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

Elodie M. Richard; Somayeh Bakhtiari; Ashley P.L. 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 I. Webster; Lisa Worgan; Hakon Hakonarson; Jiankang Li; Yiran Guo; Mahim Jain; Alyssa Blesson; Lance H. Rodan; Mary Alice Abbott; Anne Comi; Julie S. Cohen; Bader Alhaddad; Thomas Meitinger; Dominic Lenz; Andreas Ziegler; Urania Kotzaeridou; Theresa Brunet; Anna Chassevent; Constance Smith-Hicks; Joseph Ekstein; Tzvi Weiden; Andreas Hahn; Nazira Zharkinbekova; Peter Turnpenny; Arianna Tucci; Melissa Yelton; Rita Horvath; Serdal Gungor; Semra Hiz; Yavuz Oktay; Hanns Lochmuller; Marcella Zollino; Manuela Morleo; Giuseppe Marangi; Vincenzo Nigro; Annalaura Torella; Michele Pinelli; Simona Amenta; Ralf A. Husain; Benita Grossmann; Marion Rapp; Claudia Steen; Iris Marquardt; Mona Grimmel; Ute Grasshoff; G. Christoph Korenke; Marta Owczarek-Lipska; John Neidhardt; Francesca Clementina Radio; Cecilia Mancini; Dianela Judith Claps Sepulveda; Kirsty McWalter; Amber Begtrup; Amy Crunk; Maria J. Guillen Sacoto; Richard Person; Rhonda E. Schnur; Maria Margherita Mancardi; Florian Kreuder; Pasquale Striano; Federico Zara; Wendy K. Chung; Warren A. Marks; Clare L. van Eyk; Dani L. Webber; Mark A. Corbett; Kelly Harper; Jesia G. Berry; Alastair H. MacLennan; Jozef Gecz; Marco Tartaglia; Vincenzo Salpietro; John Christodoulou; Jan Kaslin; Sergio Padilla-Lopez; Kaya Bilguvar; Alexander Munchau; Zubair M. Ahmed; Robert B. Hufnagel; Michael C. Fahey; Reza Maroofian; Henry Houlden; Heinrich Sticht; Shrikant M. Mane; Aboulfazl Rad; Barbara Vona; Sheng Chih Jin; Tobias B. Haack; Christine Makowski; Yoel Hirsch; Saima Riazuddin; Michael C. Kruer

doi:10.1016/j.ajhg.2021.08.003

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

Elodie M. Richard, Somayeh Bakhtiari, Ashley P.L. 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 I. Webster, Lisa Worgan, Hakon Hakonarson, Jiankang Li, Yiran Guo, Mahim Jain, Alyssa BlessonLance H. Rodan, Mary Alice Abbott, Anne Comi, Julie S. Cohen, Bader Alhaddad, Thomas Meitinger, Dominic Lenz, Andreas Ziegler, Urania Kotzaeridou, Theresa Brunet, Anna Chassevent, Constance Smith-Hicks, Joseph Ekstein, Tzvi Weiden, Andreas Hahn, Nazira Zharkinbekova, Peter Turnpenny, Arianna Tucci, Melissa Yelton, Rita Horvath, Serdal Gungor, Semra Hiz, Yavuz Oktay, Hanns Lochmuller, Marcella Zollino, Manuela Morleo, Giuseppe Marangi, Vincenzo Nigro, Annalaura Torella, Michele Pinelli, Simona Amenta, Ralf A. Husain, Benita Grossmann, Marion Rapp, Claudia Steen, Iris Marquardt, Mona Grimmel, Ute Grasshoff, G. Christoph Korenke, Marta Owczarek-Lipska, John Neidhardt, Francesca Clementina Radio, Cecilia Mancini, Dianela Judith Claps Sepulveda, Kirsty McWalter, Amber Begtrup, Amy Crunk, Maria J. Guillen Sacoto, Richard Person, Rhonda E. Schnur, Maria Margherita Mancardi, Florian Kreuder, Pasquale Striano, Federico Zara, Wendy K. Chung, Warren A. Marks, Clare L. van Eyk, Dani L. Webber, Mark A. Corbett, Kelly Harper, Jesia G. Berry, Alastair H. MacLennan, Jozef Gecz, Marco Tartaglia, Vincenzo Salpietro, John Christodoulou, Jan Kaslin, Sergio Padilla-Lopez, Kaya Bilguvar, Alexander Munchau, Zubair M. Ahmed, Robert B. Hufnagel, Michael C. Fahey, Reza Maroofian, Henry Houlden, Heinrich Sticht, Shrikant M. Mane, Aboulfazl Rad, Barbara Vona, Sheng Chih Jin, Tobias B. Haack, Christine Makowski, Yoel Hirsch, Saima Riazuddin, Michael C. Kruer

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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 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.

