Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state-in trans with c.1462-1G>T-in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities.

中文翻译：

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CEP78中第一个错义变体的功能表征，这是与锥状营养不良，听力下降和男性生育力降低相关的奠基者等位基因。

中心体CEP78基因的失活变异体已在患有听力丧失的圆锥体营养不良症（CRDHL）中发现，这是一种不同于Usher综合征的特殊表型。在这里，我们确定了三个CRDHL家族中的第一个CEP78错义变体c.449T> C，p。（Leu150Ser）并对其进行了功能表征。该变体在两个比利时家族中以双等位基因状态存在，在第三德国家族中以c.1462-1G> T-的复合杂合状态反式存在。单倍型重建显示出创始人效应。同源性建模揭示了p。（Leu150Ser）对蛋白质稳定性的有害影响，这在患者的成纤维细胞中得到了证实。伸长的原发纤毛在精子或鼻刷中没有明显的超微结构异常，提示纤毛组装受损。来自不同家庭的两名受影响的男性表现出精子异常，导致不育。其中之一是SPAG17中复杂等位基因的杂合子载体，SPAG17是先前与常染色体隐性男性不育症相关的睫状基因。综上所述，我们的数据表明CEP78中的错义创始人等位基因位于先前与失活变体相关的相同的感音神经CRDHL表型之下。有趣的是，CEP78表型可能随着男性不育而扩大。最后，CEP78功能丧失的变异可能在误诊的Usher综合征中（无论有无精子异常）都被低估了。我们的数据表明，CEP78中的错义创建者等位基因是先前与失活变体相关的相同的感音神经CRDHL表型的基础。有趣的是，CEP78表型可能随着男性不育而扩大。最后，CEP78功能丧失的变异体在误诊的Usher综合征中（无论有无精子异常）都可能被低估。我们的数据表明，CEP78中的错义创建者等位基因是先前与失活变体相关的相同的感音神经CRDHL表型的基础。有趣的是，CEP78表型可能随着男性不育而扩大。最后，CEP78功能丧失的变异可能在误诊的Usher综合征中（无论有无精子异常）都被低估了。