We present a comprehensive molecular and epidemiological analysis of albinism in a Russian cohort, comprising 177 probands with isolated (OCA1, OCA2, OCA3, OCA4, and OA) and syndromic (HPS-associated) forms of the disease. The comparative analysis of population frequencies between the National Genetic Initiative "100,000 + Me" (NGI) project and GnomAD (v3.1.2) revealed variants in the TYR gene (NM_000372.5):c.650G>A and c.1037-7 T>A, which are specifically prevalent in the Russian population. The functional analysis was provided for variants in the TYR gene, which can probably affect splicing. Based on the population frequency in the NGI project, we calculated the minimal estimated disease frequencies for isolated forms of albinism. Using molecular genetic results, functional analysis, and ACMG classification, the diagnosis was confirmed in 71.8% (127/177) of the cases in the Russian cohort.

CFTR modulators have significantly affected the prognosis for cystic fibrosis, improving the clinical course in most patients with the F508del variant and several other CFTR gene variants. The presence of complex alleles, including more than one variant in the cis position, can change the properties of the protein and the efficacy of modulators. Objective: We aimed to describe the efficacy of CFTR modulators in the treatment of two siblings with the c.[1521_1523delCTT;1399C>T];[54-5940_273+10250del21kb] (L467F;F508del/CFTRdele2,3) genotype in clinical practice and in vitro. This article presents the clinical presentation and results of CFTR channel function assessment and personalized selection of CFTR modulators in monochorionic diamniotic twins with cystic fibrosis and the L467F;F508del/CFTRdele2,3 genotype. This is the first demonstration of the efficacy of a new CFTR modulator in patients with a complex allele and a class I variant in the genotype. The obtained results may be useful for choosing treatment strategies for patients with a complex allele and a class I variant in the genotype.

Pathogenic variants in the USH2A gene are the primary cause of both non-syndromic autosomal recessive inherited retinitis pigmentosa (RP) and the syndromic form, characterized by retinal degeneration and sensorineural hearing loss. This study presents a comparative assessment of the genetic variant spectrum in the USH2A gene among Russian patients in two clinical groups. A retrospective analysis was conducted on massive parallel panel sequencing data from 2415 blood samples of unrelated patients suspected of having hereditary retinal diseases. The copy number of USH2A exons was determined using the quantitative MLPA method with the MRC-Holland SALSA MLPA kit. Biallelic pathogenic and likely pathogenic variants in the USH2A gene were identified in 69 patients (8.7%). In the group of patients with isolated hereditary RP (55 patients), the most frequent pathogenic variants were p.(Glu4445_Ser4449delinsAspLeu) (20.9%), p.(Trp3955*) (15.5%), and p.(Cys934Trp) (5.5%). In patients with the syndromic form (14 patients), the most frequent variants were p.(Trp3955*) (35.7%) and c.8682-9A>G (17.9%). It was found that patients with isolated vision impairment rarely had two “null” variants (17.8%), whereas this was common among patients with both hearing and vision impairment (71.4%) (p ≤ 0.05), explaining the severity of the disease and the earlier onset of clinical symptoms in the syndromic form of RP. Ten previously undescribed loss-of-function variants were identified. The estimated prevalence of USH2A-associated retinal dystrophy in Russia was 1.9 per 100,000 individuals. The obtained data on the differences in the spectra of genetic variants in the USH2A gene in the two studied groups highlight the importance of establishing genotype–phenotype correlations and predicting disease severity, aiming at potential early cochlear implantation and selection of target therapy.

