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

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.; Blesson, A.; Rodan, L. H.; Abbott, M. A.; Comi, A.; Cohen, J. S.; 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, R. A.; Grossmann, B.; Rapp, M.; Steen, C.; Marquardt, I.; Grimmel, M.; Grasshoff, U.; Korenke, G. C.; Owczarek-Lipska, M.; Neidhardt, J.; Radio, F. C.; Mancini, C.; Claps Sepulveda, D. J.; McWalter, K.; Begtrup, A.; Crunk, A.; Guillen Sacoto, M. J.; Person, R.; Schnur, R. E.; Mancardi, M. M.; Kreuder, F.; Striano, P.; Zara, F.; Chung, W. K.; Marks, W. A.; van Eyk, C. L.; Webber, D. L.; Corbett, M. A.; Harper, K.; Berry, J. G.; MacLennan, A. H.; Gecz, J.; Tartaglia, M.; Salpietro, V.; Christodoulou, J.; Kaslin, J.; Padilla-Lopez, S.; Bilguvar, K.; Munchau, A.; Ahmed, Z. M.; Hufnagel, R. B.; Fahey, M. C.; Maroofian, R.; Houlden, H.; Sticht, H.; Mane, S. M.; Rad, A.; Vona, B.; Jin, S. C.; Haack, T. B.; Makowski, C.; Hirsch, Y.; Riazuddin, S.; Kruer, M. C.

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

URI

https://hdl.handle.net/11287/622267

Authors

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.

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Journal

American journal of human genetics

Type

Case Reports

Publisher

Cell Press

DOI

10.1016/j.ajhg.2021.08.003

Rights

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.

Citation

Am J Hum Genet. 2021 Oct 7;108(10):2006-2016. doi: 10.1016/j.ajhg.2021.08.003.

Publisher URL

https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(21)00302-5

Note

The article is available via Open Access. Click on the 'Additional link' above to access the full-text.

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2021 RD&E publications
Genetics and genomics

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