A Systematic Review and Meta-Analysis of Free Triiodothyronine (FT3) Levels in Humans Depending on Seasonal Air Temperature Changes: Is the Variation in FT3 Levels Related to Nonshivering Thermogenesis?

Thyroid hormones play a crucial role in regulating normal development, growth, and metabolic function. However, the controversy surrounding seasonal changes in free triiodothyronine (FT3) levels remains unresolved. Therefore, the aim of this study was to conduct a systematic review and meta-analysis of variations in FT3 levels in relation to seasonal air temperatures in the context of current knowledge about its role in nonshivering thermogenesis. Ten eligible articles with a total of 336,755 participants were included in the meta-analysis. The studies were categorized into two groups based on the air temperature: "Cold winter", where the winter temperature fell below 0 °C, and "Warm winter", where the winter temperature was above 0 °C. The analysis revealed that in cold regions, FT3 levels decreased in winter compared to summer (I2 = 57%, p < 0.001), whereas in warm regions, FT3 levels increased during winter (I2 = 28%, p < 0.001). These findings suggest that seasonal variations in FT3 levels are likely to be influenced by the winter temperature. Considering the important role of the FT3 in the nonshivering thermogenesis process, we assume that this observed pattern is probably related to the differences in use of thyroid hormones in the brown adipose tissue during adaptive thermogenesis, which may depend on intensity of cold exposure.

A common founder effect of the splice site variant c.-23 + 1G > A in GJB2 gene causing autosomal recessive deafness 1A (DFNB1A) in Eurasia.

Mutations in the GJB2 gene are known to be a major cause of autosomal recessive deafness 1A (OMIM 220290). The most common pathogenic variants of the GJB2 gene have a high ethno-geographic specificity in their distribution, being attributed to a founder effect related to the Neolithic migration routes of Homo sapiens. The c.-23 + 1G > A splice site variant is frequently found among deaf patients of both Caucasian and Asian origins. It is currently unknown whether the spread of this mutation across Eurasia is a result of the founder effect or if it could have multiple local centers of origin. To determine the origin of c.-23 + 1G > A, we reconstructed haplotypes by genotyping SNPs on an Illumina OmniExpress 730 K platform of 23 deaf individuals homozygous for this variant from different populations of Eurasia. The analyses revealed the presence of common regions of homozygosity in different individual genomes in the sample. These data support the hypothesis of the common founder effect in the distribution of the c.-23 + 1G > A variant of the GJB2 gene. Based on the published data on the c.-23 + 1G > A prevalence among 16,177 deaf people and the calculation of the TMRCA of the modified f2-haplotypes carrying this variant, we reconstructed the potential migration routes of the carriers of this mutation around the world. This analysis indicates that the c.-23 + 1G > A variant in the GJB2 gene may have originated approximately 6000 years ago in the territory of the Caucasus or the Middle East then spread throughout Europe, South and Central Asia and other regions of the world.

The Role of Nonshivering Thermogenesis Genes on Leptin Levels Regulation in Residents of the Coldest Region of Siberia.

Leptin plays an important role in thermoregulation and is possibly associated with the microevolutionary processes of human adaptation to a cold climate. In this study, based on the Yakut population (n = 281 individuals) living in the coldest region of Siberia (t°minimum -71.2 °C), we analyze the serum leptin levels and data of 14 single nucleotide polymorphisms (SNPs) of 10 genes (UCP1, UCP2, UCP3, FNDC5, PPARGC1A, CIDEA, PTGS2, TRPV1, LEPR, BDNF) that are possibly involved in nonshivering thermogenesis processes. Our results demonstrate that from 14 studied SNPs of 10 genes, 2 SNPs (the TT rs3811787 genotype of the UCP1 gene and the GG rs6265 genotype of the BDNF gene) were associated with the elevated leptin levels in Yakut females (p < 0.05). Furthermore, of these two SNPs, the rs3811787 of the UCP1 gene demonstrated more indications of natural selection for cold climate adaptation. The prevalence gradient of the T-allele (rs3811787) of UCP1 increased from the south to the north across Eurasia, along the shore of the Arctic Ocean. Thereby, our study suggests the potential involvement of the UCP1 gene in the leptin-mediated thermoregulation mechanism, while the distribution of its allelic variants is probably related to human adaptation to a cold climate.

