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

A Reghan Foley¹, Véronique Bolduc¹, Fady Guirguis¹, Sandra Donkervoort¹, Ying Hu¹, Rotem Orbach^{1

2}, Riley M McCarty¹, Apurva Sarathy¹, Gina Norato³, Beryl B Cummings⁴, Monkol Lek⁴, Anna Sarkozy⁵, Russell J Butterfield⁶, Janbernd Kirschner⁷, Andrés Nascimento⁸, Daniel Natera-de Benito⁸, Susana Quijano-Roy⁹, Tanya Stojkovic¹⁰, Luciano Merlini¹¹, Giacomo Comi¹², Monique Ryan¹³, Denise McDonald¹⁴, Pinki Munot⁵, Grace Yoon¹⁵, Edward Leung¹⁶, Erika Finanger¹⁷, Meganne E Leach^{1

17}, James Collins¹⁸, Cuixia Tian¹⁸, Payam Mohassel¹, Sarah B Neuhaus¹, Dimah Saade¹, Benjamin T Cocanougher¹⁹, Mary-Lynn Chu²⁰, Mena Scavina²¹, Carla Grosmann²², Randal Richardson²³, Brian D Kossak²⁴, Sidney M Gospe Jr²⁵, Vikram Bhise²⁶, Gita Taurina²⁷, Baiba Lace²⁸, Monica Troncoso²⁹, Mordechai Shohat³⁰, Adel Shalata³¹, Sophelia H S Chan³², Manu Jokela^{33

34}, Johanna Palmio³⁴, Göknur Haliloğlu³⁵, Cristina Jou³⁶, Corine Gartioux³⁷, Herimela Solomon-Degefa³⁸, Carolin D Freiburg³⁸, Alvise Schiavinato³⁸, Haiyan Zhou^{39

40}, Sara Aguti⁴¹, Yoram Nevo⁴², Ichizo Nishino⁴³, Cecilia Jimenez-Mallebrera⁴⁴, Shireen R Lamandé⁴⁵, Valérie Allamand³⁷, Francesca Gualandi⁴⁶, Alessandra Ferlini⁴⁶, Daniel G MacArthur⁴, Steve D Wilton^{47

