Ubiquitin-specific protease 8 (USP8) is a deubiquitinating enzyme involved in deubiquitinating the enhanced epidermal growth factor receptor for escape from degradation. Somatic variants at a hotspot in USP8 are a cause of Cushing’s disease, and a de novo germline USP8 variant at this hotspot has been described only once previously, in a girl with Cushing’s disease and developmental delay. In this study, we investigated an exome-negative patient with severe developmental delay, dysmorphic features, and multiorgan dysfunction by long-read sequencing, and identified a 22-kb de novo germline deletion within USP8 (chr15:50469966-50491995 [GRCh38]). The deletion involved the variant hotspot, one rhodanese domain, and two SH3 binding motifs, and was presumed to be generated through nonallelic homologous recombination through Alu elements. Thus, the patient may have perturbation of the endosomal sorting system and mitochondrial autophagy through the USP8 defect. This is the second reported case of a germline variant in USP8.

泛素特异性蛋白酶 8 ( USP8 ) 是一种去泛素化酶，参与去泛素化增强型表皮生长因子受体以逃避降解。USP8热点处的体细胞变异是库欣病的一个原因，而该热点处的从头种系USP8变异此前仅在一名患有库欣病和发育迟缓的女孩中被描述过一次。在本研究中，我们通过长读长测序调查了一名患有严重发育迟缓、畸形特征和多器官功能障碍的外显子组阴性患者，并在USP8内发现了 22 kb 从头种系缺失(chr15:50469966-50491995 [GRCh38]) 。该缺失涉及变异热点、一个硫氰酸酶结构域和两个 SH3 结合基序，推测是通过Alu元件的非等位同源重组产生的。因此，患者可能因USP8缺陷而扰乱内体分选系统和线粒体自噬。这是USP8中第二例报道的种系变异病例。