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

dc.citation.issue10
dc.citation.spage2006-2016
dc.citation.volume108
dc.contributor.authorRichard, E. M.
dc.contributor.authorBakhtiari, S.
dc.contributor.authorMarsh, A. P. L.
dc.contributor.authorKaiyrzhanov, R.
dc.contributor.authorWagner, M.
dc.contributor.authorShetty, S.
dc.contributor.authorPagnozzi, A.
dc.contributor.authorNordlie, S. M.
dc.contributor.authorGuida, B. S.
dc.contributor.authorCornejo, P.
dc.contributor.authorMagee, H.
dc.contributor.authorLiu, J.
dc.contributor.authorNorton, B. Y.
dc.contributor.authorWebster, R. I.
dc.contributor.authorWorgan, L.
dc.contributor.authorHakonarson, H.
dc.contributor.authorLi, J.
dc.contributor.authorGuo, Y.
dc.contributor.authorJain, M.
dc.contributor.authorBlesson, A.
dc.contributor.authorRodan, L. H.
dc.contributor.authorAbbott, M. A.
dc.contributor.authorComi, A.
dc.contributor.authorCohen, J. S.
dc.contributor.authorAlhaddad, B.
dc.contributor.authorMeitinger, T.
dc.contributor.authorLenz, D.
dc.contributor.authorZiegler, A.
dc.contributor.authorKotzaeridou, U.
dc.contributor.authorBrunet, T.
dc.contributor.authorChassevent, A.
dc.contributor.authorSmith-Hicks, C.
dc.contributor.authorEkstein, J.
dc.contributor.authorWeiden, T.
dc.contributor.authorHahn, A.
dc.contributor.authorZharkinbekova, N.
dc.contributor.authorTurnpenny, P.
dc.contributor.authorTucci, A.
dc.contributor.authorYelton, M.
dc.contributor.authorHorvath, R.
dc.contributor.authorGungor, S.
dc.contributor.authorHiz, S.
dc.contributor.authorOktay, Y.
dc.contributor.authorLochmuller, H.
dc.contributor.authorZollino, M.
dc.contributor.authorMorleo, M.
dc.contributor.authorMarangi, G.
dc.contributor.authorNigro, V.
dc.contributor.authorTorella, A.
dc.contributor.authorPinelli, M.
dc.contributor.authorAmenta, S.
dc.contributor.authorHusain, R. A.
dc.contributor.authorGrossmann, B.
dc.contributor.authorRapp, M.
dc.contributor.authorSteen, C.
dc.contributor.authorMarquardt, I.
dc.contributor.authorGrimmel, M.
dc.contributor.authorGrasshoff, U.
dc.contributor.authorKorenke, G. C.
dc.contributor.authorOwczarek-Lipska, M.
dc.contributor.authorNeidhardt, J.
dc.contributor.authorRadio, F. C.
dc.contributor.authorMancini, C.
dc.contributor.authorClaps Sepulveda, D. J.
dc.contributor.authorMcWalter, K.
dc.contributor.authorBegtrup, A.
dc.contributor.authorCrunk, A.
dc.contributor.authorGuillen Sacoto, M. J.
dc.contributor.authorPerson, R.
dc.contributor.authorSchnur, R. E.
dc.contributor.authorMancardi, M. M.
dc.contributor.authorKreuder, F.
dc.contributor.authorStriano, P.
dc.contributor.authorZara, F.
dc.contributor.authorChung, W. K.
dc.contributor.authorMarks, W. A.
dc.contributor.authorvan Eyk, C. L.
dc.contributor.authorWebber, D. L.
dc.contributor.authorCorbett, M. A.
dc.contributor.authorHarper, K.
dc.contributor.authorBerry, J. G.
dc.contributor.authorMacLennan, A. H.
dc.contributor.authorGecz, J.
dc.contributor.authorTartaglia, M.
dc.contributor.authorSalpietro, V.
dc.contributor.authorChristodoulou, J.
dc.contributor.authorKaslin, J.
dc.contributor.authorPadilla-Lopez, S.
dc.contributor.authorBilguvar, K.
dc.contributor.authorMunchau, A.
dc.contributor.authorAhmed, Z. M.
dc.contributor.authorHufnagel, R. B.
dc.contributor.authorFahey, M. C.
dc.contributor.authorMaroofian, R.
dc.contributor.authorHoulden, H.
dc.contributor.authorSticht, H.
dc.contributor.authorMane, S. M.
dc.contributor.authorRad, A.
dc.contributor.authorVona, B.
dc.contributor.authorJin, S. C.
dc.contributor.authorHaack, T. B.
dc.contributor.authorMakowski, C.
dc.contributor.authorHirsch, Y.
dc.contributor.authorRiazuddin, S.
dc.contributor.authorKruer, M. C.
dc.date.accessioned2021-12-15T14:23:45Z
dc.date.available2021-12-15T14:23:45Z
dc.date.epub2021-10-10
dc.date.issued2021-10-07
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 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.
dc.description.admin-notePublished version, accepted version (6 month embargo), submitted version
dc.description.noteThe article is available via Open Access. Click on the 'Additional link' above to access the full-text.
dc.identifier.citationAm J Hum Genet. 2021 Oct 7;108(10):2006-2016. doi: 10.1016/j.ajhg.2021.08.003.
dc.identifier.doi10.1016/j.ajhg.2021.08.003
dc.identifier.journalAmerican journal of human genetics
dc.identifier.pmcidPMC8546233
dc.identifier.pmid34626583
dc.identifier.urihttps://hdl.handle.net/11287/622267
dc.language.isoeng
dc.publisherCell Press
dc.relation.urlhttps://linkinghub.elsevier.com/retrieve/pii/S0002-9297(21)00302-5
dc.rights© 2021. Published by Elsevier Inc.
dc.rights.urihttp://creativecommons.org/publicdomain/zero/1.0/
dc.subjectATPases Associated with Diverse Cellular Activities/genetics
dc.subjectAdolescent
dc.subjectAdult
dc.subjectAlleles
dc.subjectAnimals
dc.subjectCerebral Palsy/etiology/metabolism/*pathology
dc.subjectChild, Preschool
dc.subjectEpilepsy/etiology/metabolism/*pathology
dc.subjectFemale
dc.subject*Genetic Predisposition to Disease
dc.subject*Genetic Variation
dc.subjectHearing Loss/etiology/metabolism/*pathology
dc.subjectHumans
dc.subjectInfant
dc.subjectInfant, Newborn
dc.subjectIntellectual Disability/etiology/metabolism/*pathology
dc.subjectMale
dc.subjectMuscle Spasticity/etiology/metabolism/*pathology
dc.subjectRats
dc.subjectYoung Adult
dc.subject*AAA+ superfamily
dc.subject*ATPase
dc.subject*spata5l1
dc.subject*cerebral palsy
dc.subject*epilepsy
dc.subject*intellectual disability
dc.subject*movement disorder
dc.subject*neurodevelopmental disorder
dc.subject*sensorineural hearing loss
dc.titleBi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss
dc.typeCase Reports
dc.type.versionppublish
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