Journal article

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

Elodie M Richard, Somayeh Bakhtiari, Ashley PL Marsh, Rauan Kaiyrzhanov, Matias Wagner, Sheetal Shetty, Alex Pagnozzi, Sandra M Nordlie, Brandon S Guida, Patricia Cornejo, Helen Magee, James Liu, Bethany Y Norton, Richard Webster, Lisa Worgan, Hakon Hakonarson, Jiankang Li, Yiran Guo, Mahim Jain, Alyssa Blesson Show all

AMERICAN JOURNAL OF HUMAN GENETICS | CELL PRESS | Published : 2021

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 ..

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Grants

Awarded by Cerebral PalsyAlliance Research Foundation


Awarded by ItalianMinistry of Health


Awarded by Telethon Undiagnosed Diseases Program (TUDP)


Awarded by Canadian Institutes of Health Research


Awarded by Canada Foundation for Innovation


Awarded by Canada Research Chairs Program (Canada Research Chair in Neuromuscular Genomics and Health)


Awarded by University of Tubingen


Awarded by Clinical and Translational Research Funding Program


Awarded by NIH/National Center for Advancing Translational Sciences


Awarded by Wellcome Trust


Awarded by NHMRC Early Career Research Fellowship


Awarded by Australian National Health and Medical Research Council


Awarded by Australian National Health and Medical Research Council Fellowship



Funding Acknowledgements

The 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.