Characterization of severe COL6-related dystrophy due to the recurrent variant COL6A1 c.930+189C>T

Author:

Foley A Reghan1ORCID,Bolduc Véronique1,Guirguis Fady1,Donkervoort Sandra1,Hu Ying1,Orbach Rotem12,McCarty Riley M1,Sarathy Apurva1,Norato Gina3,Cummings Beryl B4,Lek Monkol4,Sarkozy Anna5,Butterfield Russell J6,Kirschner Janbernd7ORCID,Nascimento Andrés8,Natera-de Benito Daniel8,Quijano-Roy Susana9,Stojkovic Tanya10,Merlini Luciano11,Comi Giacomo12,Ryan Monique13,McDonald Denise14,Munot Pinki5,Yoon Grace15,Leung Edward16,Finanger Erika17,Leach Meganne E117,Collins James18,Tian Cuixia18,Mohassel Payam1,Neuhaus Sarah B1,Saade Dimah1,Cocanougher Benjamin T19,Chu Mary-Lynn20,Scavina Mena21,Grosmann Carla22,Richardson Randal23,Kossak Brian D24,Gospe Sidney M25ORCID,Bhise Vikram26,Taurina Gita27,Lace Baiba28,Troncoso Monica29,Shohat Mordechai30,Shalata Adel31,Chan Sophelia H S32,Jokela Manu3334,Palmio Johanna34,Haliloğlu Göknur35,Jou Cristina36,Gartioux Corine37,Solomon-Degefa Herimela38,Freiburg Carolin D38,Schiavinato Alvise38,Zhou Haiyan3940,Aguti Sara41,Nevo Yoram42,Nishino Ichizo43ORCID,Jimenez-Mallebrera Cecilia44,Lamandé Shireen R45,Allamand Valérie37,Gualandi Francesca46,Ferlini Alessandra46,MacArthur Daniel G4ORCID,Wilton Steve D4748,Wagener Raimund38,Bertini Enrico49ORCID,Muntoni Francesco539,Bönnemann Carsten G1

Affiliation:

1. Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH , Bethesda, MD 20892 ,

2. Pediatric Neurology Institute, Dana-Dwek Children’s Hospital , Tel Aviv 64239 ,

3. Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, NIH , Bethesda, MD 20892 ,

4. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard , Cambridge, MA 02142 ,

5. Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children , London WC1N 1EH ,

6. Departments of Neurology and Pediatrics, University of Utah , Salt Lake City, UT 84132 ,

7. Department of Neuropediatrics and Muscle Disorders, Medical Center—University of Freiburg, Faculty of Medicine , Freiburg 79110 ,

8. Neuromuscular Unit, Neuropediatrics Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu. CIBERER ISCIII , Barcelona 08950 ,

9. Garches Neuromuscular Reference Center, Child Neurology and ICU Department, APHP Raymond Poincare University Hospital (UVSQ Paris Saclay) , Garches 92380 ,

10. Centre de Référence des Maladies Neuromusculaires Nord/Est/Île-de-France, Institut de Myologie, Hôpital Pitié-Salpêtrière, AP-HP , Paris 75013 ,

11. Department of Biomedical and Neuromotor Sciences, University of Bologna , Bologna 40126 ,

12. Neurology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan 20133 ,

13. Department of Neurology, The Royal Children’s Hospital , Parkville, VIC 3052 ,

14. Department of Neurodisability, Children’s Health Ireland at Tallaght , Dublin D24 TN3C ,

15. Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto , Toronto, ON M5G 1X8 ,