Upper Palaeolithic Siberian genome reveals dual ancestry of Native Americans.

The origins of the First Americans remain contentious. Although Native Americans seem to be genetically most closely related to east Asians, there is no consensus with regard to which specific Old World populations they are closest to. Here we sequence the draft genome of an approximately 24,000-year-old individual (MA-1), from Mal'ta in south-central Siberia, to an average depth of 1×. To our knowledge this is the oldest anatomically modern human genome reported to date. The MA-1 mitochondrial genome belongs to haplogroup U, which has also been found at high frequency among Upper Palaeolithic and Mesolithic European hunter-gatherers, and the Y chromosome of MA-1 is basal to modern-day western Eurasians and near the root of most Native American lineages. Similarly, we find autosomal evidence that MA-1 is basal to modern-day western Eurasians and genetically closely related to modern-day Native Americans, with no close affinity to east Asians. This suggests that populations related to contemporary western Eurasians had a more north-easterly distribution 24,000 years ago than commonly thought. Furthermore, we estimate that 14 to 38% of Native American ancestry may originate through gene flow from this ancient population. This is likely to have occurred after the divergence of Native American ancestors from east Asian ancestors, but before the diversification of Native American populations in the New World. Gene flow from the MA-1 lineage into Native American ancestors could explain why several crania from the First Americans have been reported as bearing morphological characteristics that do not resemble those of east Asians. Sequencing of another south-central Siberian, Afontova Gora-2 dating to approximately 17,000 years ago, revealed similar autosomal genetic signatures as MA-1, suggesting that the region was continuously occupied by humans throughout the Last Glacial Maximum. Our findings reveal that western Eurasian genetic signatures in modern-day Native Americans derive not only from post-Columbian admixture, as commonly thought, but also from a mixed ancestry of the First Americans.

Comparison of Predictive In Silico Tools on Missense Variants in GJB2, GJB6, and GJB3 Genes Associated with Autosomal Recessive Deafness 1A (DFNB1A).

In silico predictive software allows assessing the effect of amino acid substitutions on the structure or function of a protein without conducting functional studies. The accuracy of in silico pathogenicity prediction tools has not been previously assessed for variants associated with autosomal recessive deafness 1A (DFNB1A). Here, we identify in silico tools with the most accurate clinical significance predictions for missense variants of the GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) connexin genes associated with DFNB1A. To evaluate accuracy of selected in silico tools (SIFT, FATHMM, MutationAssessor, PolyPhen-2, CONDEL, MutationTaster, MutPred, Align GVGD, and PROVEAN), we tested nine missense variants with previously confirmed clinical significance in a large cohort of deaf patients and control groups from the Sakha Republic (Eastern Siberia, Russia): Сх26: p.Val27Ile, p.Met34Thr, p.Val37Ile, p.Leu90Pro, p.Glu114Gly, p.Thr123Asn, and p.Val153Ile; Cx30: p.Glu101Lys; Cx31: p.Ala194Thr. We compared the performance of the in silico tools (accuracy, sensitivity, and specificity) by using the missense variants in GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) genes associated with DFNB1A. The correlation coefficient (r) and coefficient of the area under the Receiver Operating Characteristic (ROC) curve as alternative quality indicators of the tested programs were used. The resulting ROC curves demonstrated that the largest coefficient of the area under the curve was provided by three programs: SIFT (AUC = 0.833, p = 0.046), PROVEAN (AUC = 0.833, p = 0.046), and MutationAssessor (AUC = 0.833, p = 0.002). The most accurate predictions were given by two tested programs: SIFT and PROVEAN (Ac = 89%, Se = 67%, Sp = 100%, r = 0.75, AUC = 0.833). The results of this study may be applicable for analysis of novel missense variants of the GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) connexin genes.

