Von Hippel–Lindau syndrome (VHLS) is a hereditary cancer syndrome with CNS hemangioblastomas, clear cell renal carcinoma, pheochromocytoma, retinal angiomas, and a number of other manifestations. VHLS is caused by a mutation in the VHL gene and is inherited in an autosomal dominant manner. However, some cases of VHLS develop de novo, and among them, there are rare patients with a mosaic form of the disease. Genetic testing in mosaic patients is prone to false-negative results due to the low copy number of a mutant allele in DNA isolated from the blood. We describe a case of molecular genetic diagnostics of VHLS in a 39-year-old patient using various methods, including mutation analysis in asynchronous primary tumors and repeated DNA analysis from blood using NGS with high coverage for the mutant position. As a result, the patient was diagnosed with a mosaic form of VHLS caused by the variant c.481C>T (p.Arg161Ter), the proportion of which in the blood DNA was 2%. We also summarized the literature data on the mosaic form of VHLS: the severity of clinical manifestations, the features of differential diagnostics of VHLS with a negative result of routine molecular genetic VHL testing, and specific options of active surveillance and treatment for mutation carriers.

Autosomal dominant dyskinesia caused by heterozygous pathogenic variants in the ADCY5 gene, which encodes adenylate cyclase-5, is a rare neurodegenerative disease with a typical early onset and is primarily associated with hyperkinesias, mostly complex ones. Nonfamilial cases caused by de novo gene variants predominate. Caffeine in the form of coffee has become a common treatment. Three cases have been described: a familial case in a 9-year-old boy and a 54-year-old mother; a nonfamilial case in a 4-year-old girl with a frequent ADCY5 variant, p.Arg418Gln; and a nonfamilial case in an 8-year-old boy with a known variant, p.Arg726Trp. In the familial case, the mother’s disease was much less severe than that of the son and did not require treatment; coffee was effective in the son.

Craniosynostoses (CS) are a congenital malformation caused by absence or premature closure of skull sutures. This leads to deformation and impaired growth of skull. Traditionally, syndromic and non-syndromic forms are distinguished. For a long time, it was believed that molecular genetic mechanisms are significant exclusively for syndromic CS. However, clear data on involvement of somatic and germinal mutations in pathogenesis of non-syndromic forms were accumulated in recent years. Currently, there are no unified clinical guidelines defining the strategy for molecular genetic diagnosis for non-syndromic CS. This creates difficulties for neurosurgeons when choosing the optimal diagnostic method. The purpose of the article was to analyze modern ideas about effectiveness of various methods of molecular diagnosis of non-syndromic CS and to evaluate their role in routine clinical practice of neurosurgical departments.

The disruption of the epigenetic mechanisms of gene expression regulation due to the emergence of pathogenic variants in genes-encoding elements of epigenetic machinery leads to the development of chromatinopathies. This group of hereditary diseases includes 179 syndromes, some of which present with overlapping phenotypes. Despite the variety of approaches to molecular diagnostics of chromatinopathies, it is not always possible to establish the molecular diagnosis by traditional methods; thus, the issue of optimizing diagnostic algorithms remains relevant. One of the most rapidly expanding areas of post-genomic molecular diagnostics is episignature detection, which relies on genome-wide DNA methylation analysis. This article aims to represent an original approach to indirect diagnostics of chromatinopathies on the example of Rubinstein–Taybi syndrome 1, which is based on the analysis of the methylation level of a limited set of loci designed to reproduce its classic episignature. In the current study, we apply two methods of targeted quantitative analysis of DNA methylation, which are relatively accessible and can be integrated into diagnostic practice. We demonstrate that Rubinstein–Taybi syndrome 1 episignature may be successfully reduced to a single locus of human genome, and that quantitative bisulfite DNA methylation analysis at this locus allows accurate identification of the Rubinstein–Taybi syndrome 1 patients.