The role of untranslated region variants in Mendelian disease: a review

Untranslated regions (UTRs) flank the protein-coding sequence of a gene. 5'UTR and 3' UTR sequences mediate post-transcriptional regulation via linear and structural elements, controlling RNA stability, cellular localisation and the rate of protein translation. Variants within both 5' and 3' UTRs have been shown to cause disease through a variety of diverse mechanisms. However, for these variants to be routinely annotated and interpreted in clinical genetic testing, we need a better understanding of these regions and the spectrum of disease-causing variants within them. In this review, we systematically assess previously identified Mendelian disease-causing variants within UTRs and catalogue their underlying mechanisms. With genome sequencing becoming readily available and increasingly incorporated in diagnostic settings, this review will provide a valuable resource for the consideration and interpretation of UTR variants.