Reconstructing Native American population history.

The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call 'First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.

Ancient human genome sequence of an extinct Palaeo-Eskimo.

We report here the genome sequence of an ancient human. Obtained from approximately 4,000-year-old permafrost-preserved hair, the genome represents a male individual from the first known culture to settle in Greenland. Sequenced to an average depth of 20x, we recover 79% of the diploid genome, an amount close to the practical limit of current sequencing technologies. We identify 353,151 high-confidence single-nucleotide polymorphisms (SNPs), of which 6.8% have not been reported previously. We estimate raw read contamination to be no higher than 0.8%. We use functional SNP assessment to assign possible phenotypic characteristics of the individual that belonged to a culture whose location has yielded only trace human remains. We compare the high-confidence SNPs to those of contemporary populations to find the populations most closely related to the individual. This provides evidence for a migration from Siberia into the New World some 5,500 years ago, independent of that giving rise to the modern Native Americans and Inuit.

High prevalence of m.1555A > G in patients with hearing loss in the Baikal Lake region of Russia as a result of founder effect.

Mitochondrial forms account approximately 1-2% of all nonsyndromic cases of hearing loss (HL). One of the most common causative variants of mtDNA is the m.1555A > G variant of the MT-RNR1 gene (OMIM 561000). Currently the detection of the m.1555A > G variant of the MT-RNR1 gene is not included in all research protocols. In this study this variant was screened among 165 patients with HL from the Republic of Buryatia, located in the Baikal Lake region of Russia. In our study, the total contribution of the m.1555A > G variant to the etiology of HL was 12.7% (21/165), while the update global prevalence of this variant is 1.8% (863/47,328). The m.1555A > G variant was notably more prevalent in Buryat (20.2%) than in Russian patients (1.3%). Mitogenome analysis in 14 unrelated Buryat families carrying the m.1555A > G variant revealed a predominant lineage: in 13 families, a cluster affiliated with sub-haplogroup A5b (92.9%) was identified, while one family had the D5a2a1 lineage (7.1%). In a Russian family with the m.1555A > G variant the lineage affiliated with sub-haplogroup F1a1d was found. Considering that more than 90% of Buryat families with the m.1555A > G variant belong to the single maternal lineage cluster we conclude that high prevalence of this variant in patients with HL in the Baikal Lake region can be attributed to a founder effect.

Autosomal and uniparental portraits of the native populations of Sakha (Yakutia): implications for the peopling of Northeast Eurasia.

BACKGROUND: Sakha--an area connecting South and Northeast Siberia--is significant for understanding the history of peopling of Northeast Eurasia and the Americas. Previous studies have shown a genetic contiguity between Siberia and East Asia and the key role of South Siberia in the colonization of Siberia. RESULTS: We report the results of a high-resolution phylogenetic analysis of 701 mtDNAs and 318 Y chromosomes from five native populations of Sakha (Yakuts, Evenks, Evens, Yukaghirs and Dolgans) and of the analysis of more than 500,000 autosomal SNPs of 758 individuals from 55 populations, including 40 previously unpublished samples from Siberia. Phylogenetically terminal clades of East Asian mtDNA haplogroups C and D and Y-chromosome haplogroups N1c, N1b and C3, constituting the core of the gene pool of the native populations from Sakha, connect Sakha and South Siberia. Analysis of autosomal SNP data confirms the genetic continuity between Sakha and South Siberia. Maternal lineages D5a2a2, C4a1c, C4a2, C5b1b and the Yakut-specific STR sub-clade of Y-chromosome haplogroup N1c can be linked to a migration of Yakut ancestors, while the paternal lineage C3c was most likely carried to Sakha by the expansion of the Tungusic people. MtDNA haplogroups Z1a1b and Z1a3, present in Yukaghirs, Evens and Dolgans, show traces of different and probably more ancient migration(s). Analysis of both haploid loci and autosomal SNP data revealed only minor genetic components shared between Sakha and the extreme Northeast Siberia. Although the major part of West Eurasian maternal and paternal lineages in Sakha could originate from recent admixture with East Europeans, mtDNA haplogroups H8, H20a and HV1a1a, as well as Y-chromosome haplogroup J, more probably reflect an ancient gene flow from West Eurasia through Central Asia and South Siberia. CONCLUSIONS: Our high-resolution phylogenetic dissection of mtDNA and Y-chromosome haplogroups as well as analysis of autosomal SNP data suggests that Sakha was colonized by repeated expansions from South Siberia with minor gene flow from the Lower Amur/Southern Okhotsk region and/or Kamchatka. The minor West Eurasian component in Sakha attests to both recent and ongoing admixture with East Europeans and an ancient gene flow from West Eurasia.