Original language	English
Pages (from-to)	2006-2016
Number of pages	11
Journal	American journal of human genetics
Volume	108
Issue number	10
DOIs	https://doi.org/10.1016/j.ajhg.2021.08.003
State	Published - Oct 7 2021

Keywords

AAA+ superfamily
ATPase
SPATA5L1
cerebral palsy
epilepsy
intellectual disability
movement disorder
neurodevelopmental disorder
sensorineural hearing loss

Access to Document

10.1016/j.ajhg.2021.08.003

Cite this

Richard, E. M., Bakhtiari, S., Marsh, A. P. L., Kaiyrzhanov, R., Wagner, M., Shetty, S., Pagnozzi, A., Nordlie, S. M., Guida, B. S., Cornejo, P., Magee, H., Liu, J., Norton, B. Y., Webster, R. I., Worgan, L., Hakonarson, H., Li, J., Guo, Y., Jain, M., ... 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. https://doi.org/10.1016/j.ajhg.2021.08.003

@article{4fc8679afd1c45edbee893dbeef523d1,

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

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 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.",

keywords = "AAA+ superfamily, ATPase, SPATA5L1, cerebral palsy, epilepsy, intellectual disability, movement disorder, neurodevelopmental disorder, sensorineural hearing loss",

author = "Richard, {Elodie M.} and Somayeh Bakhtiari and Marsh, {Ashley P.L.} and Rauan Kaiyrzhanov and Matias Wagner and Sheetal Shetty and Alex Pagnozzi and Nordlie, {Sandra M.} and Guida, {Brandon S.} and Patricia Cornejo and Helen Magee and James Liu and Norton, {Bethany Y.} and Webster, {Richard I.} and Lisa Worgan and Hakon Hakonarson and Jiankang Li and Yiran Guo and Mahim Jain and Alyssa Blesson and Rodan, {Lance H.} and Abbott, {Mary Alice} and Anne Comi and Cohen, {Julie S.} and Bader Alhaddad and Thomas Meitinger and Dominic Lenz and Andreas Ziegler and Urania Kotzaeridou and Theresa Brunet and Anna Chassevent and Constance Smith-Hicks and Joseph Ekstein and Tzvi Weiden and Andreas Hahn and Nazira Zharkinbekova and Peter Turnpenny and Arianna Tucci and Melissa Yelton and Rita Horvath and Serdal Gungor and Semra Hiz and Yavuz Oktay and Hanns Lochmuller and Marcella Zollino and Manuela Morleo and Giuseppe Marangi and Vincenzo Nigro and Annalaura Torella and Michele Pinelli and Simona Amenta and Husain, {Ralf A.} and Benita Grossmann and Marion Rapp and Claudia Steen and Iris Marquardt and Mona Grimmel and Ute Grasshoff and Korenke, {G. Christoph} and Marta Owczarek-Lipska and John Neidhardt and Radio, {Francesca Clementina} and Cecilia Mancini and {Claps Sepulveda}, {Dianela Judith} and Kirsty McWalter and Amber Begtrup and Amy Crunk and {Guillen Sacoto}, {Maria J.} and Richard Person and Schnur, {Rhonda E.} and Mancardi, {Maria Margherita} and Florian Kreuder and Pasquale Striano and Federico Zara and Chung, {Wendy K.} and Marks, {Warren A.} and {van Eyk}, {Clare L.} and Webber, {Dani L.} and Corbett, {Mark A.} and Kelly Harper and Berry, {Jesia G.} and MacLennan, {Alastair H.} and Jozef Gecz and Marco Tartaglia and Vincenzo Salpietro and John Christodoulou and Jan Kaslin and Sergio Padilla-Lopez and Kaya Bilguvar and Alexander Munchau and Ahmed, {Zubair M.} and Hufnagel, {Robert B.} and Fahey, {Michael C.} and Reza Maroofian and Henry Houlden and Heinrich Sticht and Mane, {Shrikant M.} and Aboulfazl Rad and Barbara Vona and Jin, {Sheng Chih} and Haack, {Tobias B.} and Christine Makowski and Yoel Hirsch and Saima Riazuddin and Kruer, {Michael C.}",

