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

Coppens S 1 , Deconinck N 2 , Sullivan P 3 , Smolnikov A 4 , Clayton JS 5 , Griffin KR 4 Show all authors , Jones KJ 6 , Vilain CN 1 , Kadhim H 7 , Bryen SJ 6 , Faiz F 8 , Waddell LB 6 , Evesson FJ 6 , Bakshi M 9 , Pinner JR 10 , Charlton A 11 , Brammah S 12 , Graf NS 11 , Krivanek M 11 , Tay CG 13 , Foulds NC 14 , Illingworth MA 15 , Thomas NH 15 , Ellard S 16 , Mazanti I 17 , Park SM 18 , French CE 19 , Brewster J 20 , Belteki G 21 , Hoodbhoy S 21 , Allinson K 22 , Krishnakumar D 23 , Baynam G 24 , Wood BM 25 , Ward M 24 , Vijayakumar K 26 , Syed A 26 , Murugan A 26 , Majumdar A 26 , Scurr IJ 27 , Splitt MP 28 , Moldovan C 29 , de Silva DC 30 , Senanayake K 31 , Gardeitchik T 32 , Arens Y 33 , Cooper ST 6 , Laing NG 5 , Raymond FL 19 , Jungbluth H 34 , Kamsteeg EJ 32 , Manzur A 35 , Corley SM 36 , Ravenscroft G 5 , Wilkins MR 4 , Cowley MJ 3 , Pinese M 3 , Titin Research Consortium , Phadke R 35 , Davis MR 8 , Muntoni F 35 , Oates EC 4

Affiliations 

  • 1 Hopital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium
  • 2 Department of Paediatric Neurology, Neuromuscular Reference Center, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium
  • 3 Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales, Sydney, New South Wales, Australia
  • 4 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
  • 5 Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia
  • 6 Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
  • 7 Neuropathology Unit (Anatomic Pathology Service) and Reference Center for Neuromuscular Pathology, CHU Brugmann-HUDERF, Université Libre de Bruxelles, Brussels, Belgium
  • 8 Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, Western Australia, Australia
  • 9 Department of Clinical Genetics, Liverpool Hospital, Liverpool, New South Wales, Australia
  • 10 Department of Medical Genomics, Royal Prince Alfred Hospital, The University of Sydney, Camperdown, New South Wales, Australia
  • 11 Department of Histopathology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
  • 12 Electron Microscope Unit, Department of Anatomical Pathology, Concord Repatriation General Hospital, Concord, New South Wales, Australia
  • 13 Division of Paediatric Neurology, Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 14 Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK
  • 15 Department of Paediatric Neurology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
  • 16 College of Medicine and Health, University of Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
  • 17 Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
  • 18 Department of Clinical Genetics, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
  • 19 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
  • 20 Department of Fetomaternal Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
  • 21 Neonatal Intensive Care Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
  • 22 Department of Histopathology, Cambridge University Hospitals Foundation Trust, Cambridge, UK
  • 23 Department of Paediatric Neurology, Cambridge University Hospitals Foundation Trust, Cambridge, UK
  • 24 Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia
  • 25 Fiona Stanley Hospital, Murdoch, Western Australia, Australia
  • 26 Department of Paediatric Neurology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
  • 27 Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
  • 28 Northern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne, UK
  • 29 Department of Pathology, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
  • 30 Department of Physiology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka
  • 31 Department of Histopathology, Castle Street Hospital for Women, Colombo, Sri Lanka
  • 32 Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
  • 33 Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
  • 34 Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK
  • 35 Great Ormond Street Hospital for Children, NHS Foundation Trust, Dubowitz Neuromuscular Centre, London, UK
  • 36 Systems Biology Initiative, School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, New South Wales, Australia
Ann Neurol, 2025 Jan 24.
PMID: 39853809 DOI: 10.1002/ana.27087

Abstract

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

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

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

RESULTS: Prenatal 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.

INTERPRETATION: This 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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