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More than 275 million people in the world are carriers of a heterozygous mutation of the CFTR gene, associated with cystic fibrosis, the most common autosomal recessive disease among Caucasians. Some recent studies assessed the association between carriers of CFTR variants and some pathologies, including cancer risk. The aim of this study is to analyze the landscape of germline pathogenic heterozygous CFTR variants in patients with diagnosed malignant neoplasms. For the first time in Russia, we evaluated the frequency of CFTR pathogenic variants by whole-genome sequencing in 1800 patients with cancer and compared this with frequencies of CFTR variants in the control group (1825 people) adjusted for age and 10,000 healthy individuals. In the issue, 47 out of 1800 patients (2.6%) were carriers of CFTR pathogenic genetic variants: 0.028 (42/1525) (2.8%) among breast cancer patients, 0.017 (3/181) (1.7%) among colorectal cancer patients and 0.021 (2/94) (2.1%) among ovarian cancer patients. Pathogenic CFTR variants were found in 52/1825 cases (2.85%) in the control group and 221 (2.21%) in 10,000 healthy individuals. Based on the results of the comparison, there was no significant difference in the frequency and distribution of pathogenic variants of the CFTR gene, which is probably due to the study limitations. Obviously, additional studies are needed to assess the clinical significance of the heterozygous carriage of CFTR pathogenic variants in the development of various pathologies in the future, particularly cancer. Full article

(1) Background: The inherited alpha-1 antitrypsin (A1AT) deficiency variant ‘Pi*Z’ emerged as a genetic modifier of chronic liver disease. Controversial data exist on the relevance of heterozygous Pi*Z carriage (‘Pi*MZ’ genotype) as an additional risk factor in patients with chronic viral hepatitis C to develop progressive liver fibrosis. (2) Methods: Two prospectively recruited cohorts totaling 572 patients with therapy-naïve chronic viral hepatitis C (HCV) were analyzed. The Frankfurt cohort included 337 patients and a second cohort from Leipzig included 235 patients. The stage of liver fibrosis was assessed by liver biopsy, AST-to-platelet ratio index (APRI) score and Fibrosis-4 (FIB-4) score (Frankfurt) as well as liver stiffness measurement (LSM) via transient elastography (Leipzig). All patients were genotyped for the Pi*Z variant (rs28929474) of the SERPINA1 gene. (3) Results: In the Frankfurt cohort, 16/337 (4.7%) patients carried the heterozygous Pi*Z allele while 10/235 (4.3%) in the Leipzig cohort were Pi*Z carriers. In both cohorts, there was no higher proportion of Pi*Z heterozygosity in patients with cirrhosis compared to patients without cirrhosis or patients with cirrhosis vs. no liver fibrosis. Accordingly, Pi*Z frequency was not different in histological or serological stages of liver fibrosis (F0–F4) and showed no clear association with LSM. (4) Conclusions: Evaluation in two representative HCV cohorts does not indicate Pi*Z heterozygosity as a clinically relevant disease modifier in chronic HCV infection. However, validation in even larger cohorts with longitudinal follow-up is warranted. Full article

