Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy
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Authors
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.
Issue Date
2020-02-01
Type
Journal Article
Language
eng
Keywords
*Alternative Splicing , Arthrogryposis/*diagnosis/*genetics , Child , Child, Preschool , Connectin/*genetics , Female , *Genes, Recessive , Genetic Association Studies , *Genetic Predisposition to Disease , Humans , Infant , Male , Muscular Diseases/*diagnosis/*genetics , Mutation , Pedigree , Phenotype , Radiography , *TTN metatranscript-only , *arthrogryposis , *congenital titinopathies , *intronic splice variant
Alternative Title
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.
Description
Citation
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., Vissing, J., Claeys, K. G., Urankar, K., Beleza-Meireles, A., Baptista, J., Ellard, S., Savarese, M., Johari, M., Vihola, A., Udd, B., Majumdar, A., Straub, V., Bönnemann, C. G., MacArthur, D. G., Davis, M. R. and 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), pp. 403-411.
Publisher
Wiley
License
Journal
Human Mutation