POTENTIAL NEW GENES INVOLVED IN CYSTIC FIBROSIS PHENOTYPE

Abstract

Background: Cystic fibrosis (CF) is autosomal recessive disorder characterized by chronic respiratory problems and poor growth. CF is caused by defect in transmembrane conductance regulator (CFTR) protein. CF is diagnosed by sweat chloride analysis (>60 mmol/L) with the identification of two CF-causing variants of CFTR gene. With a longstanding history of CFTR gene analysis, our laboratory identified several patients with elevated sweat chloride and clinical manifestations of CF in whom no CF-causing mutations were detected after sequencing of whole coding region and testing for large insertion/deletion of CFTR gene. In order to elucidate genetic background of conditions that mimic CF we performed whole exome sequencing (WES) in two such patients. Methods: Library preparation was done using DNA nanoball technology. Produced fastq files were mapped to hg38. VCF files were generated using GATK and annotated with InterVar and AnnoVar tools. Variants filtering for disease relevance was done using the following criteria: QC, GnomAD Allele Frequency, Functional consequences and phenotype-genotype relationship. Results: CACNA1H and MUC5B genes were found to be impaired in both patients. Similar number of variants predicted to impair protein function were detected (27 and 25) in each patient. Loss of function variants were found in 7 and 11 genes, respectively. Conclusion: Further assessment of selected variants will clarify their functional effect and relevance for the patient’s clinical phenotype. WES analysis will help identify genetic aspects of disease and assist in optimal patient management in about 0.01% of patients with elevated sweat chloride and high clinical suspicion of CF that do not carry any CF-causing variants.ABSTRACT BOOK: “Genetic Diseases from Diagnostics to Prevention and Therapy” October 05-14th Balkan Congress of Human Genetics & 9th Rare Disease SEE Meeting 2023; Skopje, October 05-07, 202