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.
GrantsR00HL143036-02 Clinical and Translational Research Funding Program SFARI JPB Foundation NEI intramural funds Ministry of Science, Research, and Art Baden-Wurttemberg University of Tubingen Canada Research Chairs Program (Canada Research Chair in Neuromuscular Genomics and Health) Canada Foundation for Innovation Canadian Institutes of Health Research and Muscular Dystrophy Canada Canadian Institutes of Health Research Telethon Undiagnosed Diseases Program (TUDP) ItalianMinistry of Health Fondazione Bambino Gesu Foundation for Barnes-Jewish Hospital NIH/National Center for Advancing Translational Sciences K99HL143036 K99/R00 1R01NS106298 R01NS107428 Tenix Foundation Hospital Research Foundation Mid-Career Fellowship Channel 7 CRF Chair for the Prevention of Childhood Disability Australian National Health and Medical Research Council Fellowship Australian National Health and Medical Research Council Cerebral Palsy Alliance Research Foundation Career Development Award NHMRC Early Career Research Fellowship National Institute for Health Research University College London Hospitals Biomedical Research Centre Wellcome Trust Cerebral PalsyAlliance Research Foundation