Understanding the contribution of synonymous mutations to human disease

Synonymous mutations, once thought to be 'silent', are now increasingly acknowledged to be able to cause changes in protein expression, conformation and function.Studies of the association of genetic variants with disease have revealed a substantial contribution of synonymous mutations to human disease risk and other complex traits. This article includes a compendium of human diseases or clinical conditions associated with synonymous mutations.Concomitantly, there has been substantial progress in understanding the mechanisms by which synonymous substitutions effect changes in the phenotype.Synonymous mutations can affect protein conformation and function by affecting post-transcriptional processing and regulation of RNA, altering the local and global structure of the mRNA and influencing the kinetics of translation.Recent estimates suggest that 5–10% of human genes contain at least one region where synonymous mutations could be harmful. Thus, synonymous SNPs identified in genome-wide association studies should be included in follow-up functional and mechanistic studies.Understanding the effect (or effects) of synonymous mutations could have important implications in the practice of medicine and biotechnology.