Evidence map›Paper›PMID 39853809›Full record

ArticleAnnals of neurology2025

Congenital Titinopathy: Comprehensive Characterization of the Most Severe End of the Disease Spectrum.

Sandra Coppens, Nicolas Deconinck, Patricia Sullivan, Andrei Smolnikov, Joshua S Clayton, Kaitlyn R Griffin, Kristi J Jones, Catheline N Vilain, Hazim Kadhim, Samantha J Bryen and 52 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Annals of neurology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

62 authors.

Sandra CoppensHopital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium.ORCID 0000-0001-9155-7506
Nicolas DeconinckDepartment of Paediatric Neurology, Neuromuscular Reference Center, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium.ORCID 0000-0003-4284-6154
Patricia SullivanChildren's Cancer Institute, Lowy Cancer Centre, University of New South Wales, Sydney, New South Wales, Australia.ORCID 0000-0002-4886-8883
Andrei SmolnikovSchool of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.ORCID 0000-0003-0983-5883
Joshua S ClaytonHarry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.ORCID 0000-0001-6039-4185
Kaitlyn R GriffinSchool of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
Kristi J JonesKids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
Catheline N VilainHopital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium.ORCID 0009-0003-2959-659X
Hazim KadhimNeuropathology Unit (Anatomic Pathology Service) and Reference Center for Neuromuscular Pathology, CHU Brugmann-HUDERF, Université Libre de Bruxelles, Brussels, Belgium.ORCID 0000-0003-4943-9172
Samantha J BryenKids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.ORCID 0000-0002-4140-8622
Fathimath FaizDepartment of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, Western Australia, Australia.
Leigh B WaddellKids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.ORCID 0000-0003-2970-6624
Frances J EvessonKids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.ORCID 0000-0002-2418-3230
Madhura BakshiDepartment of Clinical Genetics, Liverpool Hospital, Liverpool, New South Wales, Australia.
Jason R PinnerDepartment of Medical Genomics, Royal Prince Alfred Hospital, The University of Sydney, Camperdown, New South Wales, Australia.ORCID 0000-0002-8323-1802
Amanda CharltonDepartment of Histopathology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.ORCID 0000-0002-9891-8535
Susan BrammahElectron Microscope Unit, Department of Anatomical Pathology, Concord Repatriation General Hospital, Concord, New South Wales, Australia.
Nicole S GrafDepartment of Histopathology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
Michael KrivanekDepartment of Histopathology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
Chee Geap TayDivision of Paediatric Neurology, Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Nicola C FouldsWessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK.ORCID 0000-0002-5779-0096
Marjorie A IllingworthDepartment of Paediatric Neurology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Neil H ThomasDepartment of Paediatric Neurology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Sian EllardCollege of Medicine and Health, University of Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.ORCID 0000-0002-7620-5526
Ingrid MazantiDepartment of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Soo-Mi ParkDepartment of Clinical Genetics, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK.ORCID 0000-0002-0538-4547
Courtney E FrenchDepartment of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.ORCID 0000-0001-7620-1544
Jennifer BrewsterDepartment of Fetomaternal Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Gusztav BeltekiNeonatal Intensive Care Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.ORCID 0000-0002-2974-2011
Shazia HoodbhoyNeonatal Intensive Care Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Kieren AllinsonDepartment of Histopathology, Cambridge University Hospitals Foundation Trust, Cambridge, UK.
Deepa KrishnakumarDepartment of Paediatric Neurology, Cambridge University Hospitals Foundation Trust, Cambridge, UK.ORCID 0000-0001-6937-3399
Gareth BaynamGenetic Services of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia.ORCID 0000-0003-4920-9553
Bradley M WoodFiona Stanley Hospital, Murdoch, Western Australia, Australia.
Michelle WardGenetic Services of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia.
Kayal VijayakumarDepartment of Paediatric Neurology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
Amber SyedDepartment of Paediatric Neurology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
Archana MuruganDepartment of Paediatric Neurology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
Anirban MajumdarDepartment of Paediatric Neurology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.ORCID 0000-0001-8521-1138
Ingrid J ScurrDepartment of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
Miranda P SplittNorthern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne, UK.
Corina MoldovanDepartment of Pathology, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Deepthi C de SilvaDepartment of Physiology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.ORCID 0000-0003-1236-4971
Kumudu SenanayakeDepartment of Histopathology, Castle Street Hospital for Women, Colombo, Sri Lanka.
Thatjana GardeitchikDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Yvonne ArensDepartment of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.
Sandra T CooperKids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.ORCID 0000-0002-7314-5097
Nigel G LaingHarry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.ORCID 0000-0001-5111-3732
F Lucy RaymondDepartment of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.ORCID 0000-0003-2652-3355
Heinz JungbluthDepartment of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK.ORCID 0000-0002-7159-3427
Erik-Jan KamsteegDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.ORCID 0000-0001-6480-1892
Adnan ManzurGreat Ormond Street Hospital for Children, NHS Foundation Trust, Dubowitz Neuromuscular Centre, London, UK.
Susan M CorleySystems Biology Initiative, School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, New South Wales, Australia.ORCID 0000-0003-0605-6411
Gianina RavenscroftHarry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.ORCID 0000-0003-3634-211X
Marc R WilkinsSchool of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.ORCID 0000-0002-5700-5684
Mark J CowleyChildren's Cancer Institute, Lowy Cancer Centre, University of New South Wales, Sydney, New South Wales, Australia.ORCID 0000-0002-9519-5714
Mark PineseChildren's Cancer Institute, Lowy Cancer Centre, University of New South Wales, Sydney, New South Wales, Australia.ORCID 0000-0001-5078-6687
Titin Research Consortium
Rahul PhadkeGreat Ormond Street Hospital for Children, NHS Foundation Trust, Dubowitz Neuromuscular Centre, London, UK.ORCID 0000-0001-9699-2718
Mark R DavisDepartment of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, Western Australia, Australia.
Francesco MuntoniGreat Ormond Street Hospital for Children, NHS Foundation Trust, Dubowitz Neuromuscular Centre, London, UK.ORCID 0000-0002-9102-5232
Emily C OatesSchool of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.ORCID 0000-0002-8836-1681

