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*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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
Pages (from-to)403-411
Number of pages9
JournalHuman Mutation
Volume41
Issue number2
Early online date3 Dec 2019
DOIs
Publication statusPublished - Feb 2020

Keywords

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

Fingerprint

Dive into the research topics of 'Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy'. Together they form a unique fingerprint.

Cite this