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

Richard E.M. Bakhtiari S. Marsh A.P.L. Kaiyrzhanov R. Wagner M. Shetty S. Pagnozzi A. Nordlie S.M. Guida B.S. Cornejo P. Magee H. Liu J. Norton B.Y. Webster R.I. Worgan L. Hakonarson H. Li J. Guo Y. Jain M. Blesson A. Rodan L.H. Abbott M.-A. Comi A. Cohen J.S. Alhaddad B. Meitinger T. Lenz D. Ziegler A. Kotzaeridou U. Brunet T. Chassevent A. Smith-Hicks C. Ekstein J. Weiden T. Hahn A. Zharkinbekova N. Turnpenny P. Tucci A. Yelton M. Horvath R. Gungor S. Hiz S. Oktay Y. Lochmuller H. Zollino M. Morleo M. Marangi G. Nigro V. Torella A. Pinelli M. Amenta S. Husain R.A. Grossmann B. Rapp M. Steen C. Marquardt I. Grimmel M. Grasshoff U. Korenke G.C. Owczarek-Lipska M. Neidhardt J. Radio F.C. Mancini C. Claps Sepulveda D.J. McWalter K. Begtrup A. Crunk A. Guillen Sacoto M.J. Person R. Schnur R.E. Mancardi M.M. Kreuder F. Striano P. Zara F. Chung W.K. Marks W.A. van Eyk C.L. Webber D.L. Corbett M.A. Harper K. Berry J.G. MacLennan A.H. Gecz J. Tartaglia M. Salpietro V. Christodoulou J. Kaslin J. Padilla-Lopez S. Bilguvar K. Munchau A. Ahmed Z.M. Hufnagel R.B. Fahey M.C. Maroofian R. Houlden H. Sticht H. Mane S.M. Rad A. Vona B. Jin S.C. Haack T.B. Makowski C. Hirsch Y. Riazuddin S. Kruer M.C.
7 October 2021 Cell Press

American Journal of Human Genetics
2021 #108 Issue 10 2006 - 2016 pp.

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.

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

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Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, 21201, MD, United States
Barrow Neurological Institute, Phoenix Childrens Hospital, Phoenix, 85016, AZ, United States
Departments of Child Health, Neurology, Cellular, and Molecular Medicine and Program in Genetics, University of Arizona College of Medicine – Phoenix, Phoenix, 85004, AZ, United States
Department of Neuromuscular Disorders, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK, United Kingdom
Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, 81675, Germany
Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, 85764, Germany
CSIRO Health and Biosecurity, The Australian e-Health Research Centre, Brisbane, 4029, QLD, Australia
Pediatric Neuroradiology Division, Pediatric Radiology, Barrow Neurological Institute, Phoenix Childrens Hospital, Phoenix, 85016, AZ, United States
University of Arizona College of Medicine, Phoenix, 85004, AZ, United States
Mayo Clinic, Scottsdale, 85259, AZ, United States
Neurology Department, The Childrens Hospital at Westmead, Westmead, 2145, NSW, Australia
Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, 2050, NSW, Australia
Center for Applied Genomics, Childrens Hospital of Philadelphia, Philadelphia, PA, United States
Department of Computer Science, City University of Hong Kong, Kowloon, 999077, Hong Kong
Center for Applied Genomics, Childrens Hospital of Philadelphia, Philadelphia, 19104, PA, United States
Center for Data Driven Discovery in Biomedicine, Childrens Hospital of Philadelphia, Philadelphia, 19146, PA, United States
Department of Bone and Osteogenesis Imperfecta, Kennedy Krieger Institute, Baltimore, 21205, MD, United States
Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, 21211, MD, United States
Division of Genetics and Genomics, Boston Childrens Hospital, Boston, 02115, MA, United States
Department of Neurology, Boston Childrens Hospital, Boston, 02115, MA, United States
University of Massachusetts Medical School – Baystate, Baystate Childrens Hospital, Springfield, 01107, MA, United States
Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, 21205, MD, United States
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, 21287, MD, United States
Centre of Child and Adolescent Medicine, Department of Pediatric Neurology and Metabolic Medicine, Heidelberg University Hospital, Heidelberg, 69120, Germany
Department of Child Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany
Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, New York, 11211, NY, United States
Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, 9054020, Israel
Department of Child Neurology, Justus-Liebig-University Giessen, Giessen, 35392, Germany
Department of Neurology, South Kazakhstan Medical Academy, Shymkent, 160001, Kazakhstan
Clinical Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, EX1 2ED, UK, United Kingdom
Clinical Pharmacology, William Harvey Research Institute, Charterhouse Square, School of Medicine and Dentistry Queen Mary University of London, London, EC1M 6BQ, UK, United Kingdom
Penn State Health Childrens Hospital, Hershey, 17033, PA, United States
Department of Clinical Neurosciences, John Van Geest Cambridge Centre for Brain Repair, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0PY, UK, United Kingdom
Inonu University, Faculty of Medicine, Turgut Ozal Research Center, Department of Paediatric Neurology, Malatya, 44280, Turkey
Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, 35340, Turkey
Department of Pediatric Neurology, Faculty of Medicine, Dokuz Eylul University, Izmir, 35340, Turkey
Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, 35220, Turkey
Childrens 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
Università Cattolica Sacro Cuore, Facoltà di Medicina e Chirurgia, Dipartimento Scienze della Vita e Sanità Pubblica, Roma, 00168, Italy
Fondazione Policlinico A. Gemelli IRCCS, Sezione di Medicina Genomica, Roma, 00168, Italy
Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, 80078, Italy
Department of Precision Medicine, University of Campania “Luigi Vanvitelli,”, Naples, 80138, Italy
Department of Neuropediatrics, Jena University Hospital, Jena, 07747, Germany
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tuebingen, 72076, Germany
Institute of Systems Motor Science, University of Lübeck, Lübeck, 23538, Germany
Department of Paediatric and Adolescent Medicine, St Joseph Hospital, Berlin, 12101, Germany
University Childrens Hospital Oldenburg, Department of Neuropaediatric and Metabolic Diseases, Oldenburg, 26133, Germany
Human Genetics, Faculty of Medicine and Health Sciences, University of Oldenburg, Oldenburg, 26129, Germany
Junior Research Group, Genetics of Childhood Brain Malformations, Faculty VI-School of Medicine and Health Sciences, University of Oldenburg, Oldenburg, 26129, Germany
Research Center Neurosensory Science, University of Oldenburg, Oldenburg, 26129, Germany
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, 00146, Italy
GeneDx, 207 Perry Parkway, Gaithersburg, 20877, MD, United States
Unit of Child Neuropsichiatry, Department of Clinical and Surgical Neurosciences and Rehabilitation, IRCCS Giannina Gaslini, Genoa, 16147, Italy
Australian Regenerative Medicine Institute, Monash University, Clayton, 3168, VIC, Australia
Pediatric Neurology and Muscular Diseases Unit, IRRCS Istituto Giannina Gaslini, Genoa, 16148, Italy
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, 16142, Italy
Unit of Medical Genetics, IRRCS Istituto Giannina Gaslini, Genoa, 16147, Italy
Departments of Pediatrics and Medicine, Columbia University, New York, 10032, NY, United States
Department of Neurology, Cook Childrens Medical Center, Fort Worth, 76104, TX, United States
Department of Pediatrics, University of North Texas Health Science Center, Fort Worth, 76107, TX, United States
Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, 5006, SA, Australia
Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, 5000, SA, Australia
South Australian Health and Medical Research Institute, Adelaide, 5000, SA, Australia
Brain and Mitochondrial Research Group, Murdoch Childrens Research Institute, Melbourne Department of Paediatrics, University of Melbourne, Melbourne, 3052, VIC, Australia
Discipline of Child and Adolescent Health, University of Sydney, Sydney, 2006, NSW, Australia
Yale Center for Genome Analysis, Yale University, New Haven, 06520, CT, United States
Department of Genetics, Yale University School of Medicine, New Haven, 06510, CT, United States
Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, 21201, MD, United States
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, 20892, MD, United States
Department of Paediatrics, Monash University, Melbourne, 3168, VIC, Australia
Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany
Department of Otolaryngology - Head and Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen, Tübingen, 72076, Germany
Department of Genetics, Washington University School of Medicine, St. Louis, 63110, MO, United States
Centre for Rare Diseases, University of Tübingen, Tuebingen, 72074, Germany
Department of Paediatrics, Adolescent Medicine and Neonatology, Munich Clinic, Schwabing Hospital and Technical University of Munich, School of Medicine, Munich, 80804, Germany