(1) Hypophosphatasia (HPP) is a rare inherited disease caused by mutations (pathogenic variants) in the ALPL gene which encodes tissue-nonspecific alkaline phosphatase (TNSALP). HPP is characterized by impaired bone mineral metabolism due to the low enzymatic activity of TNSALP. Knowledge about the structure of the gene and the features and functions of various ALPL gene variants, taking into account population specificity, gives an understanding of the hereditary nature of the disease, and contributes to the diagnosis, prevention, and treatment of the disease. The purpose of the study was to describe the spectrum and analyze the functional features of the ALPL gene variants, considering various HPP subtypes and clinical symptoms in Russian children. (2) From 2014–2021, the study included the blood samples obtained from 1612 patients with reduced alkaline phosphatase activity. The patients underwent an examination with an assessment of their clinical symptoms and biochemical levels of TNSALP. DNA was isolated from dried blood spots (DBSs) or blood from the patients to search for mutations in the exons of the ALPL gene using Sanger sequencing. The PCR products were sequenced using a reagent BigDye Terminator 3.1 kit (Applied Biosystems). Statistical analysis was performed using the GraphPad Prism 8.01 software. (3) The most common clinical symptoms in Russian patients with HPP and two of its variants (n = 22) were bone disorders (75%), hypomyotonia (50%), and respiratory failure (50%). The heterozygous carriage of the causal variants of the ALPL gene was detected in 225 patients. A total of 2 variants were found in 27 patients. In this group (n = 27), we identified 28 unique variants of the ALPL gene, of which 75.0% were missense, 17.9% were frameshift, 3.6% were splicing variants, and 3.6% were duplications. A total of 39.3% (11/28) of the variants were pathogenic, with two variants being probably pathogenic, and 15 variants had unknown clinical significance (VUS). Among the VUS group, 28.6% of the variants (7/28) were discovered by us for the first time. The most common variants were c.571G > A (p.Glu191Lys) and c.1171del (Arg391Valfs*12), with frequencies of 48.2% (13/28) and 11% (3/28), respectively. It was found that the frequency of nonsense variants of the ALPL gene was higher (p < 0.0001) in patients with the perinatal form compared to the infantile and childhood forms of HPP. Additionally, the number of homozygotes in patients with the perinatal form exceeded (p < 0.01) the frequencies of these genotypes in children with infantile and childhood forms of HPP. On the contrary, the frequencies of the compound-heterozygous and heterozygous genotypes were higher (p < 0.01) in patients with infantile childhood HPP than in perinatal HPP. In the perinatal form, residual TNSALP activity was lower (p < 0.0005) in comparison to the infantile and childhood (p < 0.05) forms of HPP. At the same time, patients with the heterozygous and compound-heterozygous genotypes (mainly missense variants) of the ALPL gene had greater residual activity (of the TNSALP protein) regarding those homozygous patients who were carriers of the nonsense variants (deletions and duplications) of the ALPL gene. Residual TNSALP activity was lower (p < 0.0001) in patients with pathogenic variants encoding the amino acids from the active site and the calcium and crown domains in comparison with the nonspecific region of the protein. Full article

Here, we described three affected boys from two unrelated families of Ossetian-Digor origin from the Republic of North Ossetia-Alania who were admitted to the Research Centre for Medical Genetics with unspecified muscular dystrophy. High-throughput sequencing was performed and revealed two novel frameshift variants in the COL6A2 gene (NM_001849.3) in a heterozygous state each in both cases: c.508_535delinsCTGTGG and c.1659_1660del (case 1) and c.1689del and c.1659_1660del (case 2). In two cases, the same nucleotide variant in the COL6A2 gene (c.1659_1660del) was observed. We have suggested that the variant c.1659_1660del may be common in the Ossetian-Digor population because two analyzed families have the same ancestry from the same subethnic group of Ossetians). The screening for an asymptomatic carriage of the nucleotide variant c.1659_1660del in 54 healthy donors from Ossetian-Digor population revealed that the estimated carrier frequency is 0.0093 (CI: 0.0002–0.0505), which is high for healthy carriers of the pathogenic variant. Molecular genetic, anamnestic data and clinical examination results allowed us to diagnose Ullrich muscular dystrophy in those affected boys. Genetic heterogeneity and phenotypic diversity of muscular dystrophies complicate diagnosis. It is important to make a differential diagnosis of such conditions and use HTS methods to determine the most accurate diagnosis. Full article

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common medically intractable epilepsy syndrome. Although pathogenesis of HS still remains highly controversial, genetics may play a role as a predisposing factor. Previous evidence in a Japanese population revealed that the homozygotes for allele T at position −511 of the interleukin (IL)-1β gene promoter region (IL-1β-511 T/T) confers susceptibility to the development of HS. However, whether this polymorphism has an effect on IL-1β levels in MTLE-HS patients was not demonstrated. This study aimed to analyze the distribution of this particular polymorphism in a group of Turkish HS patients and correlate the polymorphism with IL-1β secretion from the lymphocytes, thus revealing a functional role for IL-1β in the etiopathogenesis of HS. A single base pair polymorphism at position −511 in the promoter region of the IL-1β gene was analyzed. The spontaneous and 1 ng/mL lipopolysaccharide-stimulated production of IL-1β by peripheral blood mononuclear cells after 4 and 24 h of incubation were measured by ELISA method. The heterozygous type (−511 C/T) was the most common genotype. There was no difference in frequency of allele −511 T between patients and controls. Analysis of IL-1β levels, genotype and allele distributions showed no significant difference among the groups (P>0.05). Nevertheless, it was seen that patients who carry a T allele at position -511 of the IL-1β gene had increased IL-1β levels. T-allele carriage may be important. Only IL-1β secretion from the lymphocytes has been assessed in this study. Considering the importance of IL-1β in the etiopathogenesis of HS, further studies are needed to evaluate locally produced IL-1β levels. Full article