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


Book Volume: 108

Pages Range: 2006-2016

Journal Issue: 10

DOI: 10.1016/j.ajhg.2021.08.003


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

How to cite


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.


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.

BibTeX: Download