Panel‐based next‐generation sequencing identifies novel mutations in Bulgarian patients with inherited retinal dystrophies

Abstract

Background Next‐generation sequencing (NGS)‐based method is being used broadly for genetic testing especially for clinically and genetically heterogeneous disorders, such as inherited retinal degenerations (IRDs) but still not routinely used for molecular diagnostics in Bulgaria. Consequently, the purpose of this study was to evaluate the effectiveness of a molecular diagnostic approach, based on targeted NGS for the identification of the disease‐causing mutations in 16 Bulgarian patients with different IRDs. Methods We applied a customized NGS panel, including 125 genes associated with retinal and other eye diseases to the patients with hereditary retinopathies. Results Systematic filtering approach coupled with copy number variation analysis and segregation study lead to the identification of 16 pathogenic and likely pathogenic variants in 12/16 (75%) of IRD patients, 2 of which novel (12.5%): ABCA4‐ c.668delA (p.K223Rfs18) and RР1‐ c.2015dupA (p.K673Efs*25). Mutations in the ABCA4, PRPH2, USH2A, BEST1, RР1, CDHR1 , and RHO genes were detected reaching a diagnostic yield between 42.9% for Retinitis pigmentosa cases and 100% for macular degeneration, Usher syndrome, and cone‐rod dystrophy patients. Conclusion Our results confirm the usefulness of targeted NGS approach based on frequently mutated genes as a comprehensive and successful genetic diagnostic tool for IRDs with significant impact on patients counseling.

Optimised, Broad NGS Panel for Inherited Eye Diseases to Diagnose 1000 Patients in Poland

“…Our study uncovers the high frequency of the copy number variant NM_206933.4:c.(4627+1_4628−1)_(4987+1_4988−1)del (deletion of exons 22–24 of USH2A ) in the Polish population, identified in 14 apparently unrelated patients (2 homozygotes) and, therefore, the second most frequent USH2A variant in our cohort ( Figure 4 ). Interestingly, this variant has been previously reported in single patients of European (in three cases—Slavic) origin [ 58 , 61 , 62 , 63 , 64 ] and, when homozygous, associated with a late-onset non-syndromic RP [ 62 ]. In our patients with the biallelic deletion of USH2A exons 22–24, late-onset RP with a partial deafness were reported, while, in the patients being compound heterozygotes in USH2A, more heterogeneous symptoms and earlier onset of RP and deafness were observed.…”

Rare host variants in ciliary expressed genes contribute to COVID-19 severity in Bulgarian patients

“…For WES analysis we applied a locally maintained DRAGEN (Illumina) secondary analysis pipeline for mapping to the GRCh37/hg19 human genome single nucleotide variants calling and quality ltering. Annotations and variant ltering were performed using VarSeq software (version 2.2.1, Golden Helix, Inc.) and as we have described previously 17 .…”