48}, Raimund Wagener³⁸, Enrico Bertini⁴⁹, Francesco Muntoni^{5

39}, Carsten G Bönnemann¹

Affiliations

¹ Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
² Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv 64239, Israel.
³ Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children, London WC1N 1EH, UK.
⁶ Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, UT 84132, USA.
⁷ Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg 79110, Germany.
⁸ Neuromuscular Unit, Neuropediatrics Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu. CIBERER ISCIII, Barcelona 08950, Spain.
⁹ Garches Neuromuscular Reference Center, Child Neurology and ICU Department, APHP Raymond Poincare University Hospital (UVSQ Paris Saclay), Garches 92380, France.
¹⁰ Centre de Référence des Maladies Neuromusculaires Nord/Est/Île-de-France, Institut de Myologie, Hôpital Pitié-Salpêtrière, AP-HP, Paris 75013, France.
¹¹ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna 40126, Italy.
¹² Neurology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20133, Italy.
¹³ Department of Neurology, The Royal Children's Hospital, Parkville, VIC 3052, Australia.
¹⁴ Department of Neurodisability, Children's Health Ireland at Tallaght, Dublin D24 TN3C, Ireland.
¹⁵ Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
¹⁶ Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3A 1S1, Canada.
¹⁷ Department of Pediatrics and Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
¹⁸ Divisions of Neurology and Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹⁹ Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC 27710, USA.
²⁰ Department of Neurology, New York University School of Medicine, New York, NY 10016, USA.
²¹ Division of Neurology, Nemours Children's Hospital Delaware, Wilmington, DE 19803, USA.
²² Department of Neurology, Rady Children's Hospital University of California San Diego, San Diego, CA 92123, USA.
²³ Department of Neurology, Gillette Children's Specialty Healthcare, St Paul, MN 55101, USA.
²⁴ Department of Neurology, Dartmouth Hitchcock Medical Center, Lebanon, NH 03766, USA.
²⁵ Department of Neurology and Pediatrics, University of Washington, Seattle, WA 98105, USA.
²⁶ Departments of Pediatrics and Neurology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA.
²⁷ Children's Clinical University Hospital, Medical Genetics and Prenatal Diagnostic Clinic, Riga 1004, Latvia.
²⁸ Riga East Clinical University, Institute of Clinical and Preventive Medicine of the University of Latvia, Riga 1586, Latvia.
²⁹ Pediatric Neuropsychiatry Service, Hospital Clínico San Borja Arriarán, Pediatric Department, Universidad de Chile, Santiago 1234, Chile.
³⁰ The Genomics Unit, Sheba Cancer Research Center, Sheba Medical Center, Ramat Gan 52621, Israel.
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, Israel.
³² Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Special Administrative Region, China.
³³ Clinical Neurosciences, University of Turku, Turku, Finland and Neurocenter, Turku University Hospital, Turku 20520, Finland.
³⁴ Neuromuscular Research Center, Tampere University and Tampere University Hospital, Tampere 33101, Finland.
³⁵ Division of Pediatric Neurology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara 06230, Turkey.
³⁶ Pathology Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Barcelona 08950, Spain.
³⁷ INSERM, Institut de Myologie, Centre de Recherche en Myologie, Sorbonne Université, Paris 75013, France.
³⁸ Center for Biochemistry, Medical Faculty, University of Cologne, Cologne 50931, Germany.
³⁹ National Institute of Health Research, Great Ormond Street Hospital Biomedical Research Centre, London WC1N 1EH, UK.
⁴⁰ Genetics and Genomic Medicine Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
⁴¹ Neurodegenerative Disease Department, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
⁴² Institute of Pediatric Neurology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
⁴³ Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
⁴⁴ Laboratorio de Investigación Aplicada en Enfermedades Neuromusculares, Unidad de Patología Neuromuscular, Servicio de Neuropediatría, Institut de Recerca Sant Joan de Déu, Barcelona 08950, Spain.
⁴⁵ Department of Paediatrics, University of Melbourne, The Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
⁴⁶ Unit of Medical Genetics, Department of Medical Sciences and Department of Mother and Child, University Hospital S. Anna Ferrara, Ferrara 44121, Italy.
⁴⁷ Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Murdoch, WA 6150, Australia.
⁴⁸ Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands, WA 6009, Australia.
⁴⁹ Research Unit of Neuromuscular and Neurodegenerative Disorders, IRCCS Ospedale Pediatrico Bambino Gesù, Rome 00146, Italy.

PMID: 40177858
PMCID: PMC12404708 (available on 2026-04-03)
DOI: 10.1093/brain/awaf116

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

A Reghan Foley et al. Brain. 2025.

. 2025 Sep 3;148(9):3215-3227.

doi: 10.1093/brain/awaf116.

