Spectrum of CFTR mutations in Chechen cystic fibrosis patients: high frequency of c.1545_1546delTA (p.Tyr515X; 1677delTA) and c.274G>A (p.Glu92Lys, E92K) mutations in North Caucasus

Abstract

BackgroundCystic fibrosis (CF; OMIM #219700) is a common autosomal recessive disease caused by pathogenic variants (henceforward mutations) in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The spectrum and frequencies of CFTR mutations vary among different populations. Characterization of the specific distribution of CFTR mutations can be used to optimize genetic counseling, foster reproductive choices, and facilitate the introduction of mutation-specific therapies. Chechens are a distinct Caucasian ethnic group of the Nakh peoples that originated from the North Caucasus. Chechens are one of the oldest ethnic groups in the Caucasus, the sixth largest ethnic group in the Russian Federation (RF), and constitute the majority population of the Chechen Republic (Chechnya). The spectrum of CFTR mutations in a representative cohort of Chechen CF patients and healthy individuals was analyzed.MethodsMolecular genetic analysis of 34 CFTR mutations (representing approx. 80–85% of mutations in multiethnic CF populations of the RF) was performed in 32 CF patients from 31 unrelated Chechen families living in Chechnya. One hundred randomly chosen healthy Chechens were analyzed for the 15 most common “Russian” mutations. The clinical symptoms in Chechen CF patients with different CFTR genotypes were investigated.ResultsHigh frequencies of c.1545_1546delTA (p.Tyr515X; 1677delTA) (52 out of 64 CFTR alleles tested; 81.3%) and c.274G > A (p.Glu92Lys, E92K) (8/64, 12.5%) mutations were found. Twenty patients were homozygous for the c.1545_1546delTA mutation, and eight were compound heterozygous for the c.1545_1546delTA and c.274G > A mutations. Three carriers of the c.1545_1546delTA mutation were also found in the cohort of 100 apparently healthy Chechens (frequency – 0.015). The c.1545_1546delTA and c.274G > A mutations are linked to the same haplotype (22–7–16–13) of intragenic Short Tandem Repeat markers, i.e., IVS1CA, IVS6aGATT, IVS8CA, and IVS17bCA.ConclusionsThe distribution of CFTR mutations in the Chechen CF population is unique regarding the high frequency of mutations c.1545_1546delTA and c.274G > A (more than 90% of the mutant alleles). The c.274G > A mutation is associated with a less severe course of CF than that observed in c.1545_1546delTA homozygotes. Testing for these two variants can be proposed as the first step of CF DNA diagnosis in the Chechen population.

Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis

“…We observed high levels of CFTR functional rescue in organoids of several subjects with rare mutations like E92K, Q237E and L159S (the last one not yet described in the CFTR2 database [4]. E92K is rescued by lumacaftor, concurring with results in heterologous cell systems [34,35]. FIS in E92K organoids was slightly higher with ivacaftor-lumacaftor than lumacaftor alone, suggesting impaired channel gating of rescued E92K.…”

Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients

“…When developing a routinely used mutation panel, the laboratory's own data [14], the results of the first collaborative study [15], and studies of other Russian laboratories (in St. Petersburg [16], Bashkortostan [17], and Tomsk [18]) were considered. The panel includes 33 pathogenic variants of the CFTR gene identified in patients from different regions of the Russian Federation, as well as the variants specific for certain ethnic groups [7][8][9][10], and allows identification of up to 85% of mutant alleles in all-Russian population [12].…”

“…Thus, the frequency of variant c.1545_1546delTA (1677delTA) for ethnic Russians is much lower than for the all-Russian sample (0.18% and 1.81%, respectively, p < 0.0001). The variant c.1545_1546delTA (1677delTA) is predominantly distributed in the North Caucasus populations (Chechens, Ingush, Kumyks) [9,12]. The frequency of variant c.262_263delTT (394delTT) for ethnic Russians is lower than for the all-Russian sample (0.54% vs. 0.94%, p = 0.074, although difference is not significant).…”

“…The frequency of variant c.274G>A (E92K) for ethnic Russian patients is almost three times less than for the all-Russian sample (1.05% vs. 3.00%, p < 0.0001). The frequency of variant c.274G>A (p.Glu92Lys, E92K) is maximum for Chuvash (up to 55%) [10], high for Tatars (6.67%), Bashkirs (6.25%) [7], Chechens (12.5%) [9]. The frequency of c.3846G>A (p.Trp1282X, W1282X) is significant higher in the all-Russian sample (RF CF Registry) than in ethnic Russian patients (1.16% vs. 1.90%, p = 0.012).…”

Clinical Presentation of the c.3844T>C (p.Trp1282Arg, W1282R) Variant in Russian Cystic Fibrosis Patients

“…For example, in the North Caucasus Federal district, three variants are most frequent: F508del (25.0%); 1677delTA (21.5%); and W1282X (17.2%), and in the Volga Federal district the most frequent variants are: F508del (50.5%); E92K (8.7%); and CFTRdele2,3 (5.0%) [ 7 ]. The study of CFTR gene variant spectra in different ethnic groups in the Russian Federation revealed a high proportion of W1282X variant (88%) in Karachay (in the Karachay–Cherkess Republic of the Russian North Caucasus) [ 8 ], 1677delTA (81.5%) and E92K (12.5%) in Chechens [ 9 ], and E92K (55%) in Chuvash [ 10 ]. The second most common variant in Chuvash CF patients is F508del (30%) [ 10 ].…”