note = "Funding Information: 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 thank Minerva Contreras and Thomas Blanpied for 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.), and Cerebral Palsy Alliance Research Foundation PG07217 award to W.M. and M.C.K. Portions of this work were also funded by the Fondazione Bambino Ges{\`u} (Vite Coraggiose), the Italian Ministry of Health (Ricerca 5 × 1000) to M.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 FDN-167281 ), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C ), the Canada Foundation for Innovation ( CFI-JELF 38412 ), and the Canada Research Chairs Program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279 ). B.V. is funded by intramural funding (fort{\"u}ne) at the University of T{\"u}bingen ( 2545-1-0 ) and the Ministry of Science, Research, and Art Baden-W{\"u}rttemberg . 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 Independence Award ( K99HL143036 and R00HL143036-02 ) and the Clinical and Translational Research Funding Program award ( CTSA1405 ). This project was 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 The Wellcome 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.{\textquoteright}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. Funding Information: 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 thank Minerva Contreras and Thomas Blanpied for 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.), and Cerebral Palsy Alliance Research Foundation PG07217 award to W.M. and M.C.K. Portions of this work were also funded by the Fondazione Bambino Ges? (Vite Coraggiose), the Italian Ministry of Health (Ricerca 5 ? 1000) to M.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 FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs Program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). B.V. is funded by intramural funding (fort?ne) at the University of T?bingen (2545-1-0) and the Ministry of Science, Research, and Art Baden-W?rttemberg. 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 Independence Award (K99HL143036 and R00HL143036-02) and the Clinical and Translational Research Funding Program award (CTSA1405). This project was 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 The Wellcome 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. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = oct,

day = "7",

doi = "10.1016/j.ajhg.2021.08.003",

language = "English",

volume = "108",

pages = "2006--2016",

journal = "American journal of human genetics",

issn = "0002-9297",

number = "10",

}

Richard, EM, Bakhtiari, S, Marsh, APL, 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, 'Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss', American journal of human genetics, vol. 108, no. 10, pp. 2006-2016. https://doi.org/10.1016/j.ajhg.2021.08.003

TY - JOUR

T1 - Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss

AU - Richard, Elodie M.

AU - Bakhtiari, Somayeh

AU - Marsh, Ashley P.L.

AU - Kaiyrzhanov, Rauan

AU - Wagner, Matias

AU - Shetty, Sheetal

AU - Pagnozzi, Alex

AU - Nordlie, Sandra M.

AU - Guida, Brandon S.

AU - Cornejo, Patricia

AU - Magee, Helen

AU - Liu, James

AU - Norton, Bethany Y.

AU - Webster, Richard I.

AU - Worgan, Lisa

AU - Hakonarson, Hakon

AU - Li, Jiankang

AU - Guo, Yiran

AU - Jain, Mahim

AU - Blesson, Alyssa

AU - Rodan, Lance H.

AU - Abbott, Mary Alice

AU - Comi, Anne

AU - Cohen, Julie S.

AU - Alhaddad, Bader

AU - Meitinger, Thomas

AU - Lenz, Dominic

AU - Ziegler, Andreas

AU - Kotzaeridou, Urania

AU - Brunet, Theresa

AU - Chassevent, Anna

AU - Smith-Hicks, Constance

AU - Ekstein, Joseph

AU - Weiden, Tzvi

AU - Hahn, Andreas

AU - Zharkinbekova, Nazira

AU - Turnpenny, Peter

AU - Tucci, Arianna

AU - Yelton, Melissa

AU - Horvath, Rita

AU - Gungor, Serdal

AU - Hiz, Semra

AU - Oktay, Yavuz

AU - Lochmuller, Hanns

AU - Zollino, Marcella

AU - Morleo, Manuela

AU - Marangi, Giuseppe

AU - Nigro, Vincenzo

AU - Torella, Annalaura

AU - Pinelli, Michele

AU - Amenta, Simona

AU - Husain, Ralf A.

