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A Recurrent Homozygous Missense Dpm3 Variant Leads to Muscle and Brain Disease Publisher Pubmed



Nagy S1, 2 ; Lau T1 ; Alavi S3 ; Karimiani EG4 ; Vallian J3 ; Ng BG5 ; Noroozi Asl S6 ; Akhondian J7 ; Bahreini A8 ; Yaghini O9 ; Uapinyoying P10 ; Bonnemann C10 ; Freeze HH5 ; Dissanayake VHW11 Show All Authors
Authors
  1. Nagy S1, 2
  2. Lau T1
  3. Alavi S3
  4. Karimiani EG4
  5. Vallian J3
  6. Ng BG5
  7. Noroozi Asl S6
  8. Akhondian J7
  9. Bahreini A8
  10. Yaghini O9
  11. Uapinyoying P10
  12. Bonnemann C10
  13. Freeze HH5
  14. Dissanayake VHW11
  15. Sirisena ND11
  16. Schmidts M12
  17. Houlden H1
  18. Morenodeluca A13
  19. Maroofian R1
Show Affiliations
Authors Affiliations
  1. 1. MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom
  2. 2. Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland
  3. 3. Division of Genetics, Department of Cellular and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
  4. 4. Molecular and Clinical Sciences Institute, St. George's, University of London, London, United Kingdom
  5. 5. Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
  6. 6. Pediatrics Endocrinology Department, Mashhad University of Medical Sciences, Mashhad, Iran
  7. 7. Pediatric Neurology Department, Ghaem hospital, Mashhad University of Medical Sciences, Mashhad, Iran
  8. 8. Karyogen Medical Genetics Laboratory, Alzahra University, Isfahan, Iran
  9. 9. Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
  10. 10. Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
  11. 11. Department of Anatomy, Genetics & Biomedical Informatics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
  12. 12. Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Germany
  13. 13. Autism & Developmental Medicine Institute, Genomic Medicine Institute, Department of Radiology, Diagnostic Medicine Institute, Danville, PA, United States

Source: Clinical Genetics Published:2022


Abstract

Biallelic pathogenic variants in the genes encoding the dolichol-phosphate mannose synthase subunits (DPM) which produce mannosyl donors for glycosylphosphatidylinositols, N-glycan and protein O- and C-mannosylation, are rare causes of congenital disorders of glycosylation. Pathogenic variants in DPM1 and DPM2 are associated with muscle–eye–brain (MEB) disease, whereas DPM3 variants have mostly been reported in patients with isolated muscle disease—dystroglycanopathy. Thus far, only one affected individual with compound heterozygous DPM3 variants presenting with myopathy, mild intellectual disability, seizures, and nonspecific white matter abnormalities (WMA) around the lateral ventricles has been described. Here we present five affected individuals from four unrelated families with global developmental delay/intellectual disability ranging from mild to severe, microcephaly, seizures, WMA, muscle weakness and variable cardiomyopathy. Exome sequencing of the probands revealed an ultra-rare homozygous pathogenic missense DPM3 variant NM_018973.4:c.221A>G, p.(Tyr74Cys) which segregated with the phenotype in all families. Haplotype analysis indicated that the variant arose independently in three families. Functional analysis did not reveal any alteration in the N-glycosylation pathway caused by the variant; however, this does not exclude its pathogenicity in the function of the DPM complex and related cellular pathways. This report provides supporting evidence that, besides DPM1 and DPM2, defects in DPM3 can also lead to a muscle and brain phenotype. © 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.
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