Γενωμική ανάλυση από δεδομένα Whole-Exome Sequencing σε ασθενείς με σπάνια νοσήματα

Abstract

Rare diseases (RDs), while individually uncommon, collectively affect an estimated 263–446 million people worldwide. Genetic testing, particularly Whole-Exome Sequencing (WES) and Whole-Genome Sequencing (WGS), has emerged as the primary diagnostic tool for these conditions. This study evaluated the diagnostic yield of both initial analysis and re-analysis of WES/WGS data from patients with suspected RDs, using two bioinformatics platforms: RD-Connect Genome-Phenome Analysis Platform (GPAP) and Franklin. The analysis cohort comprised 73 patients and achieved a diagnostic yield of 30%, while the re-analysis cohort included 106 patients with an 18% yield, results consistent with published data. Among cases with plausible diagnoses, 19 novel variants were identified. Founder variant detection across the entire cohort (n = 179) revealed a markedly high prevalence of the CTNS c.225+1G>C variant (p- value = 0.022), found in 21% of the Cretan subgroup (n = 136) and enriched among patients with renal disorders (n = 31), where the carrier frequency reached 74% (p- value = 2,5*10-7). These findings underscore the value of systematic WES/WGS analysis and re-analysis for RD diagnosis, demonstrate the contribution of novel variants to disease characterization, and highlight the clinical and population-genetic significance of founder mutations in isolated populations.Rare diseases (RDs), while individually uncommon, collectively affect an estimated 263–446 million people worldwide. Genetic testing, particularly Whole-Exome Sequencing (WES) and Whole-Genome Sequencing (WGS), has emerged as the primary diagnostic tool for these conditions. This study evaluated the diagnostic yield of both initial analysis and re-analysis of WES/WGS data from patients with suspected RDs, using two bioinformatics platforms: RD-Connect Genome-Phenome Analysis Platform (GPAP) and Franklin. The analysis cohort comprised 73 patients and achieved a diagnostic yield of 30%, while the re-analysis cohort included 106 patients with an 18% yield, results consistent with published data. Among cases with plausible diagnoses, 19 novel variants were identified. Founder variant detection across the entire cohort (n = 179) revealed a markedly high prevalence of the CTNS c.225+1G>C variant (p- value = 0.022), found in 21% of the Cretan subgroup (n = 136) and enriched among patients with renal disorders (n = 31), where the carrier frequency reached 74% (p- value = 2,5*10-7). These findings underscore the value of systematic WES/WGS analysis and re-analysis for RD diagnosis, demonstrate the contribution of novel variants to disease characterization, and highlight the clinical and population-genetic significance of founder mutations in isolated populations