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

Richard EM, Bakhtiari S, Marsh AP, Kaiyrzhanov R, Wagner M, Shetty S, Pagnozzi A, Nordlie SM, Guida BS, Cornejo P, Magee H, Liu J, Norton BY, Webster RI, Worgan L, Hakonarson H, Li J, Guo Y, Jain M, Blesson A, Rodan LH, Abbott MA, Comi A, Cohen JS, 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 RA, Grossmann B, Rapp M, Steen C, Marquardt I, Grimmel M, Grasshoff U, Korenke GC, Owczarek-Lipska M, Neidhardt J, Radio FC, Mancini C, Claps Sepulveda DJ, McWalter K, Begtrup A, Crunk A, Guillen Sacoto MJ, Person R, Schnur RE, Mancardi MM, Kreuder F, Striano P, Zara F, Chung WK, Marks WA, van Eyk CL, Webber DL, Corbett MA, Harper K, Berry JG, MacLennan AH, Gecz J, Tartaglia M, Salpietro V, Christodoulou J, Kaslin J, Padilla-Lopez S, Bilguvar K, Munchau A, Ahmed ZM, Hufnagel RB, Fahey MC, Maroofian R, Houlden H, Sticht H, Mane SM, Rad A, Vona B, Jin SC, Haack TB, Makowski C, Hirsch Y, Riazuddin S, Kruer MC (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 108

Pages Range: 2006-2016

Journal Issue: 10

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.

Authors with CRIS profile

Involved external institutions

Phoenix Children's Hospital United States (USA) (US) Justus-Liebig-Universität Gießen Germany (DE) South Kazakhstan Medical Academy Kazakhstan (KZ) University of Maryland School of Pharmacy United States (USA) (US) University College London (UCL) United Kingdom (GB) Klinikum rechts der Isar Germany (DE) Commonwealth Scientific and Industrial Research Organisation (CSIRO) Australia (AU) The Children's Hospital at Westmead Australia (AU) Royal Prince Alfred Hospital Australia (AU) Children's Hospital of Philadelphia United States (USA) (US) City University of Hong Kong (CityU) China (CN) Kennedy Krieger Institute United States (USA) (US) Boston Children's Hospital United States (USA) (US) University of Massachusetts Medical School United States (USA) (US) Universitätsklinikum Heidelberg Germany (DE) Dor Yeshorim United States (USA) (US) University of Cambridge United Kingdom (GB) Inonu Univeristy Turkey (TR) Dokuz Eylül Üniversitesi (DEU) Turkey (TR) Royal Devon & Exeter NHS Foundation Trust United Kingdom (GB) Queen Mary, University of London United Kingdom (GB) Penn State Health Children's Hospital United States (USA) (US) Children's Hospital of Eastern Ontario (CHEO) / Centre hospitalier pour enfants de l'est de l'Ontario Canada (CA) Catholic University of the Sacred Heart / Università Cattolica del Sacro Cuore Italy (IT) Telethon Institute of Genetics and Medicine (TIGEM) Italy (IT) Universitätsklinikum Jena Germany (DE) Eberhard Karls Universität Tübingen Germany (DE) Universität zu Lübeck Germany (DE) Klinikum Oldenburg Germany (DE) Carl von Ossietzky Universität Oldenburg Germany (DE) Ospedale Pediatrico Bambino Gesu Italy (IT) GeneDX United States (USA) (US) Istituto Giannina Gaslini Italy (IT) Monash University Australia (AU) University of Genova / Università degli Studi di Genova Italy (IT) Columbia University United States (USA) (US) Cook Children's Health Care System United States (USA) (US) Robinson Research Institute Australia (AU) The University of Melbourne Australia (AU) Yale School of Medicine United States (USA) (US) National Eye Institute United States (USA) (US) Universitätsklinikum Tübingen Germany (DE) Washington University United States (USA) (US) Technische Universität München (TUM) Germany (DE)

How to cite

APA:

Richard, E.M., Bakhtiari, S., Marsh, A.P., Kaiyrzhanov, R., Wagner, M., Shetty, S.,... Kruer, M.C. (2021). Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss. American Journal of Human Genetics, 108(10), 2006-2016. https://dx.doi.org/10.1016/j.ajhg.2021.08.003

MLA:

Richard, Elodie M., et al. "Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss." American Journal of Human Genetics 108.10 (2021): 2006-2016.

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