WDR26-related Skraban-Deardorff syndrome: clinical, genetic and pathomechanistic insights.

WDR26 mutations have recently been linked to Skraban-Deardorff syndrome (SKDEAS). While most WDR26 variants are truncating and are expected to destabilize the protein, the impact of missense variants on protein stability remains unclear. To delineate the clinical and genetic characteristics of SKDEAS and elucidate its underlying pathomechanism, we report two novel WDR26 variants (p.R558Sfs*24 and p.G373E) in two Chinese patients with SKDEAS. We further summarize the clinical characteristics of these cases with all previously published SKDEAS cases through a systematic review. In addition, we examine the impact of the novel frameshift variant on WDR26 mRNA stability, and evaluate how the newly identified missense variant, as well as five previously reported missense variants, affect WDR26 protein stability and degradation. Among 32 individuals with available clinical data, all exhibited global developmental delay/intellectual development delay, behavioral issues and facial dysmorphism. All 35 WDR26 variants described previously and in this study were de novo, comprising 27 truncating (77.1%) and 8 missense variants (22.9%). A number of these variants were previously shown to impair CTLH E3 complex assembly. We found that the novel p.R558Sfs*24 variant significantly decreased WDR26 mRNA levels and reduced cell proliferation in lymphoblastoid cells. Cycloheximide treatment partially restored mRNA levels, suggesting degradation via the nonsense-mediated decay pathway. All six tested missense variants (p.W172R, p.L215P, p.S254R, p.D284N, p.G373E, p.R510Q) markedly reduced WDR26 protein levels. This effect was reversed by proteasome inhibition, indicating enhanced proteasomal degradation of mutant proteins. Our identification of novel WDR26 variants expands the genetic and clinical spectrum of SKDEAS. Functional studies confirmed that both novel variants and five previously reported missense variants cause SKDEAS via loss-of-function. This is the first study to demonstrate that missense variants accelerate WDR26 degradation through the ubiquitin-proteasome pathway. Impaired cell proliferation may also contribute to SKDEAS pathogenesis.