biostudies-literatureRichard EMNCATS NIH HHSTelethonNHLBI NIH HHSMedical Research CouncilNational Institute for Health Research (NIHR)NINDS NIH HHSAtaxia UKWellcome Trust2006-2016https://www.ebi.ac.uk/biostudies/studies/S-EPMC8546233biostudies-literatureUnknown108(10)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.American journal of human geneticsBi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.PMC8546233K99 HL143036UL1 TR002345UL1 TR001863R01 NS106298GSP15001R00 HL143036MR/S006753/1MR/N027302/2MR/N027302/1ZHORVATHR01 NS107428104033/Z/14/ZWT104033AIA109915/A/15/ZWT093205 MAMR/N025431/2MR/N010035/1MR/V009346/1G1000848MR/N025431/1WT093205Yelton MEkstein JMarsh APLAmenta SGuo YHaack TBNordlie SMAlhaddad BCrunk AMaroofian RAbbott MAGuida BSShetty SPerson RMunchau AHahn AChristodoulou JHufnagel RBJain MRodan LHBilguvar KSticht HSmith-Hicks CNigro VGrimmel MMane SMKruer MCKorenke GCGecz JZollino MTucci AHiz Svan Eyk CLKaslin JZiegler ABerry JGHirsch YBakhtiari SChung WKBegtrup ANeidhardt JRiazuddin SOktay YGungor SGuillen Sacoto MJHarper KTartaglia MWebster RIJin SCRad AStriano PMcWalter KTorella APinelli MPagnozzi ANorton BYGrossmann BMakowski CLenz DMarquardt IZara FWorgan LVona BAhmed ZMMancini CRapp MKotzaeridou UKaiyrzhanov RMancardi MMCorbett MAMeitinger TMarks WAWeiden TKreuder FHoulden HLi JBlesson ALochmuller HWagner MHakonarson HClaps Sepulveda DJCohen JSFahey MCHusain RATurnpenny PRichard EMLiu JMarangi GSteen CSchnur REChassevent AOwczarek-Lipska MBrunet TWebber DLCornejo PMagee HRadio FCMacLennan AHSalpietro VComi AMorleo MHorvath RPadilla-Lopez SGrasshoff UZharkinbekova NfalseBi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.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.2021-01-01T00:00:00Z2021 Oct2026-05-31T13:00:14.6Z2025-04-06T21:52:16.787ZS-EPMC85462333462658310.1016/j.ajhg.2021.08.003