The GJB2 (Cx26) Gene Variants in Patients with Hearing Impairment in the Baikal Lake Region (Russia).

The GJB2 (Cx26) gene pathogenic variants are associated with autosomal recessive deafness type 1A (DFNB1A, OMIM #220290). Direct sequencing of the GJB2 gene among 165 hearing-impaired individuals living in the Baikal Lake region of Russia identified 14 allelic variants: pathogenic/likely pathogenic-nine variants, benign-three variants, unclassified-one variant, and one novel variant. The contribution of the GJB2 gene variants to the etiology of hearing impairment (HI) in the total sample of patients was 15.8% (26 out of 165) and significantly differed in patients of different ethnicity (5.1% in Buryat patients and 28.9% in Russian patients). In patients with DFNB1A (n = 26), HIs were congenital/early onset (92.3%), symmetric (88.5%), sensorineural (100.0%), and variable in severity (moderate-11.6%, severe-26.9% or profound-61.5%). The reconstruction of the SNP haplotypes with three frequent GJB2 pathogenic variants (c.-23+1G>A, c.35delG or c.235delC), in comparison with previously published data, supports a major role of the founder effect in the expansion of the c.-23+1G>A and c.35delG variants around the world. Comparative analysis of the haplotypes with c.235delC revealed one major haplotype G A C T (97.5%) in Eastern Asians (Chinese, Japanese and Korean patients) and two haplotypes, G A C T (71.4%) and G A C C (28.6%), in Northern Asians (Altaians, Buryats and Mongols). The variable structure of the c.235delC-haplotypes in Northern Asians requires more studies to expand our knowledge about the origin of this pathogenic variant.

Agent-Based Modeling of Autosomal Recessive Deafness 1A (DFNB1A) Prevalence with Regard to Intensity of Selection Pressure in Isolated Human Population.

An increase in the prevalence of autosomal recessive deafness 1A (DFNB1A) in populations of European descent was shown to be promoted by assortative marriages among deaf people. Assortative marriages became possible with the widespread introduction of sign language, resulting in increased genetic fitness of deaf individuals and, thereby, relaxing selection against deafness. However, the effect of this phenomenon was not previously studied in populations with different genetic structures. We developed an agent-based computer model for the analysis of the spread of DFNB1A. Using this model, we tested the impact of different intensities of selection pressure against deafness in an isolated human population over 400 years. Modeling of the "purifying" selection pressure on deafness ("No deaf mating" scenario) resulted in a decrease in the proportion of deaf individuals and the pathogenic allele frequency. Modeling of the "relaxed" selection ("Assortative mating" scenario) resulted in an increase in the proportion of deaf individuals in the first four generations, which then quickly plateaued with a subsequent decline and a decrease in the pathogenic allele frequency. The results of neutral selection pressure modeling ("Random mating" scenario) showed no significant changes in the proportion of deaf individuals or the pathogenic allele frequency after 400 years.

