Abstract
Clinical genetic testing of protein-coding regions identifies a likely causative variant in only around half of developmental disorder (DD) cases. The contribution of regulatory variation in non-coding regions to rare disease, including DD, remains very poorly understood. We screened 9,858 probands from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5' untranslated regions (5' UTRs) of genes within which variants have previously been shown to cause DD through a dominant haploinsufficient mechanism. We identified four single-nucleotide variants and two copy-number variants upstream of MEF2C in a total of ten individual probands. We developed multiple bespoke and orthogonal experimental approaches to demonstrate that these variants cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding region variants represent 23% of likely diagnoses identified in MEF2C in the DDD cohort, but these would all be missed in standard clinical genetics approaches. Nonetheless, these variants are readily detectable in exome sequence data, with 30.7% of 5' UTR bases across all genes well covered in the DDD dataset. Our analyses show that non-coding variants upstream of genes within which coding variants are known to cause DD are an important cause of severe disease and demonstrate that analyzing 5' UTRs can increase diagnostic yield. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants and dosage tolerance of the gene.
Highlights
The importance of non-coding regulatory variation in common diseases and traits has long been appreciated, but the contribution of non-coding variation to rare disease remains poorly understood.[1,2,3,4] current clinical testing approaches for rare disease focus almost exclusively on regions of the genome that code directly for protein, within which we are able to relatively accurately estimate the effect of any individual variant
Identifying de novo 50 untranslated regions (50 Untranslated regions (UTRs)) variants in individuals with DD To investigate the contribution of uAUG-creating variants to severe DD, we analyzed 29,523 high-confidence de novo mutations (DNMs) identified in exome sequencing data from 9,858 parentoffspring trios in the Developmental Disorders (DDD) study.[5]
Given that uAUG-creating variants that decrease coding sequence (CDS) translation would only be expected to be deleterious in genes that are dosage sensitive, we restricted our analysis to the 50 UTRs of 359 haploinsufficient genes from the curated DDG2P database[20] (Table S1)
Summary
The importance of non-coding regulatory variation in common diseases and traits has long been appreciated, but the contribution of non-coding variation to rare disease remains poorly understood.[1,2,3,4] current clinical testing approaches for rare disease focus almost exclusively on regions of the genome that code directly for protein, within which we are able to relatively accurately estimate the effect of any individual variant. This is primarily due to a lack of guidance on how to determine when UTR variants are likely to be pathogenic
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