  • Diana Castro
  • Ana Töpf
  • Gina O'Grady
  • Beryl Cummings
  • Katherine R Chao
  • Ben Weisburd
  • Laurent Francioli
  • Fathin Faiz
  • Adam M Bournazos
  • Ying Hu
  • Denise M Malicki
  • Helen Doyle
  • Nanna Witting
  • John Vissing
  • Kristl G Claeys
  • Kathryn Urankar
  • Ana Beleza-Meireles
  • Julia Baptista
  • Sian Ellard
  • Anirban Majumdar
  • Volker Straub
  • Carsten Bonnemann
  • Daniel G MacArthur
  • Mark R Davis
  • Sandra T Cooper
Vis graf over relationer

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 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.

OriginalsprogEngelsk
TidsskriftHuman Mutation
Vol/bind41
Udgave nummer2
Sider (fra-til)403-411
ISSN1059-7794
DOI
StatusUdgivet - 1 feb. 2020

ID: 58451214