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.

BACKGROUND: Cystic 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. METHODS: Molecular 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. RESULTS: High 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. CONCLUSIONS: The 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.

[Clinical/genetic characteristics of patients with congenital muscular dystrophy caused by mutations in the LMNA gene].

OBJECTIVE: To study clinical/genetic characteristics of congenital muscular dystrophy caused by mutations in the LMNA gene in 5 patients from the Russian population. MATERIAL AND METHODS: DNA samples of 42 probands, aged from 2 months to 9 years, with characteristic signs of congenital muscular dystrophy from nonrelated families were studied. The diagnosis was based on the results of genealogical analysis, neurological examination, serum creatine phosphokinase activity, results of electroneuromyography. RESULTS AND CONCLUSION: In the Russian population, the frequency of congenital muscular dystrophy caused by mutations in the LMNA gene is not less than 12% of all cases of this group of diseases. The results indicate the presence of major mutation c.94_96delAAC in the LMNA gene. Specific phenotypic features of this form of congenital muscular dystrophy with symptoms of progressive flaccid paralysis with predominant lesions of axial muscles and plantar flexor muscles of the foot are described.

[Clinical and Genetic Characteristics of Russian Marfan Patients].

The results of direct DNA diagnostics in nine patients with Marfan syndrome, aged from two to 52 years old, and four unhealthy relatives with the same disease from two unrelated families have been presented for the first time in Russia. Eight mutations in the gene FBN1 were revealed. One patient demonstrated a substitution with unknown clinical importance, which was previously described in the SN P database as rsl 12287730 with a frequency of incidence of 0.1%. Out of the eight mutations, two (25%) were previously described, and the other six mutations (75%) were revealed for the first time. These mutations revealed by us were of the following types: three mutations (37.5%) produced a shift in the open reading frame (two deletions and one insertion), three mutations (12.5%) involved a splicing site, and one (12.5%) nonsense mutation was also noted. Our data contradict previous reports that claimed that the majority of mutations in the FBN1 gene represented missense mutations. Such inconsistency could result from a small size of the examined sample or from substitutions that produced alteration in the splicing site (as we have demonstrated here). The distribution of the revealed mutations was uniform along the whole gene. The results of the conducted comparative analysis of genetic and phenotypic indices was in complete agreement with previously reported results. The developed direct method of DNA diagnostics was fully informative, as we managed in all nine examined patients to confirm their clinical diagnosis using a molecular and genetic approach.