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 Vissing; Kristl 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

doi:10.1002/humu.23938

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

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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 language	English (US)
Pages (from-to)	403-411
Number of pages	9
Journal	Human mutation
Volume	41
Issue number	2
DOIs	https://doi.org/10.1002/humu.23938
State	Published - Feb 1 2020

Keywords

TTN metatranscript-only
alternative splicing
arthrogryposis
congenital titinopathies
intronic splice variant

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1002/humu.23938

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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., ... 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), 403-411. https://doi.org/10.1002/humu.23938

Bryen, SJ, Ewans, LJ, Pinner, J, MacLennan, SC, Donkervoort, S, Castro, D, Töpf, A, O'Grady, G, Cummings, B, Chao, KR, Weisburd, B, Francioli, L, Faiz, F, Bournazos, AM, Hu, Y, Grosmann, C, Malicki, DM, Doyle, H, Witting, N, Vissing, J, Claeys, KG, Urankar, K, Beleza-Meireles, A, Baptista, J, Ellard, S, Savarese, M, Johari, M, Vihola, A, Udd, B, Majumdar, A, Straub, V, Bönnemann, CG, MacArthur, DG, Davis, MR & Cooper, ST 2020, 'Recurrent TTN metatranscript-only c.39974–11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy', Human mutation, vol. 41, no. 2, pp. 403-411. https://doi.org/10.1002/humu.23938

@article{8665d10c46ba49bf974451da23141366,

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

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.",

keywords = "TTN metatranscript-only, alternative splicing, arthrogryposis, congenital titinopathies, intronic splice variant",

author = "Bryen, {Samantha J.} and Ewans, {Lisa J.} and Jason Pinner and MacLennan, {Suzanna C.} and Sandra Donkervoort and Diana Castro and Ana T{\"o}pf and Gina O'Grady and Beryl Cummings and Chao, {Katherine R.} and Ben Weisburd and Laurent Francioli and Fathimath Faiz and Bournazos, {Adam M.} and Ying Hu and Carla Grosmann and Malicki, {Denise M.} and Helen Doyle and Nanna Witting and John Vissing and Claeys, {Kristl G.} and Kathryn Urankar and Ana Beleza-Meireles and Julia Baptista and Sian Ellard and Marco Savarese and Mridul Johari and Anna Vihola and Bjarne Udd and Anirban Majumdar and Volker Straub and B{\"o}nnemann, {Carsten G.} and MacArthur, {Daniel G.} and Davis, {Mark R.} and Cooper, {Sandra T.}",

