Challenges in the interpretation of whole-genome sequences leave rare disease cases undiagnosed. Cis-regulatory variants are anticipated to resolve a subset of these cases, but present a difficult problem because of their large numbers, small effect sizes, and tissue-specificity.
Advancements in experimental genomics and bioinformatics approaches are rapidly revealing the locations of cis-regulatory regions.
At least 46 regulatory disease variants have been reported that disrupt expression of a total of 40 TF genes (deregulating the regulators), suggesting TF genes are strong candidates for clinical genome interpretation.
These cases provide insights into where and how regulatory variants have been found, the diseases they cause, their mode of inheritance, and their disruption mechanisms.
Improved systems for scoring evidence of function, specific to regulatory variants, are needed.
Whole-genome sequencing is accelerating identification of noncoding variants that disrupt gene expression, although reports of such regulatory variants implicated in disease remain rare. A notable subset of described variants affect transcription factor (TF) genes and other master regulators in cis through dosage effects. From the literature, we compiled 46 regulatory variants linked to 40 TF genes implicated in rare diseases. We discuss the genomic geography of these variants and the evidence presented for their potential pathogenicity. To help advance research on candidate disease variants into the literature, we introduce an evidence framework specific to regulatory variants, which are under-represented in current variant classification guidelines. The clinical research interpretation of patient genomes may be advanced by considering regulatory variants, particularly those that deregulate TF genes.
