Introduction: Pathogenic variants in the OFD1 gene are linked to a spectrum of syndromes that exhibit partial clinical overlap. Hemizygous loss-of-function variants are considered lethal in males, while heterozygous loss-of-function variants generally result in oro-facial-digital syndrome type 1. A reported phenotype, Simpson–Golabi–Behmel syndrome type 2, was published once but remains controversial, with many specialists questioning its validity and arguing about its continued listing in the OMIM database. Methods: To investigate the genetic and phenotypic characteristics of the patients, we performed clinical exome sequencing, family-based genetic analysis, X-inactivation studies, electron microscopy, and detailed clinical assessments. Results: Three patients from unrelated families carrying loss-of-function variants in the OFD1 gene were identified, emphasizing the diverse phenotypic spectrum of OFD1-associated disorders. The first patient, a female with a heterozygous frameshift variant p.(Gln398LeufsTer2), was diagnosed with oro-facial-digital syndrome type 1. The second patient, a male with a heterozygous nonsense variant p.(Gln892Ter), presented with features resembling Simpson–Golabi–Behmel syndrome type 2, as previously reported under this diagnosis. The third patient, a male with another heterozygous nonsense variant p.(Glu879Ter), exhibited isolated primary ciliary dyskinesia without any syndromic features. Conclusions: This study contributes to the growing body of evidence on the expanding phenotypic spectrum of OFD1-associated disorders. It underscores the need for further investigation into the molecular mechanisms underlying the diverse presentations and the necessity of re-evaluating diagnostic classifications for conditions such as SGBS2 in the context of variants in the OFD1 gene.

The authors of this article analyzed the available literature with the results of studying the prevalence of complex alleles of the CFTR gene among patients with cystic fibrosis, and their pathogenicity and influence on targeted therapy with CFTR modulators. Cystic fibrosis (CF) is a multisystemic autosomal recessive disease caused by a defect in the expression of the CFTR protein, and more than 2000 genetic variants are known. Clinically significant variants are divided into seven classes. Information about the frequency of complex alleles appears in a number of registers, along with the traditional presentation of data on genetic variants. Complex alleles (those with the presence of more than two nucleotide variants on one allele) can complicate the diagnosis of the disease, and change the clinical manifestations of cystic fibrosis and the response to treatment, since each variant in the complex allele can contribute to the functional activity of the CFTR protein, changing it both in terms of increasing and decreasing function. The role of complex alleles is often underestimated, and their frequency has not been studied. At the moment, characteristic frequently encountered complex alleles have been found for several populations of patients with cystic fibrosis, but the prevalence and pathogenicity of newly detected complex alleles require additional research. In this review, more than 35 complex alleles of the CFTR gene from existing research studies were analyzed, and an analysis of their influence on the manifestations of the disease and the effectiveness of CFTR modulators was also described.

Primary ciliary dyskinesia (PCD) is a rare hereditary disorder belonging to the group of ciliopathies, with autosomal recessive, autosomal dominant, and, less frequently, X-linked inheritance patterns. The aim of this study was to investigate the genetic heterogeneity of the Russian population of PCD patients based on national registry data. The study included patients with PCD confirmed by molecular genetic testing. Quantitative data were analyzed using non-parametric statistical methods. Differences were considered statistically significant at p < 0.05. The study included 109 patients with PCD. Molecular genetic testing identified pathogenic variants in 29 autosomal recessive genes. The analysis of pathogenic variant distribution in the Russian PCD cohort revealed the highest number of changes in the DNAH5 and DNAH11 genes. 26 genetic variants in 13 genes were identified for the first time in the Russian population. Variants in the DNAH5 gene were significantly more frequent in Kartagener’s syndrome (KS) patients (32/55%) compared to those without KS (11/21.5%) (χ² = 12.8; p = 0.0004; OR = 4.48). Preliminary data indicate that the frequency spectrum of DNAH5 and DNAH11 genes in Russian patients is similar to international trends. Additionally, there is an accumulation of pathogenic variants in the DNAH5, DNAH11, CCDC39, and CFAP300 genes.

