Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy. / Bryen, Samantha J; Ewans, Lisa J; Pinner, Jason; MacLennan, Suzanna C; Donkervoort, Sandra; Castro, Diana; Töpf, Ana; O'Grady, Gina; Cummings, Beryl; Chao, Katherine R; Weisburd, Ben; Francioli, Laurent; Faiz, Fathimath; Bournazos, Adam M; Hu, Ying; Grosmann, Carla; Malicki, Denise M; Doyle, Helen; Witting, Nanna; Vissing, John; Claeys, Kristl G; Urankar, Kathryn; Beleza-Meireles, Ana; Baptista, Julia; Ellard, Sian; Savarese, Marco; Johari, Mridul; Vihola, Anna; Udd, Bjarne; Majumdar, Anirban; Straub, Volker; Bönnemann, Carsten G; MacArthur, Daniel G; Davis, Mark R; Cooper, Sandra T.
I: Human Mutation, Bind 41, Nr. 2, 29.10.2020, s. 403-411.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy
AU - Bryen, Samantha J
AU - Ewans, Lisa J
AU - Pinner, Jason
AU - MacLennan, Suzanna C
AU - Donkervoort, Sandra
AU - Castro, Diana
AU - Töpf, Ana
AU - O'Grady, Gina
AU - Cummings, Beryl
AU - Chao, Katherine R
AU - Weisburd, Ben
AU - Francioli, Laurent
AU - Faiz, Fathimath
AU - Bournazos, Adam M
AU - Hu, Ying
AU - Grosmann, Carla
AU - Malicki, Denise M
AU - Doyle, Helen
AU - Witting, Nanna
AU - Vissing, John
AU - Claeys, Kristl G
AU - Urankar, Kathryn
AU - Beleza-Meireles, Ana
AU - Baptista, Julia
AU - Ellard, Sian
AU - Savarese, Marco
AU - Johari, Mridul
AU - Vihola, Anna
AU - Udd, Bjarne
AU - Majumdar, Anirban
AU - Straub, Volker
AU - Bönnemann, Carsten G
AU - MacArthur, Daniel G
AU - Davis, Mark R
AU - Cooper, Sandra T
N1 - © 2019 Wiley Periodicals, Inc.
PY - 2020/10/29
Y1 - 2020/10/29
N2 - 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.
AB - 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.
U2 - 10.1002/humu.23938
DO - 10.1002/humu.23938
M3 - Journal article
C2 - 31660661
VL - 41
SP - 403
EP - 411
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 2
ER -
ID: 236015844