Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss

  • Am J Hum Genet. 2021 Oct 7;108(10):2006-2016. doi: 10.1016/j.ajhg.2021.08.003.
Elodie M Richard  1 ,  Somayeh Bakhtiari  2 ,  Ashley P L Marsh  2 ,  Rauan Kaiyrzhanov  3 ,  Matias Wagner  4 ,  Sheetal Shetty  2 ,  Alex Pagnozzi  5 ,  Sandra M Nordlie  2 ,  Brandon S Guida  2 ,  Patricia Cornejo  6 ,  Helen Magee  2 ,  James Liu  2 ,  Bethany Y Norton  2 ,  Richard I Webster  7 ,  Lisa Worgan  8 ,  Hakon Hakonarson  9 ,  Jiankang Li  10 ,  Yiran Guo  11 ,  Mahim Jain  12 ,  Alyssa Blesson  13 ,  Lance H Rodan  14 ,  Mary-Alice Abbott  15 ,  Anne Comi  16 ,  Julie S Cohen  16 ,  Bader Alhaddad  17 ,  Thomas Meitinger  17 ,  Dominic Lenz  18 ,  Andreas Ziegler  19 ,  Urania Kotzaeridou  19 ,  Theresa Brunet  17 ,  Anna Chassevent  20 ,  Constance Smith-Hicks  16 ,  Joseph Ekstein  21 ,  Tzvi Weiden  22 ,  Andreas Hahn  23 ,  Nazira Zharkinbekova  24 ,  Peter Turnpenny  25 ,  Arianna Tucci  26 ,  Melissa Yelton  27 ,  Rita Horvath  28 ,  Serdal Gungor  29 ,  Semra Hiz  30 ,  Yavuz Oktay  31 ,  Hanns Lochmuller  32 ,  Marcella Zollino  33 ,  Manuela Morleo  34 ,  Giuseppe Marangi  33 ,  Vincenzo Nigro  35 ,  Annalaura Torella  35 ,  Michele Pinelli  34 ,  Simona Amenta  33 ,  Ralf A Husain  36 ,  Benita Grossmann  37 ,  Marion Rapp  38 ,  Claudia Steen  39 ,  Iris Marquardt  40 ,  Mona Grimmel  37 ,  Ute Grasshoff  37 ,  G Christoph Korenke  40 ,  Marta Owczarek-Lipska  41 ,  John Neidhardt  42 ,  Francesca Clementina Radio  43 ,  Cecilia Mancini  43 ,  Dianela Judith Claps Sepulveda  43 ,  Kirsty McWalter  44 ,  Amber Begtrup  44 ,  Amy Crunk  44 ,  Maria J Guillen Sacoto  44 ,  Richard Person  44 ,  Rhonda E Schnur  44 ,  Maria Margherita Mancardi  45 ,  Florian Kreuder  46 ,  Pasquale Striano  47 ,  Federico Zara  48 ,  Wendy K Chung  49 ,  Warren A Marks  50 ,  Clare L van Eyk  51 ,  Dani L Webber  51 ,  Mark A Corbett  51 ,  Kelly Harper  51 ,  Jesia G Berry  51 ,  Alastair H MacLennan  51 ,  Jozef Gecz  52 ,  Marco Tartaglia  43 ,  Vincenzo Salpietro  47 ,  John Christodoulou  53 ,  Jan Kaslin  46 ,  Sergio Padilla-Lopez  2 ,  Kaya Bilguvar  54 ,  Alexander Munchau  38 ,  Zubair M Ahmed  55 ,  Robert B Hufnagel  56 ,  Michael C Fahey  57 ,  Reza Maroofian  3 ,  Henry Houlden  3 ,  Heinrich Sticht  58 ,  Shrikant M Mane  54 ,  Aboulfazl Rad  59 ,  Barbara Vona  59 ,  Sheng Chih Jin  60 ,  Tobias B Haack  61 ,  Christine Makowski  62 ,  Yoel Hirsch  21 ,  Saima Riazuddin  63 ,  Michael C Kruer  64
Affiliations
  • 1. Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
  • 2. Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA; Departments of Child Health, Neurology, Cellular, and Molecular Medicine and Program in Genetics, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, USA.
  • 3. Department of Neuromuscular Disorders, Institute of Neurology, University College London, Queen Square, WC1N 3BG London, UK.
  • 4. Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 5. CSIRO Health and Biosecurity, The Australian e-Health Research Centre, Brisbane, QLD 4029, Australia.
  • 6. Pediatric Neuroradiology Division, Pediatric Radiology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA; University of Arizona College of Medicine, Phoenix, AZ 85004, USA; Mayo Clinic, Scottsdale, AZ 85259, USA.
  • 7. Neurology Department, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
  • 8. Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia.
  • 9. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 10. Department of Computer Science, City University of Hong Kong, Kowloon 999077, Hong Kong.
  • 11. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Center for Data Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA.
  • 12. Department of Bone and Osteogenesis Imperfecta, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
  • 13. Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, MD 21211, USA.
  • 14. Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 15. University of Massachusetts Medical School - Baystate, Baystate Children's Hospital, Springfield, MA 01107, USA.
  • 16. Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 17. Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany.
  • 18. Centre of Child and Adolescent Medicine, Department of Pediatric Neurology and Metabolic Medicine, Heidelberg University Hospital, 69120 Heidelberg, Germany.
  • 19. Department of Child Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
  • 20. Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
  • 21. Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, New York, NY 11211, USA.
  • 22. Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Jerusalem 9054020, Israel.
  • 23. Department of Child Neurology, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
  • 24. Department of Neurology, South Kazakhstan Medical Academy, Shymkent 160001, Kazakhstan.
  • 25. Clinical Genetics, Royal Devon & Exeter NHS Foundation Trust, EX1 2ED Exeter, UK.
  • 26. Clinical Pharmacology, William Harvey Research Institute, Charterhouse Square, School of Medicine and Dentistry Queen Mary University of London, London EC1M 6BQ, UK.
  • 27. Penn State Health Children's Hospital, Hershey, PA 17033, USA.