BACKGROUND:  Certain genes are involved in the regulation of nutrient and energy metabolism. The PPARGC1A and ACE genes, the products of which provide cellular energy metabolism, are actively studied not only in the development of relationships with the physical characteristics of individuals (sports results), but also in relation to pathological changes in the body, as a result of the appearance of metabolic products with altered physicochemical properties and parameters of functional activity, leading to various diseases (obesity, type 2 diabetes, insulin resistance, metabolic syndrome). AIM:  to conduct an associative search for genetic variants of the ACE (I/D) and PPARGC1A (G/A) genes with clinical phenotypes of obesity in children. MATERIALS AND METHODS:   The study included 177 children with obesity and 135 healthy children aged 5 to 18 years. The following were studied: nutritional status, lipid and carbohydrate metabolism parameters to conduct an associative search for genetic variants of the ACE (I/D) and PPARGC1A (G/A) genes with clinical phenotypes of obesity (OB). Testing of polymorphic variants of the ACE (I/D), PPARGC1A (PGC-1) genes was performed by PCR and RFLP analysis. RESULTS: In the sample of healthy children, the I/D and I/I genotype of the ACE gene and the A/A and G/A genotypes of the PPARGC1A gene are more common. In patients with obesity, the I/D genotype and the D allele of the ACE gene, and the G/A genotype of the PPARGC1A gene are more common. The G/G genotype and the G allele of the PPARGC1A gene in obesity were associated with metabolic syndrome and hypertriglyceridemia CONCLUSION:  The I/D genotype of the ACE gene was more common in obese patients, but no associations of the genotype with metabolic risks were found. The G/G genotype of the PPARGC1A gene was more common in obese patients and was associated with the risk of developing metabolic disorders and hypertriglyceridemia.

Currently, primary ciliary dyskinesia (PCD) is one of the most common hereditary diseases of the respiratory tract. The prevalence of PCD is estimated at approximately 1 case per 10,000 - 20,000, but this figure varies significantly among studies. Despite advances in diagnostics (genetic polymorphism is associated with > 60 genes in PCD), many patients are still diagnosed late, even in adulthood. The exact prevalence of PCD in the Russian Federation is unknown. The aim of the study was to present the National Registry of Patients with PCD in the Russian Federation, which records health characteristics of the patients, their genetic diversity, assessment of the respiratory tract microbiome, and the organization of treatment. Methods. The registry included patients ( n = 109: 71 children, 38 adults) from 34 regions of the Russian Federation with a genetically confirmed diagnosis of PCD (the presence of 2 pathogenic variants, accounting for the mode of inheritance). A comprehensive diagnostic protocol according to the recommendations of the European Respiratory Society (ERS) was used. The study also included testing of respiratory tract biomaterial samples from patients using classical bacteriological methods with subsequent identification using matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry (MALDI-TOF MS). Results. The average age at diagnosis was 14.6 ± 13.8 years (median 10 years), indicating a significant diagnostic delay, especially in adults (median 32 years). In total, pathogenic variants were identified in 29 genes. The genes with an autosomal recessive inheritance pattern predominated (95.9%). The most frequent mutations were in the DNAH5 (39.4%) and DNAH11 (9.2%) genes. The most common clinical manifestations of the respiratory tract were chronic rhinosinusitis (90.8%), wet cough (93.6%), and bronchiectasis (76.3% of adults). A study of the etiologic structure of respiratory tract infections revealed that Staphylococcus aureus (53.8%) and Pseudomonas aeruginosa (38.7%) were the predominant bacteria across all age groups. Conclusion. The study revealed deficiencies in the organization of care for patients with PCD, emphasizing the need for standardized diagnostic algorithms and early molecular genetic diagnosis to improve prognosis and quality of life.