Abstract
Cystic fibrosis (CF) is caused by ~300 pathogenic CFTR variants. The heterogeneity of which, challenges molecular diagnosis and precision medicine approaches in CF. Our objective was to identify CFTR variants through high-throughput sequencing (HTS) and to predict the pathogenicity of novel variants through in 8 silico tools. Two guidelines were followed to deduce the pathogenicity. A total of 169 CF patients had genomic DNA submitted to a Targeted Gene Sequencing and we identified 63 variants (three patients had three variants). The most frequent alleles were: F508del (n = 192), G542* (n = 26), N1303K (n = 11), R1162* and R334W (n = 9). The screened variants were classified as follows: 41 – pathogenic variants [classified as (I) n = 23, (II) n = 6, (III) n = 1, (IV) n = 6, (IV/V) n = 1 and (VI) n = 4]; 14 – variants of uncertain significance; and seven novel variants. To the novel variants we suggested the classification of 6b-16 exon duplication, G646* and 3557delA as Class I. There was concordance among the predictors as likely pathogenic for L935Q, cDNA.5808T>A and I1427I. Also, Y325F presented two discordant results among the predictors. HTS and in silico analysis can identify pathogenic CFTR variants and will open the door to integration of precision medicine into routine clinical practice in the near future.
Highlights
Cystic fibrosis (CF [OMIM: #219700]) is an autosomal recessive disease, clinically characterized by complex phenotypes[1]
In this study, our primary aim was to identify genetic variants in the CFTR gene in CF patients in a referral center with the use of high-throughput sequencing; and the secondary aim was to determine the pathogenicity of novel variants, rare variants and variants of uncertain significance in the CFTR gene by computational methods in order allow classification and applicability of precision medicine, even in orphan cases
Molecular analysis of the CFTR gene was conducted and the diagnosis was confirmed after the identification of the variants in both alleles
Summary
Cystic fibrosis (CF [OMIM: #219700]) is an autosomal recessive disease, clinically characterized by complex phenotypes[1]. The classification of CFTR variants plays an important role in studies on gene/protein structure and function, and it has notably been a pillar supporting the use and applicability of targeted corrective therapies – precision medicine[8,9,10]. In the case of novel or rare variants determined by high-throughput sequencing, the classification of pathogenicity[11] and possible inclusion in the described classes of CFTR become a challenge. In this study, our primary aim was to identify genetic variants in the CFTR gene in CF patients in a referral center with the use of high-throughput sequencing; and the secondary aim was to determine the pathogenicity of novel variants, rare variants and variants of uncertain significance in the CFTR gene by computational methods in order allow classification and applicability of precision medicine, even in orphan cases. The study protocol followed the ethical principles of the Declaration of Helsinki (1964) and its subsequent amendments
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