Deregulated Regulators: Disease-Causing cis Variants in Transcription Factor Genes

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.