Introducing exome sequencing as part of the diagnostic algorithm for pediatric nephrology patients in Bulgaria - a single-center experience.

INTRODUCTION: In pediatric kidney patients, where clinical presentation is often not fully developed and renal biopsy too risky or inconclusive, it may be difficult to establish the underlying pathology. In cases such as these, genetic diagnosis may be used to guide the treatment, prognosis and counselling. Given the large number of genes involved in kidney disease, introducing next generation sequencing with extended gene panels as part of the diagnostic algorithm presents a viable solution. METHODS: A cohort of 87 consecutive independent cases (83 children and 4 terminated pregnancies) with renal disease were recruited. Exome sequencing with MiSeq or NovaSeq 6 000 (Illumina) platforms and analysis of extended gene panels was used for genetic testing. RESULTS: Depending on the presenting pathology, the cases were grouped as patients with glomerular disease, ciliopathies, congenital anomalies, renal electrolyte imbalances and chronic/acute kidney disease. The overall diagnostic yield was app. 42% (37 out of 87) with most disease-causing mutations found in COL4A3, COL4A4, COL4A5 and PKHD1 genes. A change or clarification of preliminary diagnosis, or adjustment of initial treatment plan based on the results from the genetic testing was made for app. one third of the children with meaningful genetic findings (11 out 37). DISCUSSION: Our results prove the value of targeted exome sequencing as non-invasive, versatile and reliable diagnostic tool for pediatric renal disease patients. Providing genetic diagnosis will help for better understanding of disease etiology and will give basis for optimal clinical management and insightful genetic counseling.

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

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 ß, 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.