Cellular homeostasis is maintained by deubiquitination, which plays critical roles in DNA damage repair, cell cycle progression, signal transduction, transcriptional regulation, and autophagy. The deubiquitination (DUB) module within the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex is encoded by the ATXN7L3 gene. Disease-causing variants in ATXN7L3 have been associated with an autosomal dominant neurodevelopmental disorder characterized by global developmental delay, hypotonia, speech impairment, and distinctive facial dysmorphism, known as Harel-Tora neurodevelopmental syndrome (OMIM #621377). In the present study we used whole-genome sequencing (WGS), followed by Sanger sequencing, to identify the disease-causing genetic variant. WGS identified a novel de novo nonsense variant, c. 236G>A (p. Trp79*), in the exon 4 of the ATXN7L3 gene (NM₀01382309. 1) located on chromosome 17q21. 31, segregating perfectly with the disease phenotype. Furthermore, RT-qPCR revealed a marked reduction in ATXN7L3 transcript levels in the affected individual, supporting its pathogenicity. 3D protein modeling of the mutated ATXN7L3 protein revealed substantial distortions in key secondary structural elements and loss of the C-terminal of ATXN7L3. The present study expands the mutational spectrum of the ATXN7L3 gene associated with HATONS, and helps to provide accurate genetic counseling. This will help in the management of future pregnancies within the affected family.
Tan et al. (Fri,) studied this question.