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

Hum Mutat. 2020 Feb;41(2):403-411. doi: 10.1002/humu.23938. Epub 2019 Dec 3.


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.

Keywords: TTN metatranscript-only; alternative splicing; arthrogryposis; congenital titinopathies; intronic splice variant.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Arthrogryposis / diagnosis*
  • Arthrogryposis / genetics*
  • Child
  • Child, Preschool
  • Connectin / genetics*
  • Female
  • Genes, Recessive*
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Infant
  • Male
  • Muscular Diseases / diagnosis*
  • Muscular Diseases / genetics*
  • Mutation
  • Pedigree
  • Phenotype
  • Radiography


  • Connectin
  • TTN protein, human