tRNA-histidine guanyltransferase 1-like protein (THG1L), located in the mitochondria, plays a crucial role in the tRNA maturation process. Dysfunction of THG1L results in abnormal mitochondrial tRNA modification and neurodevelopmental disorders. To date, few studies have focused on THG1L-related cerebellar ataxia. Whole-exome sequencing revealed compound heterozygous variants NM_017872.5: [c.224A > G]; [c.369-8T > G] in THG1L in a 6-year-old boy with moderate cerebellar ataxia. The variant c.224A > G was demonstrated to downregulate its RNA and protein expression, and c.369-8 T > G resulted in a 7 bp insertion before exon 3. Our case expanded the gene variation and clinical spectrum of THG1L-related cerebellar ataxia.

Heterozygous deleterious variants in SKI cause Shprintzen-Goldberg Syndrome, which is mainly characterized by craniofacial features, neurodevelopmental disorder and thoracic aorta dilatations/aneurysms. The encoded protein is a member of the transforming growth factor beta signaling. Paucity of reported studies exploring the SGS molecular pathogenesis hampers disease recognition and clinical interpretation of private variants. Here, the unpublished c.349G>A, p.[Gly117Ser] and the recurrent c.539C>T, p.[Thr180Met] SKI variants were studied combining in silico and in vitro approach. 3D comparative modeling and calculation of the interaction energy predicted that both variants alter the SKI tertiary protein structure and its interactions. Computational data were functionally corroborated by the demonstration of an increase of MAPK phosphorylation levels and alteration of cell cycle in cells expressing the mutant SKI. Our findings confirmed the effects of SKI variants on MAPK and opened the path to study the role of perturbations of the cell cycle in SGS.