note = "Funding Information: Samantha J. Bryen Lisa J. Ewans Jason Pinner Suzanna C. MacLennan Sandra Donkervoort Diana Castro Ana T{\"o}pf 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 Vissing Kristl 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. B{\"o}nnemann Daniel G. MacArthur Mark R. Davis Sandra T. Cooper sandra.cooper@sydney.edu.au Kids Neuroscience Centre, Kids Research Children's Hospital at Westmead Westmead New South Wales Australia Discipline of Child and Adolescent Health The University of Sydney Children's Hospital Westmead Clinical School Westmead New South Wales Australia Department of Medical Genomics Royal Prince Alfred Hospital Camperdown New South Wales Australia Central Clinical School University of Sydney Sydney New South Wales Australia Neurology Department Women's and Children's Hospital North Adelaide South Australia Australia School of Paediatrics and Reproductive Health University of Adelaide Adelaide South Australia Australia Neurogenetics Branch, National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda Maryland Department of Pediatrics University of Texas Southwestern Medical Center Dallas Texas John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine Newcastle University Newcastle upon Tyne United Kingdom Analytic and Translational Genetics Unit Massachusetts General Hospital Boston Massachusetts Center for Mendelian Genomics Broad Institute of Massachusetts Institute of Technology and Harvard Cambridge Massachusetts Program in Medical and Population Genetics Broad Institute of Massachusetts Institute of Technology and Harvard Cambridge Massachusetts Department of Diagnostic Genomics PathWest Laboratory Medicine Nedlands WA Australia Department of Pathology Rady Children's Hospital University of California San Diego San Diego California Department of Histopathology The Children's Hospital at Westmead, Sydney Children's Hospital Network Westmead NSW Australia Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet University of Copenhagen Copenhagen Denmark Department of Neurology University Hospitals Leuven Leuven Belgium Laboratory for Muscle Diseases and Neuropathies, Department of Neurosciences, Experimental Neurology KU Leuven‐University of Leuven Leuven Belgium Paediatric Neurology, Bristol Royal Hospital For Children University Hospitals Bristol NHS Foundation Trust Bristol United Kingdom Molecular Genetics Department Royal Devon and Exeter NHS Foundation Trust Exeter United Kingdom Institute of Biomedical and Clinical Science University of Exeter Medical School University of Exeter Exeter United Kingdom Functional Neuromics The Children's Medical Research Institute Westmead New South Wales Australia Department of Neurology Rady Children's Hospital University of California San Diego San Diego California Folkh{\"a}lsan Research Center Medicum, University of Helsinki Haartmaninkatu 8 Helsinki 00290 Finland Tampere Neuromuscular Center Tampere University Hospital Teiskontie 35 Tampere 33520 Finland Centre for Clinical Genetics Sydney Children's Hospital Randwick NSW 2031 Australia Clinical Genetics, Bristol Royal Hospital For Children University Hospitals Bristol NHS Foundation Trust Bristol United Kingdom Department of Neuropathology, Southmead Hospital University Hospitals Bristol NHS Foundation Trust Bristol United Kingdom alternative splicing arthrogryposis congenital titinopathies intronic splice variant TTN metatranscript‐only National Human Genome Research Institute HG008900 National Health and Medical Research Council APP1048816 APP1080587 APP1136197 National Eye Institute HG008900 National Heart, Lung and Blood Institute UM1 HG008900 Supporting information Funding Information: The authors thank the families for their invaluable contributions to this research, and the clinicians and health care workers involved in their assessment and management. We also thank CureCMD for their help with patient recruitment. This study was supported by the National Health and Medical Research Council of Australia (APP1048816 and APP1136197 S. T. C., APP1080587 S.T.C., D. G. M.). S. B. is supported by a Muscular Dystrophy New South Wales PhD scholarship. C. G. B. is supported by intramural funds of the National Institute of Neurological Disorders and Stroke, of the National Institutes of Health. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. All clinical cases reported herein are of utmost importance and authorship order does not reflect diminishing authorship contributions. Funding Information: The authors thank the families for their invaluable contributions to this research, and the clinicians and health care workers involved in their assessment and management. We also thank CureCMD for their help with patient recruitment. This study was supported by the National Health and Medical Research Council of Australia (APP1048816 and APP1136197 S. T. C., APP1080587 S.T.C., D. G. M.). S. B. is supported by a Muscular Dystrophy New South Wales PhD scholarship. C. G. B. is supported by intramural funds of the National Institute of Neurological Disorders and Stroke, of the National Institutes of Health. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. All clinical cases reported herein are of utmost importance and authorship order does not reflect diminishing authorship contributions. Publisher Copyright: {\textcopyright} 2019 Wiley Periodicals, Inc.",

