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

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.; Cooper, S. T.

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dc.creator	Bryen, S. J.
dc.creator	Ewans, L. J.
dc.creator	Pinner, J.
dc.creator	MacLennan, S. C.
dc.creator	Donkervoort, S.
dc.creator	Castro, D.
dc.creator	Töpf, A.
dc.creator	O'Grady, G.
dc.creator	Cummings, B.
dc.creator	Chao, K. R.
dc.creator	Weisburd, B.
dc.creator	Francioli, L.
dc.creator	Faiz, F.
dc.creator	Bournazos, A. M.
dc.creator	Hu, Y.
dc.creator	Grosmann, C.
dc.creator	Malicki, D. M.
dc.creator	Doyle, H.
dc.creator	Witting, N.
dc.creator	Vissing, J.
dc.creator	Claeys, K. G.
dc.creator	Urankar, K.
dc.creator	Beleza-Meireles, A.
dc.creator	Baptista, J.
dc.creator	Ellard, S.
dc.creator	Savarese, M.
dc.creator	Johari, M.
dc.creator	Vihola, A.
dc.creator	Udd, B.
dc.creator	Majumdar, A.
dc.creator	Straub, V.
dc.creator	Bönnemann, C. G.
dc.creator	MacArthur, D. G.
dc.creator	Davis, M. R.
dc.creator	Cooper, S. T.
dc.date	2021-09-06T12:35:15Z
dc.date	2021-09-06T12:35:15Z
dc.date	2020-02-01
dc.date.accessioned	2023-02-17T19:47:33Z
dc.date.available	2023-02-17T19:47:33Z
dc.identifier	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.
dc.identifier	31660661
dc.identifier	10.1002/humu.23938
dc.identifier	https://rde.dspace-express.com/handle/11287/621948
dc.identifier	Human Mutation
dc.identifier	PMC7306402
dc.identifier.uri	http://localhost:8080/xmlui/handle/CUHPOERS/241973
dc.description	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.
dc.description	The article is available via Open Access. Click on the 'Additional link' above to access the full-text.
dc.description	Published version, accepted version (12 month embargo), submitted version
dc.language	eng
dc.publisher	Wiley
dc.relation	https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31660661/
dc.rights	© 2019 Wiley Periodicals, Inc.
dc.rights	http://creativecommons.org/publicdomain/zero/1.0/
dc.subject	*Alternative Splicing
dc.subject	Arthrogryposis/diagnosis/genetics
dc.subject	Child
dc.subject	Child, Preschool
dc.subject	Connectin/*genetics
dc.subject	Female
dc.subject	*Genes, Recessive
dc.subject	Genetic Association Studies
dc.subject	*Genetic Predisposition to Disease
dc.subject	Humans
dc.subject	Infant
dc.subject	Male
dc.subject	Muscular Diseases/diagnosis/genetics
dc.subject	Mutation
dc.subject	Pedigree
dc.subject	Phenotype
dc.subject	Radiography
dc.subject	*TTN metatranscript-only
dc.subject	*arthrogryposis
dc.subject	*congenital titinopathies
dc.subject	*intronic splice variant
dc.subject	Ltd (Australia). Frontier Genomics has not traded (as of October, 2019). Frontier
dc.subject	Genomics Pty Ltd (Australia) has no existing financial relationships that will
dc.subject	benefit from publication of these data. The remaining co-authors do not have any
dc.subject	relationships, financial or otherwise, that may result in a perceived conflict of
dc.subject	interest.
dc.title	Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy
dc.type	Journal Article
dc.type	Published