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.

精子发生相关的 5 样 1 (SPATA5L1) 代表编码未知功能蛋白质的孤儿基因。我们报告了SPATA5L1 中的28 个双等位基因变体与来自 28 个（26 个无关）家庭的 47 个人的感音神经性听力损失有关。此外，25/47 受累个体 (53%) 出现小头畸形、发育迟缓/智力障碍、脑瘫和/或癫痫。建模表明变体对蛋白质的破坏作用，主要是通过对蛋白质结构域的不稳定影响。脑成像显示脑容量减少、胼胝体变薄和脑室周围白质软化，定量容量测定显示几个人的白质体积显着减少。大鼠海马神经元的免疫荧光成像显示 Spata5l1 在神经元和神经胶质细胞核中的定位以及在神经元中更突出的表达。在啮齿动物的内耳中，Spata5l1 在神经感觉毛细胞和内耳支持细胞中表达。对来自受影响个体的成纤维细胞进行的转录组学分析能够通过主要成分区分受影响个体和对照组。差异表达基因和网络的分析表明 SPATA5L1 在细胞表面粘附受体功能、细胞内粘着斑以及 DNA 复制和有丝分裂中发挥作用。总的来说，我们的结果表明双等位基因SPATA5L1变异导致以感音神经性听力损失 (SNHL) 为特征的人类疾病，伴或不伴非进行性混合神经发育表型。