Autosomal recessive variants c.953A>C and c.97-1G>C in NSUN2 causing intellectual disability: a molecular dynamics simulation study of loss-of-function mechanisms.

Genetic analysis using whole exome sequencing in these families identified two novel mutations in the (NM_017755.5). Family-A segregated a novel missense variant c.953A>C; p.Tyr318Ser in exon-9 of the . The variant substituted an amino acid Tyr318, highly conserved among different animal species and located in the functional domain of known as "SAM-dependent methyltransferase RsmB/NOP2-type". Whereas in family B, we identified a novel splice site variant c.97-1G>C that affects the splice acceptor site of . The identified splice variant (c.97-1G>C) was predicted to result in the skipping of exon-2, which would lead to a frameshift followed by a premature stop codon (p. His86Profs16). Furthermore, it could result in the termination of translation and synthesis of dysfunctional protein, most likely leading to nonsense-mediated decay. The dynamic consequences of missense variant was further explored together with wildtype through molecular dynamic simulations, which uncovered the disruption of function due to a gain in structural flexibility. The present molecular genetic study further extends the mutational spectrum of to be involved in ID and its genetic heterogeneity in the Pakistani population.