Relationships between Uncoupling Protein Genes UCP1, UCP2 and UCP3 and Irisin Levels in Residents of the Coldest Region of Siberia.

Currently, it is known that irisin can participate in the processes of thermoregulation and browning of adipose tissue, and, therefore, it is possible that it is involved in the microevolutionary mechanisms of adaptation to a cold. The aim of this study is to investigate the relationship between the uncoupling protein genes (UCP1, UCP2, UCP3) and the irisin levels in the residents of the coldest region of Siberia. The sample consisted of 279 Yakut people (185 females, 94 males, average age 19.8 ± 2.03 years). The females plasma irisin concentration was 8.33 ± 2.74 mcg/mL and the males was 7.76 ± 1.86 mcg/mL. Comparative analysis of irisin levels with the genotypes of six studied SNP-markers in females revealed a significant association of irisin with rs1800849-UCP3. The TT genotype of rs1800849 was associated with elevated levels of irisin (p = 0.01). It was also found that this TT genotype in females was associated with reduced weight and height (p = 0.03). We searched for natural selection signals for the T-allele rs1800849-UCP3; as a result of which, it was found that this allele has a significantly high frequency of distribution in northern (45%, CI: 0.42-0.484) compared with southern Asian populations (28%, CI: 0.244-0.316) (p = 0.01). The results obtained indicate the probable involvement of irisin and the UCP3 gene in thermoregulation, and the spread of its allelic variants is probably related to adaptation to a cold climate.

Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect.

Hereditary forms of hearing impairment (HI) caused by GJB2 (Cx26) mutations are the frequent sensory disorders registered among newborns in various human populations. In this study, we present data on the molecular, audiological and population features of autosomal recessive deafness 1A (DFNB1A) associated with the donor splicing site IVS1+1G>A mutation of GJB2 gene in Yakut population isolate of the Sakha Republic (Yakutia) located in Eastern Siberia (Russian Federation). The Yakut population exhibits high frequency of some Mendelian disorders, which are rare in other populations worldwide. Mutational analysis of GJB2 gene in 86 unrelated Yakut patients with congenital HI without other clinical features has been performed. In this study, we registered a large cohort of Yakut patients homozygous for the IVS1+1G>A mutation (70 unrelated deaf subjects in total). Detailed audiological analysis of 40 deaf subjects with genotype IVS1+1G>A/IVS1+1G>A revealed significant association of this genotype with mostly symmetrical bilateral severe to profound HI (85% severe-to-profound HI versus 15% mild-to-moderate HI, P<0.05). The highest among six investigated Eastern Siberian populations carrier frequency of the IVS1+1G>A mutation (11.7%) has been found in Yakut population. Reconstruction of 140 haplotypes with IVS1+1G>A mutation demonstrates the common origin of all mutant chromosomes found in Yakuts. The age of mutation was estimated to be approximately 800 years. These findings characterize Eastern Siberia as the region with the most extensive accumulation of the IVS1+1G>A mutation in the world as a result of founder effect.

Autosomal recessive cataract (CTRCT18) in the Yakut population isolate of Eastern Siberia: a novel founder variant in the FYCO1 gene.