Authors

Affiliations

¹ Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
² Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv 64239, Israel.
³ Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children, London WC1N 1EH, UK.
⁶ Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, UT 84132, USA.
⁷ Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg 79110, Germany.
⁸ Neuromuscular Unit, Neuropediatrics Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu. CIBERER ISCIII, Barcelona 08950, Spain.
⁹ Garches Neuromuscular Reference Center, Child Neurology and ICU Department, APHP Raymond Poincare University Hospital (UVSQ Paris Saclay), Garches 92380, France.
¹⁰ Centre de Référence des Maladies Neuromusculaires Nord/Est/Île-de-France, Institut de Myologie, Hôpital Pitié-Salpêtrière, AP-HP, Paris 75013, France.
¹¹ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna 40126, Italy.
¹² Neurology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20133, Italy.
¹³ Department of Neurology, The Royal Children's Hospital, Parkville, VIC 3052, Australia.
¹⁴ Department of Neurodisability, Children's Health Ireland at Tallaght, Dublin D24 TN3C, Ireland.
¹⁵ Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
¹⁶ Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3A 1S1, Canada.
¹⁷ Department of Pediatrics and Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
¹⁸ Divisions of Neurology and Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹⁹ Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC 27710, USA.
²⁰ Department of Neurology, New York University School of Medicine, New York, NY 10016, USA.
²¹ Division of Neurology, Nemours Children's Hospital Delaware, Wilmington, DE 19803, USA.
²² Department of Neurology, Rady Children's Hospital University of California San Diego, San Diego, CA 92123, USA.
²³ Department of Neurology, Gillette Children's Specialty Healthcare, St Paul, MN 55101, USA.
²⁴ Department of Neurology, Dartmouth Hitchcock Medical Center, Lebanon, NH 03766, USA.
²⁵ Department of Neurology and Pediatrics, University of Washington, Seattle, WA 98105, USA.
²⁶ Departments of Pediatrics and Neurology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA.
²⁷ Children's Clinical University Hospital, Medical Genetics and Prenatal Diagnostic Clinic, Riga 1004, Latvia.
²⁸ Riga East Clinical University, Institute of Clinical and Preventive Medicine of the University of Latvia, Riga 1586, Latvia.
²⁹ Pediatric Neuropsychiatry Service, Hospital Clínico San Borja Arriarán, Pediatric Department, Universidad de Chile, Santiago 1234, Chile.
³⁰ The Genomics Unit, Sheba Cancer Research Center, Sheba Medical Center, Ramat Gan 52621, Israel.
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, Israel.
³² Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Special Administrative Region, China.
³³ Clinical Neurosciences, University of Turku, Turku, Finland and Neurocenter, Turku University Hospital, Turku 20520, Finland.
³⁴ Neuromuscular Research Center, Tampere University and Tampere University Hospital, Tampere 33101, Finland.
³⁵ Division of Pediatric Neurology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara 06230, Turkey.
³⁶ Pathology Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Barcelona 08950, Spain.
³⁷ INSERM, Institut de Myologie, Centre de Recherche en Myologie, Sorbonne Université, Paris 75013, France.
³⁸ Center for Biochemistry, Medical Faculty, University of Cologne, Cologne 50931, Germany.
³⁹ National Institute of Health Research, Great Ormond Street Hospital Biomedical Research Centre, London WC1N 1EH, UK.
⁴⁰ Genetics and Genomic Medicine Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
⁴¹ Neurodegenerative Disease Department, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
⁴² Institute of Pediatric Neurology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
⁴³ Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
⁴⁴ Laboratorio de Investigación Aplicada en Enfermedades Neuromusculares, Unidad de Patología Neuromuscular, Servicio de Neuropediatría, Institut de Recerca Sant Joan de Déu, Barcelona 08950, Spain.
⁴⁵ Department of Paediatrics, University of Melbourne, The Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
⁴⁶ Unit of Medical Genetics, Department of Medical Sciences and Department of Mother and Child, University Hospital S. Anna Ferrara, Ferrara 44121, Italy.
⁴⁷ Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Murdoch, WA 6150, Australia.
⁴⁸ Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands, WA 6009, Australia.
⁴⁹ Research Unit of Neuromuscular and Neurodegenerative Disorders, IRCCS Ospedale Pediatrico Bambino Gesù, Rome 00146, Italy.

PMID: 40177858
PMCID: PMC12404708 (available on 2026-04-03)
DOI: 10.1093/brain/awaf116

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.

Keywords: COL6A1 c.930+189C>T; COL6A1 intron 11; collagen VI-related dystrophy; pseudoexon; splice-modulating; translational promise.

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Conflict of interest statement

The authors report no competing interests.

References

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

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

Authors

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Abstract

Conflict of interest statement

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