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

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dc.authoridvan Eyk, Clare L/0000-0003-0345-9944
dc.authoridGecz, Jozef/0000-0002-7884-6861
dc.authoridZollino, Marcella/0000-0003-4871-9519
dc.authoridTartaglia, Marco/0000-0001-7736-9672
dc.authoridChristodoulou, John/0000-0002-8431-0641
dc.authoridMancardi, Maria Margherita/0000-0001-5122-4029
dc.authoridLenz, Dominic/0000-0002-9561-8190
dc.authorwosidvan Eyk, Clare L/P-8334-2019
dc.authorwosidNigro, Vincenzo/AAB-2274-2022
dc.authorwosidWagner, Matias/L-4532-2019
dc.authorwosidRadio, Francesca Clementina/I-9417-2014
dc.authorwosidKaslin, Jan V/E-7780-2010
dc.authorwosidGecz, Jozef/X-3469-2019
dc.authorwosidZollino, Marcella/AAC-3891-2022
dc.contributor.authorRichard, Elodie M.
dc.contributor.authorBakhtiari, Somayeh
dc.contributor.authorMarsh, Ashley P. L.
dc.contributor.authorKaiyrzhanov, Rauan
dc.contributor.authorWagner, Matias
dc.contributor.authorShetty, Sheetal
dc.contributor.authorPagnozzi, Alex
dc.date.accessioned2024-08-04T20:50:45Z
dc.date.available2024-08-04T20:50:45Z
dc.date.issued2021
dc.departmentİnönü Üniversitesien_US
dc.description.abstractSpermatogenesis-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 Spata511 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata511 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.en_US
dc.description.sponsorshipCerebral PalsyAlliance Research Foundation [PG07217]; Fondazione Bambino Gesu; ItalianMinistry of Health [53 1000]; Telethon Undiagnosed Diseases Program (TUDP) [GSP15001]; Canadian Institutes of Health Research [FDN167281]; Canadian Institutes of Health Research and Muscular Dystrophy Canada; Canada Foundation for Innovation [CFIJELF 38412]; Canada Research Chairs Program (Canada Research Chair in Neuromuscular Genomics and Health) [950-232279]; University of Tubingen [2545-1-0]; Ministry of Science, Research, and Art Baden-Wurttemberg; NEI intramural funds; JPB Foundation; SFARI; Clinical and Translational Research Funding Program [CTSA1405]; Foundation for Barnes-Jewish Hospital; NIH/National Center for Advancing Translational Sciences [UL1TR002345]; Wellcome Trust [WT093205 MA, WT104033AIA]; National Institute for Health Research University College London Hospitals Biomedical Research Centre; NHMRC Early Career Research Fellowship [GNT1156820]; Cerebral Palsy Alliance Research Foundation Career Development Award; Australian National Health and Medical Research Council [1099163]; Australian National Health and Medical Research Council Fellowship [1041920]; Channel 7 CRF Chair for the Prevention of Childhood Disability; Hospital Research Foundation Mid-Career Fellowship; Tenix Foundation; [R01NS107428]; [1R01NS106298]; [K99/R00]; [K99HL143036]; [R00HL143036-02]; National Health and Medical Research Council of Australia [1099163] Funding Source: NHMRC; MRC [MR/V009346/1, MR/N010035/1, MR/N025431/2, MR/S006753/1, MR/N025431/1] Funding Source: UKRI; Newton Fund [MR/N027302/1, MR/N027302/2] Funding Source: UKRIen_US
dc.description.sponsorshipThe authors are grateful to the participants and their families, without whose support this work would not have been possible. K.Mc., A.B., A.C., M.J.G.S., R.E.P., and R.E.S. are employees of GeneDx. We thankMinervaContrerasandThomasBlanpiedfor assisting with neuronal culture and the CIBR platform (UMSOM, Baltimore, MD, USA). This work was supported in part by R01NS107428 (S.R.), 1R01NS106298 (M.C.K.), andCerebral PalsyAlliance Research Foundation PG07217 award to W.M. and M.C.K. Portions of this work were also funded by the Fondazione Bambino Gesu (Vite Coraggiose), the ItalianMinistry of Health (Ricerca 53 1000) toM.T.A., and in part by Telethon Undiagnosed Diseases Program (TUDP, GSP15001). H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFIJELF 38412), and the Canada Research Chairs Program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). B.V. is funded by intramural funding (fortune) at the University of Tubingen (2545-1-0) and the Ministry of Science, Research, and Art Baden-Wurttemberg. R.H. is supported by NEI intramural funds. W.K.C. receives support from the JPB Foundation and SFARI. S.C.J. is supported by a K99/R00 Pathway to IndependenceAward (K99HL143036 andR00HL143036-02) andthe Clinical and Translational Research Funding Program award (CTSA1405). This projectwas funded in part by The Foundation for Barnes-Jewish Hospital and their generous donors and by the NIH/National Center for Advancing Translational Sciences grant UL1TR002345. Several families were enrolled as part of the SYNaPS Study Group collaboration funded by TheWellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). This research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A.P.L.M. was supported by a NHMRC Early Career Research Fellowship (GNT1156820). S.B.'s contributions were funded by a Cerebral Palsy Alliance Research Foundation Career Development Award. C.v.E., M.A.C., and A.H.M. were supported by Australian National Health and Medical Research Council Project Grant (1099163). J.G. was supported by Australian National Health and Medical Research Council Fellowship (1041920) and Channel 7 CRF Chair for the Prevention of Childhood Disability. C.v.E. was supported by The Hospital Research Foundation Mid-Career Fellowship. C.v.E., M.A.C., A.H.M., and J.G. were supported by infrastructure funding from the Tenix Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.en_US
dc.identifier.doi10.1016/j.ajhg.2021.08.003
dc.identifier.endpage2016en_US
dc.identifier.issn0002-9297
dc.identifier.issn1537-6605
dc.identifier.issue10en_US
dc.identifier.pmid34626583en_US
dc.identifier.scopus2-s2.0-85116905632en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage2006en_US
dc.identifier.urihttps://doi.org/10.1016/j.ajhg.2021.08.003
dc.identifier.urihttps://hdl.handle.net/11616/100260
dc.identifier.volume108en_US
dc.identifier.wosWOS:000705304300014en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherCell Pressen_US
dc.relation.ispartofAmerican Journal of Human Geneticsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectRenal-Functionen_US
dc.subjectLocien_US
dc.titleBi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing lossen_US
dc.typeArticleen_US

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