High frequency of complex CFTR alleles associated with c.1521_1523delCTT (F508del) in Russian cystic fibrosis patients.

Cystic fibrosis (CF, MIM# 219,700) is an autosomal recessive disease caused by pathogenic variants within the CFTR gene. It was shown that genetic variants located in cis can affect disease severity or treatment response because of additive or epistatic effects. Studies on the prevalence of complex alleles in Russian CF patients have just begun. Aim To evaluate frequencies and genetic background of complex alleles carrying c.1521_1523delCTT (F508del) and c.1399C>T (L467F), c.2562T>G (T854=) or c.4389G>A (Q1463=) in cis; to determine clinical consequences of complex allele c.[1399C>T;1521_1523delCTT] ([L467;F508del]) in Russian CF patients. Methods Sequencing of coding regions of CFTR gene and analysis of polymorphic markers in CF patients carrying F508del variant. Comparing of clinical features in two groups patients having genotypes [L467F;F508del];[F508del] (group 1) and [F508del];[F508del] (group 2). Results Frequency of [L467F;F508del] allele linked to 2-2-21-6-17-13 haplotype was 4.42%, of [F508del;T854=;Q1463=] allele linked to haplotype 1-2-21-6-17-13 - 2.2% in F508del chromosomes. No differences in disease severity in patients carrying complex allele [L467F;F508del] and patients homozygous for F508del was found. Conclusion The frequency of complex alleles associated with F508del was at least 6.6% in Russian CF patients, which should be taken into account for the decision on optimal treatment options with CFTR modulators.

Genetic Variant c.245A>G (p.Asn82Ser) in GIPC3 Gene Is a Frequent Cause of Hereditary Nonsyndromic Sensorineural Hearing Loss in Chuvash Population.

Hereditary nonsyndromic sensorineural hearing loss is a disease in which hearing loss occurs due to damage to the organ of the inner ear, the auditory nerve, or the center in the brain that is responsible for the perception of sound, characterized by wide locus and allelic heterogeneity and different types of inheritance. Given the diversity of population of the Russian Federation, it seems necessary to study the ethnic characteristics of the molecular causes of the disease. The aim is to study the molecular and genetic causes of hereditary sensorineural hearing loss in Chuvash, the fifth largest ethnic group in Russia. DNA samples of 26 patients from 21 unrelated Chuvash families from the Republic of Chuvashia, in whom the diagnosis of hereditary sensorineural hearing loss had been established, were analyzed using a combination of targeted Sanger sequencing, multiplex ligase-dependent probe amplification, and whole exome sequencing. The homozygous variant NM_133261.3(GIPC3):c.245A>G (p.Asn82Ser) is the major molecular cause of hereditary sensorineural hearing loss in 23% of Chuvash patients (OMIM #601869). Its frequency was 25% in patients and 1.1% in healthy Chuvash population. Genotyping of the NM_133261.3(GIPC3):c.245A>G (p.Asn82Ser) variant in five neighboring populations from the Volga-Ural region (Russian, Udmurt, Mary, Tatar, Bushkir) found no evidence that this variant is common in those populations.