Congenital autosomal recessive cataract with unknown genetic etiology is one of the most common Mendelian diseases among the Turkic-speaking Yakut population (Eastern Siberia, Russia). To identify the genetic cause of congenital cataract spread in this population, we performed whole-exome sequencing (Illumina NextSeq 500) in one Yakut family with three affected siblings whose parents had preserved vision. We have revealed the novel homozygous c.1621C>T transition leading to premature stop codon p.(Gln541*) in exon 8 of the FYCO1 gene (NM_024513.4). Subsequent screening of c.1621C>T p.(Gln541*) revealed this variant in a homozygous state in 25 out of 29 Yakut families with congenital cataract (86%). Among 424 healthy individuals from seven populations of Eastern Siberia (Russians, Yakuts, Evenks, Evens, Dolgans, Chukchi, and Yukaghirs), the highest carrier frequency of c.1621C>T p.(Gln541*) was found in the Yakut population (7.9%). DNA samples of 25 homozygous for c.1621C>T p.(Gln541*) patients with congenital cataract and 114 unaffected unrelated individuals without this variant were used for a haplotype analysis based on the genotyping of six STR markers (D3S3512, D3S3685, D3S3582, D3S3561, D3S1289, and D3S3698). The structure of the identified haplotypes indicates a common origin for all of the studied mutant chromosomes bearing c.1621C>T p.(Gln541*). The age of the с.1621C>T p.(Gln541*) founder haplotype was estimated to be approximately 260 ± 65 years (10 generations). These findings characterize Eastern Siberia as the region of the world with the most extensive accumulation of the unique variant c.1621C>T p.(Gln541*) in the FYCO1 gene as a result of the founder effect.

Carrier frequency of GJB2 gene mutations c.35delG, c.235delC and c.167delT among the populations of Eurasia.

Hearing impairment is one of the most common disorders of sensorineural function and the incidence of profound prelingual deafness is about 1 per 1000 at birth. GJB2 gene mutations make the largest contribution to hereditary hearing impairment. The spectrum and prevalence of some GJB2 mutations are known to be dependent on the ethnic origin of the population. This study presents data on the carrier frequencies of major GJB2 mutations, c.35delG, c.167delT and c.235delC, among 2308 healthy persons from 18 various populations of Eurasia: Russians, Bashkirs, Tatars, Chuvashes, Udmurts, Komi-Permyaks and Mordvins (Volga-Ural region of Russia); Belarusians and Ukrainians (East Europe); Abkhazians, Avars, Cherkessians and Ingushes (Caucasus); Kazakhs, Uighurs and Uzbeks (Central Asia); and Yakuts and Altaians (Siberia). The data on c.35delG and c.235delC mutation prevalence in the studied ethnic groups can be used to investigate the prospective founder effect in the origin and prevalence of these mutations in Eurasia and consequently in populations around the world.

The Role of Leptin Levels in Adaptation to Cold Climates.

Currently, adipose tissue is considered an endocrine organ that produces hormone-active substances, including leptin, which can play a key role in thermoregulation processes. Therefore, we performed a meta-analysis to investigate the influence of the climatic environment on leptin levels. A systematic literature search in the databases was carried out on 10 January 2020. Finally, 22 eligible articles were included in the current meta-analysis and a total of 13,320 participants were covered in the final analysis. It was shown that males of the "North" subgroup demonstrated significantly higher levels of leptin (10.02 ng/mL; CI: 7.92-12.13) than males of the "South" subgroup (4.9 ng/mL; CI: 3.71-6.25) (p = 0.0001). On the contrary, in the female group, a similar pattern was not detected (p = 0.91). Apparently, in order to maintain body temperature, higher leptin levels are required. The results of the study indicate that such effects are most pronounced in males and to a smaller extent in females, apparently due to a relatively high initial concentration of leptin in females. The correlation between leptin levels and climatic environment data support the hypothesis of leptin-mediated thermoregulation as an adaptive mechanism to cold climates.

A new approach to estimating the prevalence of hereditary hearing loss: An analysis of the distribution of sign language users based on census data in Russia.