Inherited retinal diseases (IRDs) are a clinically heterogeneous group of retinal pathologies associated with vision loss due to dysfunction or degeneration of photoreceptor and retinal pigment epithelium. Autosomal recessive forms of IRDs account for more than 55% of all diseases in this group on average worldwide. This study presents data on frequent pathogenic and likely pathogenic variants in recessive IRDs genes obtained from a retrospective analysis of high-throughput sequencing data from a large Russian cohort of patients with suspected hereditary non-syndromic retinal pathology. Data from 1470 unrelated patients were analyzed. Pathogenic and likely pathogenic variants were identified in the zygosity required for the development of the diseasein 643 patients (43.74%). It was found that 9 genes (ABCA4, CNGB3, USH2A, RPE65, CRB1, CNGA3, CEP290, GUCY2D, PDE6H) account for 73.3% of all molecularly confirmed cases of IRDs in Russian patients. An analysis of the spectrum of nucleotide variants of these genes was carried out, and 17 variants were identified that occur with an allelic frequency of more than 1% for each gene. In light of obtained data, the diagnostic systems based on the multiplex ligation-dependent probe amplification reaction (MLPA) were developed. The informativity of the two systems for diagnosing autosomal recessive non-syndromic forms of inherited retinal diseases is 16.4%, the informativity for all forms of non-syndromic retinal diseases exceeds 7%. For a group of patients with achromatopsia, a study using one of the systems will make it possible to establish a diagnosis in 62.5% of cases.

Background: oculocutaneous albinism (OCA) is a hereditary impairment of skin, hair, and eye pigmentation. The most common form of albinism is autosomal recessive albinism, caused by mutations in the TYR gene, accounting for approximately 40–50% of all cases of the disease in European populations. Common hypomorphic variants in the TYR gene could lead to a mild form of albinism in a compound heterozygous state with a pathogenic variant. Methods: we examined by allele specific MLPA a cohort consisting of 118 unrelated patients with albinism and 10 parents of these patients. The control cohort consisted of 200 unexamined Russian residents. Results: the patients with albinism were divided into three groups: without pathogenic variants in the TYR gene—70 patients, with one pathogenic variant in the TYR gene—20 patients, and with two pathogenic variants in the TYR gene—28 patients. Among the 20 patients with a single heterozygous variant in the TYR gene, 15 patients had the c.575C>A p.(Ser192Tyr) variant, and 15 had the c.1205G>A p.(Arg402Gln) variant. Both the c.575C>A p.(Ser192Tyr) and c.1205G>A p.(Arg402Gln) variants were identified in 12 patients. In addition to the aforementioned variants, an intronic variant c.1185-6208A>G (rs147546939) was identified in seven patients. Conclusions: the frequencies and the number of alleles c.575A, c.1205A, and c.1185-6208G in different groups of patients and the control group were compared. In this study, we demonstrate that the complex alleles [c.575C>A p.(Ser192Tyr); c.1205G>A p.(Arg402Gln)] and [c.575C>A p.(Ser192Tyr); c.1185-6208A>G; c.1205G>A p.(Arg402Gln)] are associated with oculocutaneous albinism, which is consistent with findings from other researchers.

