MAN2A2-related glycosylation defects in autism and cognitive delay.

Glycosylation is a post-translational modification essential for proper protein folding and function, with significant roles in diverse biological processes, including neurogenesis. MAN2A2 enzyme is required for proper N-glycan trimming/maturation in the N-glycosylation pathway. Whole-exome sequencing of a trio revealed two potentially causative variants in the MAN2A2 gene in a patient with autism spectrum disorder (ASD) and cognitive delay. The first variant, c.1679G > A (p.Arg560Gln), was inherited from the unaffected father. It is located within the alpha-mannosidase middle functional domain, a region essential for mannose metabolism and alpha-mannosidase enzymatic activity. The second variant, c.3292C > T (p.Gln1098Ter), was inherited from the mother and it generated a premature stop codon. These variants resulted in a compound heterozygous condition in the patient. Prediction using the DOMINO tool suggested an autosomal recessive inheritance pattern. Notably, the MAN2A2 gene is highly expressed in several brain regions. The encoded enzyme, an alpha-mannosidase, is localized to the Golgi apparatus, the cellular organelle where the processing and maturation of N-glycans occurs. In silico analyses consistently classified both variants as likely pathogenic, supported by structural prediction analyses that indicated significant disruptions in protein architecture. Glycosylation analyses demonstrated impaired N-glycosylation, evidenced by the accumulation of immature serum glycoprotein N-glycans including disease-specific hybrid-type species. Further investigations are essential to elucidate the role of this gene in ASD and cognitive delay.