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

doi:10.1016/j.ajhg.2021.08.003

Case Reports

. 2021 Oct 7;108(10):2006-2016.

doi: 10.1016/j.ajhg.2021.08.003.

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

Elodie M Richard¹, Somayeh Bakhtiari², Ashley P L Marsh², Rauan Kaiyrzhanov³, Matias Wagner⁴, Sheetal Shetty², Alex Pagnozzi⁵, Sandra M Nordlie², Brandon S Guida², Patricia Cornejo⁶, Helen Magee², James Liu², Bethany Y Norton², Richard I Webster⁷, Lisa Worgan⁸, Hakon Hakonarson⁹, Jiankang Li¹⁰, Yiran Guo¹¹, Mahim Jain¹², Alyssa Blesson¹³, Lance H Rodan¹⁴, Mary-Alice Abbott¹⁵, Anne Comi¹⁶, Julie S Cohen¹⁶, Bader Alhaddad¹⁷, Thomas Meitinger¹⁷, Dominic Lenz¹⁸, Andreas Ziegler¹⁹, Urania Kotzaeridou¹⁹, Theresa Brunet¹⁷, Anna Chassevent²⁰, Constance Smith-Hicks¹⁶, Joseph Ekstein²¹, Tzvi Weiden²², Andreas Hahn²³, Nazira Zharkinbekova²⁴, Peter Turnpenny²⁵, Arianna Tucci²⁶, Melissa Yelton²⁷, Rita Horvath²⁸, Serdal Gungor²⁹, Semra Hiz³⁰, Yavuz Oktay³¹, Hanns Lochmuller³², Marcella Zollino³³, Manuela Morleo³⁴, Giuseppe Marangi³³, Vincenzo Nigro³⁵, Annalaura Torella³⁵, Michele Pinelli³⁴, Simona Amenta³³, Ralf A Husain³⁶, Benita Grossmann³⁷, Marion Rapp³⁸, Claudia Steen³⁹, Iris Marquardt⁴⁰, Mona Grimmel³⁷, Ute Grasshoff³⁷, G Christoph Korenke⁴⁰, Marta Owczarek-Lipska⁴¹, John Neidhardt⁴², Francesca Clementina Radio⁴³, Cecilia Mancini⁴³, Dianela Judith Claps Sepulveda⁴³, Kirsty McWalter⁴⁴, Amber Begtrup⁴⁴, Amy Crunk⁴⁴, Maria J Guillen Sacoto⁴⁴, Richard Person⁴⁴, Rhonda E Schnur⁴⁴, Maria Margherita Mancardi⁴⁵, Florian Kreuder⁴⁶, Pasquale Striano⁴⁷, Federico Zara⁴⁸, Wendy K Chung⁴⁹, Warren A Marks⁵⁰, Clare L van Eyk⁵¹, Dani L Webber⁵¹, Mark A Corbett⁵¹, Kelly Harper⁵¹, Jesia G Berry⁵¹, Alastair H MacLennan⁵¹, Jozef Gecz⁵², Marco Tartaglia⁴³, Vincenzo Salpietro⁴⁷, John Christodoulou⁵³, Jan Kaslin⁴⁶, Sergio Padilla-Lopez², Kaya Bilguvar⁵⁴, Alexander Munchau³⁸, Zubair M Ahmed⁵⁵, Robert B Hufnagel⁵⁶, Michael C Fahey⁵⁷, Reza Maroofian³, Henry Houlden³, Heinrich Sticht⁵⁸, Shrikant M Mane⁵⁴, Aboulfazl Rad⁵⁹, Barbara Vona⁵⁹, Sheng Chih Jin⁶⁰, Tobias B Haack⁶¹, Christine Makowski⁶², Yoel Hirsch²¹, Saima Riazuddin⁶³, Michael C Kruer⁶⁴

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: sriazuddin@som.umaryland.edu.
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: kruerm@arizona.edu.

PMID: 34626583
PMCID: PMC8546233
DOI: 10.1016/j.ajhg.2021.08.003

Case Reports

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

Elodie M Richard et al. Am J Hum Genet. 2021.

. 2021 Oct 7;108(10):2006-2016.

doi: 10.1016/j.ajhg.2021.08.003.

Authors

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: sriazuddin@som.umaryland.edu.
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: kruerm@arizona.edu.

PMID: 34626583
PMCID: PMC8546233
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.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

**Figure 1**
Prevalent clinical features of individuals with bi-allelic variants in *SPATA5L1* (A) Bar graph illustrating the prevalence of the most relevant clinical features from the 25 individuals for whom full datasets were available from 18 families with the neurodevelopmental phenotype. Blue: individuals with the clinical feature. Gray: individuals without the clinical feature. (B) Representative clinical features of individuals carrying bi-allelic *SPATA5L1* variants with the severe neurodevelopmental phenotype, showing subtle and non-specific dysmorphic features, including downslanting palpebral fissures, bitemporal narrowing, and depressed nasal bridge.

