Reanalysis of Whole Genome Sequencing Resolves Genetically Undiagnosed Patients With "RNUopathies"

Neurodevelopmental disorders (NDD) are a group of complex conditions characterized by marked phenotypic heterogeneity, primarily involving impairments in cognitive, emotional, and motor development. Approximately 40%-60% of patients with rare NDD remain genetically undiagnosed. Recently, RNU2-2 and RNU5B-1 have been identified as novel genes underlying the "RNUopathies" a syndromic NDD caused by variants in non-coding spliceosomal genes. In this study, we aimed to focus on RNU2-2 and RNU5B-1 by analyzing the whole-genome sequencing (WGS) data from 18326 Chinese individuals (including 2970 trios and 9416 samples without parental data), among whom 4900 had confirmed NDD phenotypes. Reanalysis of WGS data solved the previously undiagnosed cases of four patients with NDD carrying de novo variants in RNU genes, including three patients carrying the RNU2-2 variants (two cases with n.4G>A and one case with n.35A>G), and one case with an unreported RNU5B-1 variant (n.38C>T). In this study, detailed phenotypic elaboration and comparison with previous studies help clinicians in more effective diagnosis of NDD and underscore the importance of reanalyzing negative genetic data, which deepens our understanding of the "RNUopathies."