Abstract Background There is a vast number of screening studies described in the literature from the beginning of the twenty-first century to the present day. Many of these studies are related to the estimation of Fabry disease (FD) morbidity among patients from high-risk groups, including adult patients with hypertrophic cardiomyopathy (HCM) and left ventricular hypertrophy (LVH). These studies show diverse detection frequencies (0–12%) depending on the methodology. Our study is the only example of large-scale selective FD screening based on the implementation of next-generation sequencing technology (NGS) as a first-level test to estimate FD morbidity in the Russian population over 18 years of age burdened with HCM. Methods The study included 1009 patients (578 males and 431 females), with a median age of 50 years, who were diagnosed with HCM according to current clinical guidelines. In the first stage of screening, all patients underwent molecular genetic testing (NGS method) of target regions. These regions included the coding sequences of 17 genes and mutations that can lead to the development of HCM. Lysosomal globotriaosylsphingosine (lyso-Gb3) concentrations and α-galactosidase A (α-gal A) enzyme activity were measured in the second stage of screening to reveal pathogenic or likely pathogenic variants in the GLA gene. Results We revealed 8 (0.8%) patients (3 (37.5%) males and 5 (62.5%) females) with an average age of 59 ± 13.3 years who had pathogenic, likely pathogenic variants and variants of uncertain significance (VUS) in the GLA gene (NM_000169.2) as a result of selective screening of 1009 Russian patients with HCM. FD was confirmed via biochemical tests in a male with the pathogenic variant c.902G > A, p.R301Q as well as in two females with likely pathogenic variants c.897C > A, p.D299E and c.1287_1288dup, p.*430Fext*?. These tests showed reduced enzymatic activity and increased substrate concentration. However, a female with the pathogenic variant c.416A > G, p.N139S and with normal enzymatic activity only had increased substrate concentrations. The revealed nucleotide variants and high values of biochemical indicators (lyso-Gb3) in these 4 patients allowed us to estimate the FD diagnosis among 1009 Russian patients with HCM. Mild extracardiac manifestations were observed in these four patients; however, both biochemical values within the reference range in females with the c.971T > G, p.L324W (VUS) variant. α-gal A activity and lyso-Gb3 concentrations were also within the normal range in two males with hemizygous variants, c.546T > C, p.D182D and c.640-794_640-791del (we regarded them as VUS), and in one female with the c.427G > A, p.A143T variant (with conflicting interpretations of pathogenicity). Conclusion The prevalence rate of FD among 1,009 adult Russian patients with HCM was 0.4%. We recommend FD screening among adult patients of both sexes with HCM and an undefined genetic cause via NGS method with subsequent analysis of α-gal A activity and lyso-Gb3 concentration in patients with pathogenic, likely pathogenic variants, and VUS. This strategy identifies patients with an atypical form of FD that is characterized by high residual activity of α-gal A, low concentrations of lyso-Gb3, and minor extracardiac manifestations.

Epidermolysis bullosa (EB) is the umbrella term for a group of rare inherited skin fragility disorders caused by mutations in the different genes encoding structural proteins participating in the formation and functioning of dermoepidermal junction. Pathogenic genetic variants lead to polymorphic clinical phenotypes combined into 4 main types in accordance with the current nomenclature. 121 Russian children from 113 families aged 1 month to 17 year and 3 month, median 8 years with clinical manifestations of the EB symptom complex were selected for carrying out molecular genetic diagnostics. Next generation sequencing (NGS) was developed for identification of pathogenic variants in targeted regions of 24 genes. Diagnostic approach using NGS allowed to reveal 108 various mutant alleles. 57 variants were not described earlier. The most common form of epidermolysis bullosa is dystrophic, it was revealed in 77 (63,6%) children. EB simplex was detected in 35 (28,9%), EB junction was detected in 7 (5,8%) and the rarest Kindler syndrome was detected in 2 patients (1,7%) Missense mutation c.425A>G and splicing mutation c.682+1G>A in COL7A1 gene can be considered as major variants for Russian children with EB. In addition, we found that novel deletion c.3577del (p.A1193Lfs*72) revealed in homozygous state in 6 unrelated children living in Dagestan and 5 of them are representatives of the Dargwa ethnic group with high degree of traditionally consanguineous marriages. Pathogenic variants were found in all children which indicates that NGS can be used for identification of the etiological reasons of hereditary dermatosis with EB symptom complex successfully.