The absence of comparable epidemiological data challenges the correct estimation of the prevalence of congenital hearing loss (HL) around the world. Sign language (SL) is known as the main type of communication of deaf people. We suggest that the distribution of SL can be interpreted as an indirect indicator of the prevalence of congenital HL. Since a significant part of congenital HL is due to genetic causes, an assessment of the distribution of SL users can reveal regions with an extensive accumulation of hereditary HL. For the first time, we analyzed the data on the distribution of SL users that became available for the total population of Russia by the 2010 census. Seventy-three out of 85 federal regions of Russia were ranked into three groups by the 25th and 75th percentiles of the proportion of SL users: 14 regions-"low proportion"; 48 regions-"average proportion"; and 11 regions-"high proportion". We consider that the observed uneven prevalence of SL users can reflect underlying hereditary forms of congenital HL accumulated in certain populations by specific genetic background and population structure. At least, the data from this study indicate that the highest proportions of SL users detected in some Siberian regions are consistent with the reported accumulation of specific hereditary HL forms in indigenous Yakut, Tuvinian and Altaian populations.

A serological survey of echinococcosis, toxocariasis and trichinellosis among rural inhabitants of Central Yakutia.

In 2018, a seroepidemiological survey was carried out in 3 ulus, or districts (Churapchinsky, Megino-Kangalassky and Ust-Aldansky) in Central Yakutia (Sakha Republic, Russian Federation) about 3 helminth zoonoses, namely, echinococcosis (alveolar or cystic), toxocariasis and trichinellosis. Ninety rural volunteers agreed to answer a questionnaire that inquired about demographic and environmental parameters along with food habits. Then they were asked to provide a venous blood sample. Serological investigations were carried out by enzyme-linked immunosorbent assay. Four subjects tested positive for echinococcosis, 1 for toxocariasis and 2 for trichinellosis. No demographic or environmental or dietary possible risk factor was found to be associated with these positive results. In conclusion, only echinococcosis and trichinellosis appeared to be in Yakutia as health threats among the 3 investigated zoonoses.

A rare case of Waardenburg syndrome with unilateral hearing loss caused by nonsense variant c.772C>T (p.Arg259*) in the MITF gene in Yakut patient from the Eastern Siberia (Sakha Republic, Russia).

Waardenburg syndrome (WS) is an orphan genetic disease with autosomal dominant pattern of inheritance characterised by varying degrees of hearing loss accompanied by skin, hair and iris pigmentation abnormalities. Four types of WS differing in phenotypic characteristics are now described. We performed a Sanger sequencing of coding regions of genes PAX3, MITF, SOX10 and SNAI2 in the patient with WS from a Yakut family living in the Sakha Republic. No changes were found in the PAX3, SOX10 and SNAI2 coding regions while a previously reported heterozygous transition c.772C>T (p.Arg259*) in exon 8 of the MITF gene was found in this patient. This patient presents rare phenotype of WS type 2: congenital unilateral hearing loss, unilateral heterochromia of irises, and absence of skin/hair depigmentation and dystopia canthorum. Audiological variability in WS type 2, caused by the c.772C>T (p.Arg259*) variant in the MITF gene, outlines the importance of molecular analysis and careful genotype-phenotype comparisons in order to optimally inform patients about the risk of hearing loss. The results of this study confirm the association of pathogenic variants in the MITF gene with WS type 2 and expanded data on the variability of audiological features of the WS.

A novel pathogenic variant c.975G>A (p.Trp325*) in the POU3F4 gene in Yakut family (Eastern Siberia, Russia) with the X-linked deafness-2 (DFNX2).

Here, we report a novel hemizygous transition c.975G>A (p.Trp325*) in POU3F4 gene (Xq21) found in two deaf half-brothers from one Yakut family (Eastern Siberia, Russia) with identical inner ear abnormalities ("corkscrew" cochlea with an absence of modiolus) specific to X-linked deafness-2 (DFNX2). Comprehensive clinical evaluation (CT and MR-imaging, audiological and stabilometric examinations) of available members of this family revealed both already known (mixed progressive hearing loss) and additional (enlargement of semicircular canals and postural disorders) clinical DFNX2 features in affected males with c.975G>A (p.Trp325*). Moreover, mild enlargement of semicircular canals, postural abnormalities and different types of hearing thresholds were found in female carrier of this POU3F4-variant.