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

Area of Science:

• Genomics
• Human Genetics
• Molecular Biology

Background:

• Whole-genome sequencing aids in identifying noncoding variants affecting gene expression.
• Regulatory variants, especially those impacting transcription factor (TF) genes, are increasingly recognized in rare diseases.
• Current variant classification guidelines often under-represent regulatory variants.

Purpose of the Study:

• To compile and analyze known regulatory variants linked to TF genes in rare diseases.
• To discuss the genomic distribution and evidence for pathogenicity of these variants.
• To introduce a novel evidence framework for classifying regulatory variants.

Main Methods:

• Literature review to identify regulatory variants associated with TF genes and rare diseases.
• Analysis of variant genomic location and existing evidence for pathogenicity.
• Development of a new evidence framework tailored for regulatory variants.

Main Results:

• A compilation of 46 regulatory variants affecting 40 TF genes implicated in rare diseases was created.
• The genomic landscape and pathogenicity evidence for these variants were analyzed.
• A new framework for evaluating regulatory variant evidence was proposed.

Conclusions:

• Regulatory variants, particularly those affecting TF genes, are important contributors to rare diseases.
• The proposed evidence framework can enhance the clinical interpretation of patient genomes.
• Further research and standardized classification are needed for regulatory variants in disease diagnosis.