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

Kamenarova, Kunka; Mihova, Kalina; Veleva, Nevyana; Mermeklieva, Elena; Mihaylova, Bilyana; Dimitrova, Galina; Oscar, Alexander; Shandurkov, Iliyan; Cherninkova, Sylvia; Kaneva, Radka

doi:10.1002/mgg3.1997

Cited by 4 publications

(2 citation statements)

References 54 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Matczyńska,

Beć-Gajowniczek,

Sivitskaya

et al. 2024

Biomedicines

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Advances in gene therapy and genome editing give hope that new treatments will soon be available for inherited eye diseases that together affect a significant proportion of the adult population. New solutions are needed to make genetic diagnosis fast and affordable. This is the first study of such a large group of patients with inherited retinal dystrophies (IRD) and inherited optic neuropathies (ION) in the Polish population. It is based on four years of diagnostic analysis using a broad, targeted NGS approach. The results include the most common pathogenic variants, as well as 91 novel causative variants, including frameshifts in the cumbersome RPGR ORF15 region. The high frequency of the ABCA4 complex haplotype p.(Leu541Pro;Ala1038Val) was confirmed. Additionally, a deletion of exons 22–24 in USH2A, probably specific to the Polish population, was uncovered as the most frequent copy number variation. The diagnostic yield of the broad NGS panel reached 64.3% and is comparable to the results reported for genetic studies of IRD and ION performed for other populations with more extensive WES or WGS methods. A combined approach to identify genetic causes of all known diseases manifesting in the posterior eye segment appears to be the optimal choice given the currently available treatment options and advanced clinical trials.

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Section: Discussionmentioning

confidence: 99%

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

Matczyńska,

Beć-Gajowniczek,

Sivitskaya

et al. 2024

Biomedicines

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“…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 .…”

Section: Methodsmentioning

confidence: 99%

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

Kamenarova,

Kachakova-Yordanova,

Baymakova

et al. 2024

Preprint

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a pneumonia with extremely heterogeneous clinical presentation, ranging from asymptomatic to severely ill patients. Previous studies have reported links between the presence of host genetic variants and the outcome of the COVID-19 infection. In our study, we used whole exome sequencing in a cohort of 444 SARS-CoV-2 patients, admitted to hospital in the period October-2020-April-2022, to search for associations between rare pathogenic/potentially pathogenic variants and COVID-19 progression. We used gene prioritization-based analysis in genes that have been reported by host genetic studies. Although we did not identify correlation between the presence of rare pathogenic variants and COVID-19 outcome, in critically ill patients we detected known mutations in a number of genes associated with severe disease related to cardiovascular disease, primary ciliary dyskinesia, cystic fibrosis, DNA damage repair response, coagulation, primary immune disorder, hemoglobin subunit β, and others. Additionally, we report 93 novel pathogenic variants found in severely infected patients who required intubation or died. A network analysis showed main component, consisting of 13 highly interconnected genes related to epithelial cilium. In conclusion, we have detected rare pathogenic host variants that may have influenced the COVID-19 outcome in Bulgarian patients.

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

Kamenarova

Mihova

Veleva

et al. 2022

Molec Gen & Gen Med

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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.

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

Cited by 4 publications

References 54 publications

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

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

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

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

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