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Lunapark Deficiency Leads to an Autosomal Recessive Neurodevelopmental Phenotype With a Degenerative Course, Epilepsy and Distinct Brain Anomalies Publisher



Accogli A1, 2 ; Zaki MS3 ; Alowain M4 ; Otaif MY5 ; Jackson A6, 7 ; Argilli E8 ; Chandler KE6, 7 ; De Goede CGEL9 ; Cora T10 ; Alvi JR11 ; Eslahi A12, 13 ; Asl Mohajeri MS12 ; Ashtiani S14 ; Au PYB14 Show All Authors
Authors
  1. Accogli A1, 2
  2. Zaki MS3
  3. Alowain M4
  4. Otaif MY5
  5. Jackson A6, 7
  6. Argilli E8
  7. Chandler KE6, 7
  8. De Goede CGEL9
  9. Cora T10
  10. Alvi JR11
  11. Eslahi A12, 13
  12. Asl Mohajeri MS12
  13. Ashtiani S14
  14. Au PYB14
  15. Scocchia A15
  16. Alakurtti K15
  17. Pagnamenta AT16
  18. Toosi MB17, 18
  19. Karimiani EG19, 20
  20. Mojarrad M12, 13, 21
  21. Arab F22
  22. Duymus F10, 23
  23. Scantlebury MH24
  24. Yesil G25
  25. Rosenfeld JA26, 27
  26. Turkyilmaz A28
  27. Gunes Sag Er S29
  28. Sultan T11
  29. Ashrafzadeh F17
  30. Zahra T30
  31. Rahman F30
  32. Maqbool S30
  33. Abdelhamid MS31
  34. Issa MY3
  35. Efthymiou S32
  36. Bauer P33
  37. Zifarelli G33
  38. Salpietro V32, 34
  39. Alhassnan Z4, 35
  40. Banka S6, 7
  41. Sherr EH8
  42. Gleeson JG36, 37
  43. Striano P38, 39
  44. Houlden H32
  45. Severino M40
  46. Maroofian R32
Show Affiliations
Authors Affiliations
  1. 1. Division of Medical Genetics, Department of Specialized Medicine, McGill University, Montreal, H3G 1A4, Canada
  2. 2. Department of Human Genetics, McGill University, Montreal, H3A 0C7, QC, Canada
  3. 3. Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, 12622, Egypt
  4. 4. Department of Medical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia
  5. 5. Department of Pediatric, Neurology Section, Abha Maternity and Childern Hospital, Abha, 62521, Saudi Arabia
  6. 6. Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom
  7. 7. Manchester Centre for Genomic Medicine, University of Manchester, St Mary’s Hospital, Manchester Academic Health Science Centre, Manchester, M13 9WL, United Kingdom
  8. 8. Department of Neurology, University of California, San Francisco, San Francisco, 94143, CA, United States
  9. 9. Department of Paediatric Neurology, Clinical Research Facility, Lancashire Teaching Hospital NHS Trust, Preston, PR2 9HT, United Kingdom
  10. 10. Department of Medical Genetics, Selcuk University School of Medicine, Konya, 42100, Turkey
  11. 11. Department of Pediatric Neurology, Institute of Child Health, Children’s Hospital, Lahore, 54590, Pakistan
  12. 12. Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, 917794-8564, Iran
  13. 13. Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, 9137-86177, Iran
  14. 14. Alberta Children’s Hospital Research Institute, Department of Medical Genetics, University of Calgary, T2N 4Z6, AB, Canada
  15. 15. Blueprint Genetics Inc, Marlborough, 01752, MA, United States
  16. 16. NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, United Kingdom
  17. 17. Pediatric Neurology Department, Mashhad University of Medical Sciences, Mashhad, 913791-6847, Iran
  18. 18. Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, 91375-33116, Iran
  19. 19. Molecular and Clinical Sciences Institute, St. George’s, University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom
  20. 20. Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, 91869-51591, Iran
  21. 21. Genetic Center of Khorasan Razavi, Mashhad, 91877-53831, Iran
  22. 22. Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, 1411713135, Iran
  23. 23. Department of Medical Genetics, Konya City Hospital, Konya, 42020, Turkey
  24. 24. Departments of Pediatrics and Clinical Neuroscience, University of Calgary, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, Owerko Center, University of Calgary, T2N 4N1, AB, Canada
  25. 25. Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, 34093, Turkey
  26. 26. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, TX, United States
  27. 27. Baylor Genetics Laboratories, Houston, 77021, TX, United States
  28. 28. Department of Medical Genetics, Karadeniz Technical University Faculty of Medicine, Trabzon, 61080, Turkey
  29. 29. Clinics of Pediatric Neurology, Kartal Dr. Lutfi Kirdar City Hospital, Stanbul, 34890, Turkey
  30. 30. Department of Developmental-Behavioral Pediatrics, University of Child Health Sciences, The Children’s Hospital, Lahore, 54590, Pakistan
  31. 31. Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, 12622, Egypt
  32. 32. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom
  33. 33. CENTOGENE, Rostock, 18057, Germany
  34. 34. Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, 67100, Italy
  35. 35. College of Medicine, Alfaisal University, Riyadh, 11533, Saudi Arabia
  36. 36. Department of Neurosciences, University of California, La Jolla, San Diego, 92093, United States
  37. 37. Rady Children’s Institute for Genomic Medicine, San Diego, 92123, United States
  38. 38. Department of Neurosciences Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, 16132, Italy
  39. 39. Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto ‘Giannina Gaslini’, Genoa, 16147, Italy
  40. 40. Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, 16146, Italy

Source: Brain Communications Published:2023


Abstract

LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy and nonspecific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK-related disorder. Exome or genome sequencing was carried out in 11 families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified 12 distinct homozygous loss-of-function variants in 16 individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor (‘ear-of-the-lynx’ sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK-related disorder and expand the list of neurological disorders presenting with the ‘ear-of-the-lynx’ sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction. © 2023 The Author(s). Published by Oxford University Press on behalf of Infectious Diseases Society of America.