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.