Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss,American Journal of Human Genetics

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Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2021-10-08 , 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 ₅₅ , Michael C Kruer ₂

Affiliation

Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
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.
Department of Neuromuscular Disorders, Institute of Neurology, University College London, Queen Square, WC1N 3BG London, UK.
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.
CSIRO Health and Biosecurity, The Australian e-Health Research Centre, Brisbane, QLD 4029, Australia.
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.
Neurology Department, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia.
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Computer Science, City University of Hong Kong, Kowloon 999077, Hong Kong.
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.
Department of Bone and Osteogenesis Imperfecta, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, MD 21211, USA.
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
University of Massachusetts Medical School - Baystate, Baystate Children's Hospital, Springfield, MA 01107, USA.
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.
Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany.
Centre of Child and Adolescent Medicine, Department of Pediatric Neurology and Metabolic Medicine, Heidelberg University Hospital, 69120 Heidelberg, Germany.
Department of Child Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, New York, NY 11211, USA.
Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Jerusalem 9054020, Israel.
Department of Child Neurology, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
Department of Neurology, South Kazakhstan Medical Academy, Shymkent 160001, Kazakhstan.
Clinical Genetics, Royal Devon & Exeter NHS Foundation Trust, EX1 2ED Exeter, UK.
Clinical Pharmacology, William Harvey Research Institute, Charterhouse Square, School of Medicine and Dentistry Queen Mary University of London, London EC1M 6BQ, UK.
Penn State Health Children's Hospital, Hershey, PA 17033, USA.
Department of Clinical Neurosciences, John Van Geest Cambridge Centre for Brain Repair, University of Cambridge School of Clinical Medicine, CB2 0PY Cambridge, UK.
Inonu University, Faculty of Medicine, Turgut Ozal Research Center, Department of Paediatric Neurology, 44280 Malatya, Turkey.
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.
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.
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.
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.
Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Naples, Italy.
Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Naples, Italy; Department of Precision Medicine, University of Campania "Luigi Vanvitelli," 80138 Naples, Italy.
Department of Neuropediatrics, Jena University Hospital, 07747 Jena, Germany.
Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tuebingen, Germany.
Institute of Systems Motor Science, University of Lübeck, 23538 Lübeck, Germany.
Department of Paediatric and Adolescent Medicine, St Joseph Hospital, 12101 Berlin, Germany.
University Children's Hospital Oldenburg, Department of Neuropaediatric and Metabolic Diseases, 26133 Oldenburg, Germany.
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.
Human Genetics, Faculty of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany; Research Center Neurosensory Science, University of Oldenburg, 26129 Oldenburg, Germany.
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
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, VIC 3168, Australia.
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.
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.
Departments of Pediatrics and Medicine, Columbia University, New York, NY 10032, USA.
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.
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.
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.
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.
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.
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.
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Department of Paediatrics, Monash University, Melbourne, VIC 3168, Australia.
Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Department of Otolaryngology - Head and Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tübingen, 72074 Tuebingen, Germany.
Department of Paediatrics, Adolescent Medicine and Neonatology, Munich Clinic, Schwabing Hospital and Technical University of Munich, School of Medicine, 80804 Munich, Germany.

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.

中文翻译：

SPATA5L1 中的双等位基因变异导致智力障碍、痉挛性肌张力障碍性脑瘫、癫痫和听力损失

精子发生相关的 5 样 1 (SPATA5L1) 代表编码未知功能蛋白质的孤儿基因。我们报告了SPATA5L1中的 28 个双等位基因变体与来自 28 个（26 个无关）家庭的 47 名个体的感觉神经性听力损失有关。此外，25/47 受影响的个体 (53%) 出现小头畸形、发育迟缓/智力残疾、脑瘫和/或癫痫。建模表明变体对蛋白质的破坏性影响，主要是通过对蛋白质结构域的不稳定影响。脑成像显示脑容量减少、胼胝体变薄和脑室周围白质软化，定量容量显示几个人的白质体积显着减少。大鼠海马神经元中的免疫荧光成像显示 Spata5l1 在神经元和神经胶质细胞核中的定位以及在神经元中更突出的表达。在啮齿动物内耳中，Spata5l1 在神经感觉毛细胞和内耳支持细胞中表达。用来自受影响个体的成纤维细胞进行的转录组学分析能够通过主要成分区分受影响的与对照。对差异表达基因和网络的分析表明 SPATA5L1 在细胞表面粘附受体功能、细胞内粘着斑以及 DNA 复制和有丝分裂中的作用。总的来说，我们的结果表明双等位基因SPATA5L1变体导致一种人类疾病，其特征是感觉神经性听力损失 (SNHL)，有或没有非进行性混合神经发育表型。

更新日期：2021-10-09

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