Non-coding variants are a rare cause of recessive developmental disordersin transwith coding variants

Abstract

Purpose: Identifying pathogenic non-coding variants in individuals with developmental disorders (DD) is challenging due to the large search space. It is common to find a single protein-altering variant in a recessive gene in DD patients, but the prevalence of pathogenic non-coding second hits in trans with these is unknown. Methods: In 4,073 genetically undiagnosed rare disease trio probands from the 100,000 Genomes project, we identified rare heterozygous loss-of-function (LoF) or ClinVar pathogenic variants in recessive DD-associated genes. Using stringent region-specific filtering, we identified rare non-coding variants on the other haplotype. Identified genes were clinically evaluated for phenotypic fit, and where possible, we performed functional testing using RNA-sequencing. Results: We found 2,430 probands with one or more rare heterozygous pLoF or ClinVar pathogenic variants in recessive DD-associated genes, for a total of 3,761 proband-variant pairs. For 1,366 (36.3%) of these pairs, we identified at least one rare non-coding variant in trans. After stringent bioinformatic filtering and clinical review, five were determined to be a good clinical fit (in ALMS1, NPHP3, LAMA2, IGHMBP2 and GAA). Conclusion: We developed a pipeline to systematically identify and annotate compound heterozygous coding/non-coding genotypes. Using this approach we uncovered new diagnoses and conclude that this mechanism is a rare cause of DDs.

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

“…Despite our strict filtering approach, the relatively modest number of new diagnoses given the size of the GEL cohort suggests that the proportion of currently undiagnosed individuals that will likely be diagnosed through regular assessment of proximal promoter and UTR regions will also be modest. This is in-line with the conclusions of our recent work looking for non-coding variants in recessive disease genes(68). Nevertheless, our diagnostic yield is likely an underestimate.…”

“…Hence it is much harder to identify disease-causing non-coding variants in more heterogeneous conditions and/or disorders where de novo variants are not a frequent disease mechanism. However, the same annotation approach can be applied to inherited variants(68).…”