Spectrum and genotyping strategies of “dark” genetic matter in germline susceptibility genes of tumor syndromes

Purpose

Despite the widespread use of high-throughput genotyping strategies, certain mutation types remain understudied. We provide an overview of these often overlooked mutation types, with representative examples from common hereditary cancer syndromes.

Methods

We conducted a comprehensive review of the literature and locus-specific variant databases to summarize the germline pathogenic variants discovered through non-routine genotyping methods. We evaluated appropriate detection and analysis methods tailored for these specific genetic aberrations. Additionally, we performed in silico splice predictions on deep intronic variants registered in the ClinVar database.

Results

Our study suggests that, aside from founder mutations, most cases are sporadic. However, we anticipate a relatively high likelihood of splice effects for deep intronic variants. The findings underscore the significant clinical utility of genome sequencing techniques and the importance of applying relevant analysis methods.