year = "2020",

month = feb,

day = "1",

doi = "10.1002/humu.23938",

language = "English (US)",

volume = "41",

pages = "403--411",

journal = "Human mutation",

issn = "1059-7794",

publisher = "Wiley-Liss Inc.",

number = "2",

}

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 - Funding Information: 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 Vissing Kristl 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 sandra.cooper@sydney.edu.au Kids Neuroscience Centre, Kids Research Children's Hospital at Westmead Westmead New South Wales Australia Discipline of Child and Adolescent Health The University of Sydney Children's Hospital Westmead Clinical School Westmead New South Wales Australia Department of Medical Genomics Royal Prince Alfred Hospital Camperdown New South Wales Australia Central Clinical School University of Sydney Sydney New South Wales Australia Neurology Department Women's and Children's Hospital North Adelaide South Australia Australia School of Paediatrics and Reproductive Health University of Adelaide Adelaide South Australia Australia Neurogenetics Branch, National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda Maryland Department of Pediatrics University of Texas Southwestern Medical Center Dallas Texas John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine Newcastle University Newcastle upon Tyne United Kingdom Analytic and Translational Genetics Unit Massachusetts General Hospital Boston Massachusetts Center for Mendelian Genomics Broad Institute of Massachusetts Institute of Technology and Harvard Cambridge Massachusetts Program in Medical and Population Genetics Broad Institute of Massachusetts Institute of Technology and Harvard Cambridge Massachusetts Department of Diagnostic Genomics PathWest Laboratory Medicine Nedlands WA Australia Department of Pathology Rady Children's Hospital University of California San Diego San Diego California Department of Histopathology The Children's Hospital at Westmead, Sydney Children's Hospital Network Westmead NSW Australia Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet University of Copenhagen Copenhagen Denmark Department of Neurology University Hospitals Leuven Leuven Belgium Laboratory for Muscle Diseases and Neuropathies, Department of Neurosciences, Experimental Neurology KU Leuven‐University of Leuven Leuven Belgium Paediatric Neurology, Bristol Royal Hospital For Children University Hospitals Bristol NHS Foundation Trust Bristol United Kingdom Molecular Genetics Department Royal Devon and Exeter NHS Foundation Trust Exeter United Kingdom Institute of Biomedical and Clinical Science University of Exeter Medical School University of Exeter Exeter United Kingdom Functional Neuromics The Children's Medical Research Institute Westmead New South Wales Australia Department of Neurology Rady Children's Hospital University of California San Diego San Diego California Folkhälsan Research Center Medicum, University of Helsinki Haartmaninkatu 8 Helsinki 00290 Finland Tampere Neuromuscular Center Tampere University Hospital Teiskontie 35 Tampere 33520 Finland Centre for Clinical Genetics Sydney Children's Hospital Randwick NSW 2031 Australia Clinical Genetics, Bristol Royal Hospital For Children University Hospitals Bristol NHS Foundation Trust Bristol United Kingdom Department of Neuropathology, Southmead Hospital University Hospitals Bristol NHS Foundation Trust Bristol United Kingdom alternative splicing arthrogryposis congenital titinopathies intronic splice variant TTN metatranscript‐only National Human Genome Research Institute HG008900 National Health and Medical Research Council APP1048816 APP1080587 APP1136197 National Eye Institute HG008900 National Heart, Lung and Blood Institute UM1 HG008900 Supporting information Funding Information: The authors thank the families for their invaluable contributions to this research, and the clinicians and health care workers involved in their assessment and management. We also thank CureCMD for their help with patient recruitment. This study was supported by the National Health and Medical Research Council of Australia (APP1048816 and APP1136197 S. T. C., APP1080587 S.T.C., D. G. M.). S. B. is supported by a Muscular Dystrophy New South Wales PhD scholarship. C. G. B. is supported by intramural funds of the National Institute of Neurological Disorders and Stroke, of the National Institutes of Health. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. All clinical cases reported herein are of utmost importance and authorship order does not reflect diminishing authorship contributions. Funding Information: The authors thank the families for their invaluable contributions to this research, and the clinicians and health care workers involved in their assessment and management. We also thank CureCMD for their help with patient recruitment. This study was supported by the National Health and Medical Research Council of Australia (APP1048816 and APP1136197 S. T. C., APP1080587 S.T.C., D. G. M.). S. B. is supported by a Muscular Dystrophy New South Wales PhD scholarship. C. G. B. is supported by intramural funds of the National Institute of Neurological Disorders and Stroke, of the National Institutes of Health. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. All clinical cases reported herein are of utmost importance and authorship order does not reflect diminishing authorship contributions. Publisher Copyright: © 2019 Wiley Periodicals, Inc.

PY - 2020/2/1

Y1 - 2020/2/1

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.

KW - TTN metatranscript-only

KW - alternative splicing

KW - arthrogryposis

KW - congenital titinopathies

KW - intronic splice variant

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U2 - 10.1002/humu.23938

DO - 10.1002/humu.23938

M3 - Article

C2 - 31660661

AN - SCOPUS:85076122380

SN - 1059-7794

VL - 41

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EP - 411

JO - Human mutation

JF - Human mutation

IS - 2

ER -

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

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