  • 28. Department of Clinical Neurosciences, John Van Geest Cambridge Centre for Brain Repair, University of Cambridge School of Clinical Medicine, CB2 0PY Cambridge, UK.
  • 29. Inonu University, Faculty of Medicine, Turgut Ozal Research Center, Department of Paediatric Neurology, 44280 Malatya, Turkey.
  • 30. Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, 35340 Izmir, Turkey; Department of Pediatric Neurology, Faculty of Medicine, Dokuz Eylul University, 35340 Izmir, Turkey.
  • 31. Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, 35340 Izmir, Turkey; Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, 35220 Izmir, Turkey.
  • 32. Children's Hospital of Eastern Ontario Research Institute; Division of Neurology, Department of Medicine, The Ottawa Hospital, and Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
  • 33. Università Cattolica Sacro Cuore, Facoltà di Medicina e Chirurgia, Dipartimento Scienze della Vita e Sanità Pubblica, 00168 Roma, Italy; Fondazione Policlinico A. Gemelli IRCCS, Sezione di Medicina Genomica, 00168 Roma, Italy.
  • 34. Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Naples, Italy.
  • 35. Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Naples, Italy; Department of Precision Medicine, University of Campania "Luigi Vanvitelli," 80138 Naples, Italy.
  • 36. Department of Neuropediatrics, Jena University Hospital, 07747 Jena, Germany.
  • 37. Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tuebingen, Germany.
  • 38. Institute of Systems Motor Science, University of Lübeck, 23538 Lübeck, Germany.
  • 39. Department of Paediatric and Adolescent Medicine, St Joseph Hospital, 12101 Berlin, Germany.
  • 40. University Children's Hospital Oldenburg, Department of Neuropaediatric and Metabolic Diseases, 26133 Oldenburg, Germany.
  • 41. Human Genetics, Faculty of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany; Junior Research Group, Genetics of Childhood Brain Malformations, Faculty VI-School of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany.
  • 42. Human Genetics, Faculty of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany; Research Center Neurosensory Science, University of Oldenburg, 26129 Oldenburg, Germany.
  • 43. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • 44. GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
  • 45. Unit of Child Neuropsichiatry, Department of Clinical and Surgical Neurosciences and Rehabilitation, IRCCS Giannina Gaslini, Genoa 16147, Italy.
  • 46. Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3168, Australia.
  • 47. Pediatric Neurology and Muscular Diseases Unit, IRRCS Istituto Giannina Gaslini, 16148 Genoa, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16142 Genoa, Italy.
  • 48. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16142 Genoa, Italy; Unit of Medical Genetics, IRRCS Istituto Giannina Gaslini, 16147 Genoa, Italy.
  • 49. Departments of Pediatrics and Medicine, Columbia University, New York, NY 10032, USA.
  • 50. Department of Neurology, Cook Children's Medical Center, Fort Worth, TX 76104, USA; Department of Pediatrics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
  • 51. Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5006, Australia; Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5000, Australia.
  • 52. Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5006, Australia; Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5000, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.
  • 53. Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Melbourne Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Discipline of Child and Adolescent Health, University of Sydney, Sydney, NSW 2006, Australia.
  • 54. Yale Center for Genome Analysis, Yale University, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 55. Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
  • 56. Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 57. Department of Paediatrics, Monash University, Melbourne, VIC 3168, Australia.
  • 58. Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • 59. Department of Otolaryngology - Head and Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
  • 60. Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 61. Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tübingen, 72074 Tuebingen, Germany.
  • 62. Department of Paediatrics, Adolescent Medicine and Neonatology, Munich Clinic, Schwabing Hospital and Technical University of Munich, School of Medicine, 80804 Munich, Germany.
  • 63. Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. Electronic address: [email protected].
  • 64. Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA; Departments of Child Health, Neurology, Cellular, and Molecular Medicine and Program in Genetics, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, USA. Electronic address: [email protected].
PMID: 34626583 DOI: 10.1016/j.ajhg.2021.08.003
Abstract

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and Mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

Keywords
AAA+ superfamily; ATPase; SPATA5L1; cerebral palsy; epilepsy; intellectual disability; movement disorder; neurodevelopmental disorder; sensorineural hearing loss.