**Figure 2**
Neuroimaging features in individuals harboring bi-allelic predicted-deleterious variants in *SPATA5L1* (A) T1 and T2/FLAIR MRI images were assessed for the presence of periventricular leukomalacia (defined as T2 hyperintensity and/or diminished white matter volume/ex vacuo ventriculomegaly evident adjacent to the ventricles); anterior temporal lobe hypoplasia; widened Sylvian fissures (characterized as diminished coverage of the insular cortex), diminished cortical volume; and thin/dysplastic corpus callosum. Ages were 4 years old (1-1, 1-2), 21 years old (7-9), 10 years old (8-10), 7 years old (8-11), 6 years old (8-12), and 1 year old (12-16). (B) Boxplot of six structural measures quantified from brain MRI volumes, represented as Z scores, in comparison to an age-matched control cohort of typically developing children.

**Figure 3**
Distribution and predicted structural effects of *SPATA5L1* variants (A) Alternative splicing leads to two distinct *SPATA5L1* transcripts (top), resulting in a full-length and short isoform (bottom). The variant numbering is based on the full-length transcript and isoform, GenBank: NM_024063.3 and GenBank: NP_076968.2. Non-coding and coding regions of exons are denoted by flat-edged and pointed-edged rectangles, respectively. (B) Structural effects of a subset of variants identified in this study were evaluated with a three-dimensional model of SPATA5L1 based on the structure of the homologous ATPase p97 (PDB: 5FTN). The SPATA5L1 structure is shown in ribbon presentation, depicting the N-terminal domain (green) and two conserved ATPase domains (AAA, blue and cyan). ATP ligands are shown in stick presentation. Altered residues are highlighted as balls and labeled. Red and orange balls indicate variants that were classified as deleterious by two or one methods, respectively. Yellow balls indicate variants that were predicted to have little effect on protein structure. The variants depicted in more detail in Figure S3 are labeled in bold letters.

**Figure 4**
*Spata5l1* is expressed in the inner ear and the brain of rodents/humans (A) *SPATA5L1* is expressed in all cellular subtypes of the human brain (Brain RNA-Seq database). (B) Representative immunofluorescent labeling of endogenous SPATA5L1 (green) in rat hippocampal neurons in culture highlight the co-localization of the protein within the nuclei of neurons (MAP2), as well as the nuclei of glial cells (red): microglia (IBA1), astrocytes (GFAP), and oligodendrocytes (Olig2). Signal intensity of SPATA5L1 immunolabeling suggests protein expression is higher in neurons compared to glial cells. Arrows indicate the localization of SPATA5L1 in the nuclei of glial cells. All images are projections of confocal optical section stacks. Scale bar: 25 μm. (C) *Spata5l1* is expressed at low levels in hair cells (inner and outer) as well as supporting cells (pillar and Deiter cells) in adult mice (adapted from gEAR portal). HC, hair cells. (D) Representative immunofluorescent labeling of endogenous SPATA5L1 (green) in Sprague Dawley rat organ of Corti at E20. Immunolabeling shows SPATA5L1 is present in the hair and pillar cells of the organ of Corti. DAPI (blue) and Rhodamine Phalloidin (red) were used for counterstaining the nuclei and the cytoskeleton, respectively. All images are projections of confocal optical section stacks. Scale bar: 10 μm.

**Figure 5**
Analysis of gene expression patterns in *SPATA5L1* fibroblasts by RNA-seq reveals differential expression of DNA replication and mitosis-related genes (A) Principal-component analysis plot shows a differential clustering of SPATA5L1 samples (n = 4) from control samples (n = 4). (B) Transcriptomic heatmap of the top 20 differentially expressed genes (top ten with fold change > 1.5 and p < 0.05 and bottom 10 with fold change < 0.5 and p < 0.05). Red/yellow colors represent highly expressed genes and blue colors represent under-expressed genes for these 20 genes in the respective case and control samples. The legend corresponds to expression values. (C) Volcano plot highlighting genes with large fold changes that are either significantly upregulated or downregulated between SPATA5L1 and control samples. Log₂ fold change of normalized counts (red dots indicate genes with p < 10⁻¹⁶). (D) Over-representation analysis (ORA) for downregulated genes (log₂ fold change < −1, p < 0.05) for GO-BP (Gene Ontology Biological Processes). (E) Over-representation analysis (ORA) for downregulated genes (log₂ fold change < −1, p < 0.05) for GO-CC (Gene Ontology Cellular Components). (F) Over-representation analysis (ORA) for downregulated genes (log₂ fold change < −1, p < 0.05) for GO-CC and GO-MF (Gene Ontology Molecular Functions).

