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Type: Journal article
Title: Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss
Author: 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.
et al.
Citation: American Journal of Human Genetics, 2021; 108(10):2006-2016
Publisher: Elsevier
Issue Date: 2021
ISSN: 0002-9297
Statement of
Elodie M.Richard, Somayeh Bakhtiari, Ashley P.L.Marsh, Rauan Kaiyrzhanov, Matias Wagner, Sheetal Shetty ... et al.
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
cerebral palsy
intellectual disability
movement disorder
neurodevelopmental disorder
sensorineural hearing loss
Rights: Copyright status unknown
DOI: 10.1016/j.ajhg.2021.08.003
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Appears in Collections:Medicine publications

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