Cystic fibrosis (CF; OMIM # 219700) is an autosomal recessive disease caused by a mutation in the CFTR gene (OMIM * 602421), characterised by a variable clinical picture ranging from a relatively mild disease course with monosymptomatic manifestations to severe multiorgan lesions [[1]]. The prevalence of CF in European countries is about 1 in 2500–4500 newborns and in the Russian Federation, it is 1 in 10,000 newborns [1]. The spectrum and frequencies of CFTR mutations vary widely among different populations and ethnic groups.

The spectrum of CFTR mutations specific to Russian CF patients has been recently identified. Moreover, the creation of the Russian Cystic Fibrosis Patient Registry (RCF-PR) and the provisions of the National Consensus documents on CF care have made it possible to combine data from clinical trials and researches conducted in different centres to better clarify the frequency of mutations both in the Russian Federation itself and in specific regions within the Federation [2,3]. According to the RCF-PR 2016,the ten most common mutations (frequency) are: F508del (52.06%), CFTRdele2.3 (5.71%), E92K (2.67%), 2143delT (2.06%), 3849+10kbC>T (2.04%), 2184insA (1.87%), W1282X (1.82%), N1303K (1.47%), 1677delTA (1.44%), and G542X (1.35%). Mutation c.411_412insCTA (p.Leu138dup, L138ins) can be considered common in Russian patients since its frequency exceeds 1% (1.15%) of the total number of identified mutant alleles (ranging from 0.29–2.89% across different regions) [2,3]. The frequency of this mutation in Europe has not been determined due to the rarity of this particular pathological allele in European populations [1]. Indeed, the L138ins mutation is not included in the panel of routinely analysed CFTR mutations in European countries. The purpose of this study is to describe the genotypic features of the L138ins mutation in Russian CF patients.

DNA was isolated from whole blood samples of CF patients using a DNA extraction kit (Promega, USA). Molecular genetic testing for the c.411_412insCTA (p.Leu138dup, L138ins) mutation was performed using amplified fragment length polymorphism (AFLP) analysis as part of the testing for frequent CFTR mutations in 1700 CF patients and was conducted in the Laboratory of Genetic Epidemiology at the Research Centre for Medical Genetics, Moscow [4]. Sanger sequencing to confirm the c.411_412insCTA (p.Leu138dup, L138ins) mutation presence was performed in 37 CF patients. Analysis of DNA markers IVS1CA, IVS6aGATT, IVS8CA, and IVS17bCA was performed in 24 CF patients carrying the c.411_412insCTA (p.Leu138dup, L138ins) mutation and their parents using a previously described procedure [5]. This research project was approved by the Ethics committee of the Research Center for Medical Genetics (Moscow). CF patients, or their fiduciaries, provided written informed consent.

In 2000, while testing for the 621+1G>T mutation in a Russian CF patient using RFLP test, the abnormal mobility of the exon 4 fragment of the CFTR gene was first observed (Figure 1). Sequencing confirmed the presence of a CFTR mutation (L138ins) not previously found in the Russian population (Figure 2). By 2006, the L138ins mutation was detected in six unrelated CF patients from Moscow and the Moscow region [4]. Subsequently, the L138ins mutation was also identified in two patients from the Krasnodar region [6]. Currently, the L138ins mutation is included in the panel of common CFTR mutations routinely tested for in the Russian population [3].

The work was carried within the state assignment of Ministry of Science and Higher Education of the Russian Federation for Medical Genetics and in part with the financial support of the Russian Fund for Fundamental Research (RFFR) (project No. 20-015-00061) (expeditions, DNA research, writing the manuscript) and Czech Ministry of Health CZ.2.16/3.1.00/24022OPPK; IP00064203/6003 for University Hospital Motol (general management of the project, reviewing the manuscript).