Funding

Australian NHMRC Fellowship GNT1122952Australian NHMRC Ideas Grant GNT2002640Australian NHMRC Investigator Grant GNT1176265Australian NHMRC Neil Hamilton Fairley Early Career Research Fellowship GNT1090428Belgian Association Against Neuromuscular DiseasesBelgian Kids' Fund for Pediatric ResearchBelgian Royal Academy of MedicineFonds ErasmeLuminesce Alliance - Innovation for Children's HealthMRC and BRC Neuromuscular Centre BiobankMuscular Dystrophy UKNational Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation TrustNew South Wales State Government Research Attraction and Acceleration ProgramNHS England Highly Specialised Services to the Dubowitz Neuromuscular CentreUniversity College London
6 · The paper itself

Abstract

Congenital titinopathy has recently emerged as one of the most common congenital muscle disorders.

objectiveTo better understand the presentation and clinical needs of the under-characterized extreme end of the congenital titinopathy severity spectrum.

methodsWe comprehensively analyzed the clinical, imaging, pathology, autopsy, and genetic findings in 15 severely affected individuals from 11 families.

resultsPrenatal features included hypokinesia or akinesia and growth restriction. Six pregnancies were terminated. Nine infants were born at or near term with severe-to-profound weakness and required resuscitation. Seven died following withdrawal of life support. Two surviving children require ongoing respiratory support. Most cohort members had at least 1 disease-causing variant predicted to result in some near-normal-length titin expression. The exceptions, from 2 unrelated families, had homozygous truncating variants predicted to induce complete nonsense mediated decay. However, subsequent analyses suggested that the causative variant in each family had an additional previously unrecognized impact on splicing likely to result in some near-normal-length titin expression. This impact was confirmed by minigene assay for 1 variant.

interpretationThis study confirms the clinical variability of congenital titinopathy. Severely affected individuals succumb prenatally/during infancy, whereas others survive into adulthood. It is likely that this variability is because of differences in the amount and/or length of expressed titin. If confirmed, analysis of titin expression could facilitate clinical prediction and increasing expression might be an effective treatment strategy. Our findings also further-support the hypothesis that some near-normal-length titin expression is essential to early prenatal survival. Sometimes expression of normal/near-normal-length titin is due to disease-causing variants having an additional impact on splicing. ANN NEUROL 2025;97:611-628.

Indexed as

ConnectinAdultChildChild, PreschoolFemaleHumansInfantInfant, NewbornMaleSeverity of Illness IndexConnectinTTN protein, human

Identifiers

PMID39853809
PMCPMC11889535

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.