Abstract
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.
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Acknowledgements
This work was supported by AMED under grant numbers JP23ek0109674, JP23ek0109549, JP23ek0109617, JP23ek0109648 (NM); JSPS KAKENHI under grant numbers JP23H02829 (SM), JP23H02877 (TM), JP22K15901 (AF), JP21K07869 (EK), JP23K07229 (YU), and JP23K15353 (NT); and the Takeda Science Foundation (TM and NaM). We thank Catherine Perfect, MA (Cantab), from Edanz (https://jp.edanz.com/ac), for editing a draft of this manuscript.
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Conceptualization: MS, NM; Data Curation: MS, KI; Investigation: MS, KK, KT, FI, YW, NO; Visualization and Writing-original draft: MS; Writing-review and editing: NT, YU, EK, AF, KM, SM, TM, NM.
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Sakamoto, M., Kurosawa, K., Tanoue, K. et al. A heterozygous germline deletion within USP8 causes severe neurodevelopmental delay with multiorgan abnormalities. J Hum Genet 69, 85–90 (2024). https://doi.org/10.1038/s10038-023-01209-2
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DOI: https://doi.org/10.1038/s10038-023-01209-2