16. Department of Pediatrics and Child Health, University of Manitoba , Winnipeg, MB R3A 1S1 ,

17. Department of Pediatrics and Neurology, Oregon Health & Science University , Portland, OR 97239 ,

18. Divisions of Neurology and Pediatrics, Cincinnati Children’s Hospital Medical Center , Cincinnati, OH 45229 ,

19. Division of Medical Genetics, Department of Pediatrics, Duke University , Durham, NC 27710 ,

20. Department of Neurology, New York University School of Medicine , New York, NY 10016 ,

21. Division of Neurology, Nemours Children’s Hospital Delaware , Wilmington, DE 19803 ,

22. Department of Neurology, Rady Children’s Hospital University of California San Diego , San Diego, CA 92123 ,

23. Department of Neurology, Gillette Children’s Specialty Healthcare , St Paul, MN 55101 ,

24. Department of Neurology, Dartmouth Hitchcock Medical Center , Lebanon, NH 03766 ,

25. Department of Neurology and Pediatrics, University of Washington , Seattle, WA 98105 ,

26. Departments of Pediatrics and Neurology, Rutgers Robert Wood Johnson Medical School, Rutgers University , New Brunswick, NJ 08901 ,

27. Children’s Clinical University Hospital, Medical Genetics and Prenatal Diagnostic Clinic , Riga 1004 ,

28. Riga East Clinical University, Institute of Clinical and Preventive Medicine of the University of Latvia , Riga 1586 ,

29. Pediatric Neuropsychiatry Service, Hospital Clínico San Borja Arriarán, Pediatric Department, Universidad de Chile , Santiago 1234 ,

30. The Genomics Unit, Sheba Cancer Research Center, Sheba Medical Center , Ramat Gan 52621 ,

31. The Simon Winter Institute for Human Genetics, Bnai Zion Medical Center, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology , Haifa 32000 ,

32. Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong, Special Administrative Region ,

33. Clinical Neurosciences, University of Turku, Turku, Finland and Neurocenter, Turku University Hospital , Turku 20520 ,

34. Neuromuscular Research Center, Tampere University and Tampere University Hospital , Tampere 33101 ,

35. Division of Pediatric Neurology, Department of Pediatrics, Hacettepe University Faculty of Medicine , Ankara 06230 ,

36. Pathology Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu , Barcelona 08950 ,

37. INSERM, Institut de Myologie, Centre de Recherche en Myologie, Sorbonne Université , Paris 75013 ,

38. Center for Biochemistry, Medical Faculty, University of Cologne , Cologne 50931 ,

39. National Institute of Health Research, Great Ormond Street Hospital Biomedical Research Centre , London WC1N 1EH ,

40. Genetics and Genomic Medicine Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London , London WC1N 1EH ,

41. Neurodegenerative Disease Department, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,

42. Institute of Pediatric Neurology, Schneider Children’s Medical Center of Israel , Petach Tikva ,

43. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry , Tokyo 187-8502 ,

44. Laboratorio de Investigación Aplicada en Enfermedades Neuromusculares, Unidad de Patología Neuromuscular, Servicio de Neuropediatría, Institut de Recerca Sant Joan de Déu , Barcelona 08950 ,

45. Department of Paediatrics, University of Melbourne, The Murdoch Children’s Research Institute , Parkville, VIC 3052 ,

46. Unit of Medical Genetics, Department of Medical Sciences and Department of Mother and Child, University Hospital S. Anna Ferrara , Ferrara 44121 ,

47. Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University , Murdoch, WA 6150 ,

48. Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, The University of Western Australia , Nedlands, WA 6009 ,

49. Research Unit of Neuromuscular and Neurodegenerative Disorders, IRCCS Ospedale Pediatrico Bambino Gesù , Rome 00146 ,

Abstract

Abstract Collagen VI-related dystrophies manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterized by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognized later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of collagen VI-related dystrophy, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA sequencing and whole-genome sequencing, we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterized an international cohort of 44 patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen VI genes. Patients manifest a consistently severe phenotype characterized by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy to successfully suppress the pseudoexon insertion, resulting in normal COL6A1 transcripts. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant.

Funder

NIH National Institute of Neurological Disorders and Stroke

NIH Medical Research Scholars Program

GREGoR Consortium

National Human Genome Research Institute

Deutsche Forschungsgemeinschaft

Instituto de Salud Carlos III

Publisher

Oxford University Press (OUP)

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