Введение. Синдром Клайнфельтера (СК) – аномалия половых хромосом, характеризующаяся высокой распространенностью в различных популяциях, гипергонадотропным гипогонадизмом и мужским бесплодием, выраженной клинической вариабельностью симптомов и часто поздней диагностикой. Причины фенотипической вариабельности СК, в том числе роль генетических, эпигенетических и средовых факторов, до сих пор недостаточно изучены. Цель: исследование влияния CAG-полиморфизма гена андрогенового рецептора (AR) и родительского происхождения дополнительной Х-хромосомы на клинико-лабораторные показатели у пациентов с СК. Методы. Обследованы 34 пациента с СК от 5 до 18 лет, имеющие кариотипы 47,XXY (n=32); 48,XXYY (n=1) и mos 47,ХХY[22]/46,XY[8] (n=1). Два пациента являлись монозиготными близнецами, остальные не были родственниками. Родительское происхождение Х-хромосом определяли путём генотипирования пациентов и родителей по (CAG)n-полиморфному локусу гена AR и (GAAA)n полиморфному локусу, расположенному вблизи гена RP2. Влияние родительского происхождения дополнительной хромосомы Х и количества CAG-повторов на клинико-лабораторные показатели оценено у 22 подростков с кариотипом 47,ХХY, достигших стадии полового развития по Таннеру ≥2, не получавших заместительную терапию препаратами тестостерона на момент обследования. Результаты. Количество CAG-повторов в гене AR у пациентов с СК варьировало от 16 до 27, 22 аллеля (32,4%) содержали 20 или 21 повтор. По числу CAG-повторов группа из 22 подростков с СК была разделена на 3 подгруппы: носители «коротких» аллелей ((CAG)n ≤19; 6 пациентов), «средних» аллелей ((CAG)n=20–25; 12 пациентов) и «длинных» аллелей ((CAG)n ≥26; 4 пациента). Сравнительный анализ данных антропометрии (SDS роста и ИМТ, ΔSDS сегментов тела) не выявил статистически значимых различий между подгруппами. В группе носителей «длинных» аллелей отмечены более высокие уровни тестостерона и инсулина, больший объем тестикул по сравнению с носителями «средних» и «коротких» аллелей. По уровням гонадотропинов (ЛГ, ФСГ), показателям метаболического профиля (ХС общего, ЛПНП, ЛПВП, ТГ), исследуемые группы также не различались. Родительское происхождение дополнительной Х-хромосомы установлено у 33 пациентов, из них у 22 (67%) выявлено материнское происхождение (Хm), у 11 (33%) – отцовское (Хр). Анализ влияния происхождения хромосомы Х на показатели антропометрии, гормонального и липидного профиля у отобранных для исследования 22 подростков (из них 15 с дополнительной Хm, 7 с дополнительной Хр) не выявил статистически значимых различий между подгруппами. Таким образом, существенного влияния родительского происхождения дополнительной Х-хромосомы на клинические и гормонально-метаболические показатели в исследованной выборке пациентов с СК не выявлено. Introduction. Klinefelter syndrome (KS) is a sex chromosome abnormality characterized by high prevalence in various populations, hypergonadotropic hypogonadism, male infertility, pronounced clinical variability of symptoms and commonly late diagnosis. The causes of phenotypic variability of KS, including the influence of genetic, epigenetic and environment factors on it, is still not well understood. Aim: evaluation of the CAG polymorphism of androgen receptor (AR) gene and the parental origin of the X chromosomes on clinical and laboratory parameters in Klinefelter syndrome patients. Methods. We examined 34 KS patients 5-18 years of age with following karyotypes: 47,XXY (n=32); 48,XXYY (n=1) и mos 47,ХХY[22]/46,XY[8] (n=1). Two patients were monozygotic twins, the other patients were unrelated. Parental origin of the X chromosomes was determined by genotyping for (CAG)n polymorphism of the AR gene and (GAAA)n polymorphism, near to the RP2 gene, in patients and parents. The influence of the origin of the additional X chromosome and CAG-repeats of AR gene on the clinical and laboratory parameters was assessed in 22 adolescents with a karyotype 47,XXY, who had reached the Tanner stage of sexual development ≥2, and not received testosterone replacement therapy at the time of examination. Results. The number of CAG repeats of the AR gene in KS patients was ranged from 16 to 27, and 22 alleles (32.4%) contained from 20 or 21 repeats. According to CAG-repeats, a group of 22 adolescents with KS was divided into 3 subgroups: carriers of “short” alleles ((CAG) n ≤19; 6 patients), “medium” alleles ((CAG)n=20–25; 12 patients) and “long” alleles ((CAG)n ≥26; 4 patients) alleles. Comparative analysis of anthropometric data (SDS of height and BMI, ΔSDS of body segments) did not reveal statistically significant differences between subgroups. In the group of carriers of “long” alleles, higher levels of testosterone and insulin and a larger testicular volume were noted compared to carriers of “medium” and “short” alleles. The study groups also did not differ in the levels of gonadotropins (LH, FSH) and metabolic profile indicators (total cholesterol, LDL, HDL, TG). The parental origin of the additional X chromosome was established in 33 patients, of which 22 (67%) patients had maternal origin (Xm), and 11 (33%) individuals had paternal origin (Xp). Analysis of the influence of the origin of the X chromosome on anthropometric indicators, hormonal and lipid profiles in 22 adolescents selected for the study (additional Xm, n=15; additional Xp, n=7) did not reveal statistically significant differences between the subgroups. No significant influence of the parental origin of the additional X chromosome and the CAG polymorphism of the androgen receptor gene on clinical and hormonal-metabolic parameters in our sample of KS patients, was found.