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References

1. Tanaka A.J., Cho M.T., Millan F., Juusola J., Retterer K., Joshi C., Niyazov D., Garnica A., Gratz E., Deardorff M. Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss. Am. J. Hum. Genet. 2015;97:457–464. - PMC - PubMed
1. Liu Y., Black J., Kisiel N., Kulesz-Martin M.F. SPAF, a new AAA-protein specific to early spermatogenesis and malignant conversion. Oncogene. 2000;19:1579–1588. - PubMed
1. Puusepp S., Kovacs-Nagy R., Alhaddad B., Braunisch M., Hoffmann G.F., Kotzaeridou U., Lichvarova L., Liiv M., Makowski C., Mandel M. Compound heterozygous SPATA5 variants in four families and functional studies of SPATA5 deficiency. Eur. J. Hum. Genet. 2018;26:407–419. - PMC - PubMed
1. Köttgen A., Glazer N.L., Dehghan A., Hwang S.J., Katz R., Li M., Yang Q., Gudnason V., Launer L.J., Harris T.B. Multiple loci associated with indices of renal function and chronic kidney disease. Nat. Genet. 2009;41:712–717. - PMC - PubMed
1. Kubo Y., Imaizumi T., Ando M., Nakatochi M., Yasuda Y., Honda H., Kuwatsuka Y., Kato S., Kikuchi K., Kondo T. Association between kidney function and genetic polymorphisms in atherosclerotic and chronic kidney diseases: A cross-sectional study in Japanese male workers. PLoS ONE. 2017;12:e0185476. - PMC - PubMed

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[1] Tanaka A.J., Cho M.T., Millan F., Juusola J., Retterer K., Joshi C., Niyazov D., Garnica A., Gratz E., Deardorff M. Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss. Am. J. Hum. Genet. 2015;97:457–464. - PMC - PubMed

[2] Tanaka A.J., Cho M.T., Millan F., Juusola J., Retterer K., Joshi C., Niyazov D., Garnica A., Gratz E., Deardorff M. Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss. Am. J. Hum. Genet. 2015;97:457–464. - PMC - PubMed

[3] Liu Y., Black J., Kisiel N., Kulesz-Martin M.F. SPAF, a new AAA-protein specific to early spermatogenesis and malignant conversion. Oncogene. 2000;19:1579–1588. - PubMed

[4] Liu Y., Black J., Kisiel N., Kulesz-Martin M.F. SPAF, a new AAA-protein specific to early spermatogenesis and malignant conversion. Oncogene. 2000;19:1579–1588. - PubMed

[5] Puusepp S., Kovacs-Nagy R., Alhaddad B., Braunisch M., Hoffmann G.F., Kotzaeridou U., Lichvarova L., Liiv M., Makowski C., Mandel M. Compound heterozygous SPATA5 variants in four families and functional studies of SPATA5 deficiency. Eur. J. Hum. Genet. 2018;26:407–419. - PMC - PubMed

[6] Puusepp S., Kovacs-Nagy R., Alhaddad B., Braunisch M., Hoffmann G.F., Kotzaeridou U., Lichvarova L., Liiv M., Makowski C., Mandel M. Compound heterozygous SPATA5 variants in four families and functional studies of SPATA5 deficiency. Eur. J. Hum. Genet. 2018;26:407–419. - PMC - PubMed

[7] Köttgen A., Glazer N.L., Dehghan A., Hwang S.J., Katz R., Li M., Yang Q., Gudnason V., Launer L.J., Harris T.B. Multiple loci associated with indices of renal function and chronic kidney disease. Nat. Genet. 2009;41:712–717. - PMC - PubMed

[8] Köttgen A., Glazer N.L., Dehghan A., Hwang S.J., Katz R., Li M., Yang Q., Gudnason V., Launer L.J., Harris T.B. Multiple loci associated with indices of renal function and chronic kidney disease. Nat. Genet. 2009;41:712–717. - PMC - PubMed

[9] Kubo Y., Imaizumi T., Ando M., Nakatochi M., Yasuda Y., Honda H., Kuwatsuka Y., Kato S., Kikuchi K., Kondo T. Association between kidney function and genetic polymorphisms in atherosclerotic and chronic kidney diseases: A cross-sectional study in Japanese male workers. PLoS ONE. 2017;12:e0185476. - PMC - PubMed

[10] Kubo Y., Imaizumi T., Ando M., Nakatochi M., Yasuda Y., Honda H., Kuwatsuka Y., Kato S., Kikuchi K., Kondo T. Association between kidney function and genetic polymorphisms in atherosclerotic and chronic kidney diseases: A cross-sectional study in Japanese male workers. PLoS ONE. 2017;12:e0185476. - PMC - PubMed

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

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

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