Systematic identification of disease-causing promoter and untranslated region variants in 8,040 undiagnosed individuals with rare disease

Abstract

BackgroundBoth promoters and untranslated regions (UTRs) have critical regulatory roles, yet variants in these regions are largely excluded from clinical genetic testing due to difficulty in interpreting pathogenicity. The extent to which these regions may harbour diagnoses for individuals with rare disease is currently unknown.MethodsWe present a framework for the identification and annotation of potentially deleterious proximal promoter and UTR variants in known dominant disease genes. We use this framework to annotatede novovariants (DNVs) in 8,040 undiagnosed individuals in the Genomics England 100,000 genomes project, which were subject to strict region-based filtering, clinical review, and validation studies where possible. In addition, we performed region and variant annotation-based burden testing in 7,862 unrelated probands against matched unaffected controls.ResultsWe prioritised eleven DNVs and identified an additional variant overlapping one of the eleven. Ten of these twelve variants (82%) are in genes that are a strong match to the individual’s phenotype and six had not previously been identified. Through burden testing, we did not observe a significant enrichment of potentially deleterious promoter and/or UTR variants in individuals with rare disease collectively across any of our region or variant annotations.ConclusionsOverall, we demonstrate the value of screening promoters and UTRs to uncover additional diagnoses for previously undiagnosed individuals with rare disease and provide a framework for doing so without dramatically increasing interpretation burden.

A Massively Parallel Screen of 5′UTR Mutations Identifies Variants Impacting Translation and Protein Production in Neurodevelopmental Disorder Genes

“…5′UTR variants also represent an additional pool of prospective causal variants for autism and related disorders in particular: numerous syndromic neurodevelopmental disorders are caused by loss of function in genes that regulate translation initiation either globally, in the case of EIF3G, PTEN, and TSC1/2, or for a subset of transcripts, as with DDX3X and FMRP (Calviello et al, 2021;Darnell et al, 2011;Satterstrom et al, 2020;Snijders Blok et al, 2015;Vignoli et al, 2015). Likewise, 5' UTR mutations in known neurodevelopmental disorder genes NF2, MEF2C and SETD5 have now been found in individuals with symptoms consistent with these syndromes (Martin-Geary et al, 2023;Whiffin et al, 2020;Wright et al, 2021). Therefore, to functionally characterize and screen for new variants of interest, we developed a screening strategy to prioritize likely functional and thus potentially causal variants from among 997 de novo mutations discovered in autism probands and their families.…”