Molecular Genetic Cause Research Articles

Genetics of Primary Adrenal Insufficiency Beyond CAH in Saudi Arabian Population.

The use of exome sequencing (ES) has helped in detecting many variants and genes that cause primary adrenal insufficiency (PAI). The diagnosis of PAI is difficult and can be life-threatening if not treated urgently. Consanguinity can impact the detection of recessively inherited genes. Here, we report families with PAI in a consanguineous population of Saudi Arabia. A cohort of 47 PAI patients (41 males and six females) representing 30 families was recruited. The cohort excluded congenital adrenal hyperplasia (CAH) cases and had a known consanguinity of 70%. Using ES, molecular genetic causes of PAI were investigated. In 30 unrelated families with PAI, pathogenic/likely pathogenic variants were detected in 27 families with a diagnostic yield of (90%). Clinically associated variants of uncertain significance (VUS) were identified in a further two PAI families (7%). Hemizygous variants in ABCD1 were the most common cause of PAI in this cohort (16 families) leading to adrenoleukodystrophy. A total of six novel variants were detected, of which four were predicted to be pathogenic (P) / likely pathogenic (LP) and two were VUS. Four pathogenic variants in ABCD1, NR0B1, and MC2R were detected in 10 families suggesting founder mutations. In this cohort, ES detected a diagnostic molecular abnormality in 90% of patients with PAI phenotypes. X-linked inheritance is the most common cause of PAI and founder mutations likely contributed to a high diagnostic yield.

PROSPECTS OF HISTOMORPHOLOGICAL AND GENETIC DIAGNOSIS OF AUTOPSY-NEGATIVE SUDDEN CARDIAC DEATH

The article presents the prospects of histological and genetic diagnosis in cases of sudden cardiac death, where initial autopsy results do not reveal any obvious pathological changes. In recent years, there has been an increase in cases of autopsy-negative sudden cardiac death, creating a foundation for the development of methods for more accurate diagnosis of the causes of fatal outcomes and potential prevention of similar cases in the future. The article discusses modern methods of histological examination of heart tissues, as well as approaches to molecular genetic testing that may be useful in identifying subclinical conditions leading to sudden cardiac death. Molecular genetic methods for studying sudden cardiac death are still underexplored; therefore, the intersection of medical genetics, pathological anatomy, and forensic expertise is a very important and promising area in domestic medicine. Currently, there are few large-scale studies on the molecular genetic causes of sudden cardiac death in Russia, making the direction of diagnosing such fatal outcomes at the intersection of medical genetics, pathological anatomy, and forensic expertise particularly significant and promising in domestic medicine. This brief overview summarizes the results of histological and genetic diagnostics in cases of sudden cardiac death.

Expansion of phenotypic and genotypic data in autism spectrum disorders due to variants in the CHD8 gene.

Autism spectrum disorders are a group of the most common disorders of neuropsychiatric development, characterized by difficulties in social interaction and adherence to stereotypic behavioral patterns. This group of conditions frequently co-occurs with intellectual disability, epilepsy, attention-deficit hyperactivity disorder, connective tissue disorders and others. Among the most common molecular-genetic causes of autism spectrum disorders are pathogenic variants in the CHD8 gene. CHD8 codes for chromodomain-helicase-DNA-binding protein 8 - a chromatin remodeler that regulates cellular proliferation and brain development in embryogenesis. 6 children and 1 adult (mother of 1 of the children) and were found to have clinically significant variants in CHD8 on whole genome sequencing (3 children and 1 adult had likely pathogenic variants, 3 children- variants of unknown significance). Their phenotype consisted of autism spectrum disorders, developmental delay, ataxia, overgrowth and other signs typically observed in patients with pathogenic variants in CHD8, as well as common comorbidities of autism spectrum disorders, such as attention-deficit hyperactivity disorder and connective tissue disorders. Additionally, 4 patients had hepatomegaly and 2- hyperbilirubinemia (1 had both) - clinical features have not been previously associated with pathogenic variants in CHD8. 2 patients also presented with cardiovascular abnormalities, primarily arrythmias and, in 1 case, cardiomyopathy- also uncharacteristic of patients with pathogenic variants in CHD8. Further research is required to determine the mechanisms underlying the abovementioned clinical features, which are likely carried out through complex interactions between CHD8 and other regulatory proteins.

Molecular-genetic causes of nephrocalcinosis in Russian children and their impact on the renal and extrarenal phenotypes