Department of Otorhinolaryngology Head and Neck Surgery
Barrow Neurological Institute
Departments of Child Health
Department of Neuromuscular Disorders
Institute of Human Genetics
Institute of Neurogenomics
CSIRO Health and Biosecurity
Pediatric Neuroradiology Division
University of Arizona College of Medicine
Mayo Clinic
Neurology Department
Department of Medical Genomics
Center for Applied Genomics
Department of Computer Science
Center for Applied Genomics
Center for Data Driven Discovery in Biomedicine
Department of Bone and Osteogenesis Imperfecta
Center for Autism and Related Disorders
Division of Genetics and Genomics
Department of Neurology
University of Massachusetts Medical School – Baystate
Department of Neurology and Developmental Medicine
Department of Neurology
Centre of Child and Adolescent Medicine
Department of Child Neurology and Metabolic Medicine
Dor Yeshorim
Dor Yeshorim
Department of Child Neurology
Department of Neurology
Clinical Genetics
Clinical Pharmacology
Penn State Health Childrens Hospital
Department of Clinical Neurosciences
Inonu University
Izmir Biomedicine and Genome Center
Department of Pediatric Neurology
Department of Medical Biology
Childrens Hospital of Eastern Ontario Research Institute
Università Cattolica Sacro Cuore
Fondazione Policlinico A. Gemelli IRCCS
Telethon Institute of Genetics and Medicine
Department of Precision Medicine
Department of Neuropediatrics
Institute of Medical Genetics and Applied Genomics
Institute of Systems Motor Science
Department of Paediatric and Adolescent Medicine
University Childrens Hospital Oldenburg
Human Genetics
Junior Research Group
Research Center Neurosensory Science
Genetics and Rare Diseases Research Division
GeneDx
Unit of Child Neuropsichiatry
Australian Regenerative Medicine Institute
Pediatric Neurology and Muscular Diseases Unit
Department of Neurosciences
Unit of Medical Genetics
Departments of Pediatrics and Medicine
Department of Neurology
Department of Pediatrics
Robinson Research Institute
Adelaide Medical School
South Australian Health and Medical Research Institute
Brain and Mitochondrial Research Group
Discipline of Child and Adolescent Health
Yale Center for Genome Analysis
Department of Genetics
Department of Biochemistry and Molecular Biology
Ophthalmic Genetics and Visual Function Branch
Department of Paediatrics
Institute of Biochemistry
Department of Otolaryngology - Head and Neck Surgery
Department of Genetics
Centre for Rare Diseases
Department of Paediatrics

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