The work has begun to study the structure of pseudofinite acts over a monoid. A theorem on the finiteness of an arbitrary cyclic subacts of S-act is proved under the condition that this S-act is pseudofinite and the number of types of isomorphisms of finite cyclic S-acts is finite. It is shown that a coproduct of finite S-acts is pseudofinite. As a consequence, it is shown that any S-act, where S is a finite group, is pseudofinite.

We introduce the notion of a partially ordered abelian algebra which is a natural generalization of the notion of an abelian algebra. We describe partially ordered abelian groupoids with identity, finite quasigroups, regular semigroups, semisimple semigroups, and semigroups with minimal left and right ideals.

Inherited retinal diseases (IRDs) constitute a prevalent group of inherited ocular disorders characterized by marked genetic diversity alongside moderate clinical variability. Among these, ABCA4-related eye pathology stands as a prominent form affecting the retina. In this study, we conducted an in-depth analysis of 96 patients harboring ABCA4 variants in the European part of Russia. Notably, the complex allele c.[1622T>C;3113C>T] (p.Leu541Pro;Ala1038Val, or L541P;A1038V) and the variant c.5882G>A (p.Gly1961Glu or G1961E) emerged as primary contributors to this ocular pathology within this population. Additionally, we elucidated distinct disease progression characteristics associated with the G1961E variant. Furthermore, our investigation revealed that patients with loss-of-function variants in ABCA4 were more inclined to develop phenotypes distinct from Stargardt disease. These findings provide crucial insights into the genetic and clinical landscape of ABCA4-related retinal dystrophies in this specific population.

An axiomatizability criterion is found for the class of subdirectly irreducible S-acts over a commutative monoid. As a corollary, a number of properties are presented which a commutative monoid should satisfy provided that the class of subdirectly irreducible acts over it is axiomatizable. The question about a complete description of monoids over which the class of subdirectly irreducible acts is axiomatizable remains open even for the case of a commutative monoid.

We prove the general properties of morphisms of Chu spaces and functors with a value in the category $Chu(SS-Act)$ of Chu spaces over the category $SS-Act$. As a consequence, for the category $Chu(SS-Act)$ the existence of coproducts and some products is proved, monomorphisms and epimorphisms are characterized; in terms of this category the characteristics of separable and complete separable Chu spaces are given.

X-linked centronuclear myopathy is caused by pathogenic variants in the MTM1 gene, which encodes myotubularin, a phosphatidylinositol 3-phosphate (PI3P) phosphatase. This form of congenital myopathy predominantly affects males. This study presents a case of X-linked myotubular myopathy in a female carrier of a pathogenic c.1261-10A>G variant in the MTM1 gene.

We prove the general properties of morphisms of Chu spaces and functors with a value in the category 𝐶ℎ𝑢(𝑆𝑆 − 𝐴𝑐𝑡) of Chu spaces over the category 𝑆𝑆 − 𝐴𝑐𝑡. As a consequence, for the category 𝐶ℎ𝑢(𝑆𝑆 −𝐴𝑐𝑡) the existence of coproducts and some products is proved, monomorphisms and epimorphisms are characterized; in terms of this category the characteristics of separable and complete separable Chu spaces are given.