Clinical significance of non-coding variants identified by whole exome sequencing in 691 patients

Background. Analysis of non-coding regions of the genome, sufficiently covered in whole exome sequencing (WES) data, may improve the diagnosis of hereditary diseases.
Objective: To assess the frequency and spectrum of clinically significant variants in intronic and other non-coding regions identified in WES data, and to review patient diagnoses.
Methods. The study included 691 patients. DNA was extracted from venous blood, and WES was performed using Agilent All Exon v8 probes and the G-400 platform (MGI Tech). Data analysis included quality control, read processing, variant calling, and annotation. Only clinically significant non-coding variants were selected.
Results. A total of 18 unique variants in 17 genes were identified in 31 patients (4.49%), all in heterozygous states, with the most frequent variants found in SPTA1, HGD, and GAA. The diagnosis was revised for one (0.145%) patient with POLR3A variants leading to leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism.
Conclusion. Clinically significant variants in non-coding regions (beyond the canonical ±1-2 splice sites) should be considered during WES data interpretation.

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