AU - Grossmann, Benita

AU - Rapp, Marion

AU - Steen, Claudia

AU - Marquardt, Iris

AU - Grimmel, Mona

AU - Grasshoff, Ute

AU - Korenke, G. Christoph

AU - Owczarek-Lipska, Marta

AU - Neidhardt, John

AU - Radio, Francesca Clementina

AU - Mancini, Cecilia

AU - Claps Sepulveda, Dianela Judith

AU - McWalter, Kirsty

AU - Begtrup, Amber

AU - Crunk, Amy

AU - Guillen Sacoto, Maria J.

AU - Person, Richard

AU - Schnur, Rhonda E.

AU - Mancardi, Maria Margherita

AU - Kreuder, Florian

AU - Striano, Pasquale

AU - Zara, Federico

AU - Chung, Wendy K.

AU - Marks, Warren A.

AU - van Eyk, Clare L.

AU - Webber, Dani L.

AU - Corbett, Mark A.

AU - Harper, Kelly

AU - Berry, Jesia G.

AU - MacLennan, Alastair H.

AU - Gecz, Jozef

AU - Tartaglia, Marco

AU - Salpietro, Vincenzo

AU - Christodoulou, John

AU - Kaslin, Jan

AU - Padilla-Lopez, Sergio

AU - Bilguvar, Kaya

AU - Munchau, Alexander

AU - Ahmed, Zubair M.

AU - Hufnagel, Robert B.

AU - Fahey, Michael C.

AU - Maroofian, Reza

AU - Houlden, Henry

AU - Sticht, Heinrich

AU - Mane, Shrikant M.

AU - Rad, Aboulfazl

AU - Vona, Barbara

AU - Jin, Sheng Chih

AU - Haack, Tobias B.

AU - Makowski, Christine

AU - Hirsch, Yoel

AU - Riazuddin, Saima

AU - Kruer, Michael C.

N1 - Funding Information: 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 thank Minerva Contreras and Thomas Blanpied for 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.), and Cerebral Palsy Alliance Research Foundation PG07217 award to W.M. and M.C.K. Portions of this work were also funded by the Fondazione Bambino Gesù (Vite Coraggiose), the Italian Ministry of Health (Ricerca 5 × 1000) to M.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 FDN-167281 ), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C ), the Canada Foundation for Innovation ( CFI-JELF 38412 ), and the Canada Research Chairs Program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279 ). B.V. is funded by intramural funding (fortüne) at the University of Tübingen ( 2545-1-0 ) and the Ministry of Science, Research, and Art Baden-Württemberg . 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 Independence Award ( K99HL143036 and R00HL143036-02 ) and the Clinical and Translational Research Funding Program award ( CTSA1405 ). This project was 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 The Wellcome 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. Funding Information: 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 thank Minerva Contreras and Thomas Blanpied for 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.), and Cerebral Palsy Alliance Research Foundation PG07217 award to W.M. and M.C.K. Portions of this work were also funded by the Fondazione Bambino Ges? (Vite Coraggiose), the Italian Ministry of Health (Ricerca 5 ? 1000) to M.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 FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs Program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). B.V. is funded by intramural funding (fort?ne) at the University of T?bingen (2545-1-0) and the Ministry of Science, Research, and Art Baden-W?rttemberg. 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 Independence Award (K99HL143036 and R00HL143036-02) and the Clinical and Translational Research Funding Program award (CTSA1405). This project was 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 The Wellcome 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. The authors declare no competing interests. Publisher Copyright: © 2021

PY - 2021/10/7

Y1 - 2021/10/7

N2 - 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.

AB - 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.

KW - AAA+ superfamily

KW - ATPase

KW - SPATA5L1

KW - cerebral palsy

KW - epilepsy

KW - intellectual disability

KW - movement disorder

KW - neurodevelopmental disorder

KW - sensorineural hearing loss

UR - http://www.scopus.com/inward/record.url?scp=85116905632&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2021.08.003

DO - 10.1016/j.ajhg.2021.08.003

M3 - Article

C2 - 34626583

AN - SCOPUS:85116905632

SN - 0002-9297

VL - 108

SP - 2006

EP - 2016

JO - American journal of human genetics

JF - American journal of human genetics

IS - 10

ER -

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

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