Role of synonymous and noncoding variations
Overall five synonymous variants and two noncoding variants were observed in our cohort. Synonymous mutations are often considered as silent mutations due to degeneracy of genetic code. But they may have important consequences and is now recognized to be crucial in influencing gene expression, conformation and in cellular function32. Although our study shows only three probands to harbour likely pathogenic alleles there is a preponderance of synonymous and noncoding variants among all the stuttering individuals screened. Complex disorders often tend to have multiple mutations. A mutation may not be detrimental individually but the joint effect of multiple variants in the same gene or different genes can contribute to a disorder but however predictions are limited to single variant33.
In our study the recurrence of the pathogenic variants in lysosomal pathway corroborates the causative role for them in stuttering. The importance of the implicated genes can be understood by its recurrence in other ethnic populations. Identification of recurrent mutations helps in cost effective screening in a large sample of PWS. However, it should be borne in mind that scope of this study is limited because our screening includes only the exons that were previously reported.