Introduction. Nephrocalcinosis (NC) is defined as the deposition of calcium oxalate or calcium phosphate in the intratubular lumen and/or kidney interstitium. Recent studies have reported that NC might be a specific sign of hereditary kidney diseases with various phenotypic manifestations. The rate of genetic mutation as a rule was higher in children with earlier onset and positive family history. Purpose. To study the causes, characterize the genotype and phenotype in Russian children with NC. Materials and methods. A single-center retrospective-prospective cohort study included 91 patient under the age of 18 years, 57 (62.6%) boys and 34 (37.4%) girls with bilateral NC. We analyzed the phenotype and kidney function in NC children classified into 3 groups according to etiology: 1) primary tubulopathies; 2) tubulopathies due to metabolic and endocrine disorders; 3) NC, unconfirmed by molecular genetic research. Results. Pathogenic nucleotide variants were identified in 51 (56%) children with a predominance in the genes CLCN5, CYP24A1, AGXT, HPRT1 described in patients with Dent disease (OMIM 300009), primary hyperoxaluria type 1 (OMIM 259900), idiopathic infantile hypercalcemia type 1 (OMIM 143880), Lesh–Nihan syndrome (OMIM 300322) respectively. The median age of detection of NC was 16 years, 4 [3.9; 52.2 months, among which 42 (46.1%) children were under the age of 1 year, 44 (48.4%) aged 1 to 10 years, 5 (5.5%) older than 10 years. Various bone deformities prevailed among the extrarenal manifestations (19 (20.4%)). Over 3 years of follow-up (n = 51) the average GFR changed from 102.5 ± 26.0 ml/min/1.73 m2 to 94.5 ± 21.9 ml/min/1.73 m2 (p = 0.002); over 5 years of follow-up (n = 31) from 104.7 ± 23.9 ml/min/1.73 m2 to 89.6 ± 25.1 ml/min/1.73 m2 (p = 0.002), that was statistically significant in the group of primary tubulopathies (p = 0.030; p = 0.002). At baseline, the average GFR value was lower in NC stages 2 and 3. Conclusion. Conducting a molecular genetic study in NC children, in addition to early diagnosis of diseases with variable renal prognosis and will also help to achieve effectiveness in the timely prescription of pathogenetic and symptomatic therapy.

Diagnosis of Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is primary electrical heart disease characterized by development of polymorphic, including bidirectional, ventricular tachycardia in response to adrenergic stimulation caused by physical or emotional stress. The major CPVT’s clinical manifestation is faintness caused by exercises, emotional stress, or beta-adrenergic agonists administration. This disease has high mortality rate without any treatment. The difficulties of preclinical diagnosis as well as late diagnosis after CPVT’s clinical signs manifestation dictate the need to analyze and systematize all the data on disease’s causes, clinical manifestations, and existing diagnostic approaches. This work has particular focus on the analysis of the disease molecular genetic causes and the spectrum of associated disorders in patients with CPVT regarding its diagnosis, management, and prognosis. Future research topics were determined for improving diagnosis quality and reducing mortality of patients with CPVT.

Genetic variation and molecular profiling of congenital malformations of the female genital tract based on whole-genome sequencing.

Congenital malformations of the female genital tract (CM-FGT) are characterized by abnormal development of the fallopian tubes, uterus, and vagina, often accompanied by malformations in the urinary system, bones and hearing. However, no definitive pathogenic genes and molecular genetic causes have been identified. We present the largest whole-genome sequencing study of CM-FGT to date, analyzing 590 individuals in China: 95 patients, 442 case-controls, and 53 familial controls. Among the patients, 5.3% carried known CM-FGT-related variants. Pedigree and case-control analyses in two dimensions of coding and non-coding regulatory regions revealed seven novel de novo copy number variations, 12 rare single-nucleotide variations, and 10 rare 3' untranslated region (UTR) mutations in genes related to CM-FGT, particularly highlighting ASH1L as a pathogenic gene. Single-cell sequencing data showed that the majority of CM-FGT-related risk genes are spatiotemporally specifically expressed early in uterus development. In conclusion, this study identified novel variants related to CM-FGT, particularly highlighting ASH1L as a pathogenic gene. The findings provide insights into the genetic variants underlying CM-FGT, with single-cell sequencing data revealing spatiotemporal specific expression patterns of key risk genes early in uterine development. This study significantly advances the understanding of CM-FGT etiology and genetic landscape, offering new opportunities for prenatal screening.

Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings

Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype–phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams.

Characterization of 13 Novel Genetic Variants in Genes Associated with Epilepsy: Implications for Targeted Therapeutic Strategies.

Childhood epilepsies are caused by heterogeneous underlying disorders where approximately 40% of the origins of epilepsy can be attributed to genetic factors. The application of next-generation sequencing (NGS)has revolutionized molecular diagnostics and has enabled the identification of disease-causing genes and variants in childhood epilepsies.The objective of this study was to use NGS to identify variants in patients with childhood epilepsy, to expand the variant spectrum and discover potential therapeutic targets. In our study, 55 children with epilepsy of unknown etiology were analyzed bycombining clinical-exome and whole-exome sequencing. Novel variants were characterized using various in silico algorithms for pathogenicity and structure prediction. The molecular genetic cause of epilepsy was identified in 28 patients and the overall diagnostic success rate was 50.9%. We identified variants in 22 different genes associated with epilepsy that correlate well with the described phenotype. SCN1A gene variants were found in five unrelated patients, while ALDH7A1 and KCNQ2 gene variants were found twice. In the other 19 genes, variants were found only in a single patient. This includes genes such as ASH1L, CSNK2B, RHOBTB2, and SLC13A5, which have only recently been associated with epilepsy. Almost half of diagnosed patients (46.4%) carried novel variants. Interestingly, we identified variants in ALDH7A1, KCNQ2, PNPO, SCN1A, and SCN2A resulting ingene-directed therapy decisions for 11 children from our study, including four children who all carried novel SCN1A genetic variants. Described novel variants will contribute to a better understanding of the European genetic landscape, while insights into the genotype-phenotype correlation will contribute to a better understanding of childhood epilepsies worldwide. Given the expansion of molecular-based approaches, each newly identified genetic variant could become a potential therapeutic target.

Diagnosis and management of non-CAH 46,XX disorders/differences in sex development.

Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in NR3C1, resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the CYP19A1 gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the SRY; copy number variants in NR2F2, NR0B1, SOX3, SOX9, SOX10, and FGF9, and sequence variants in NR5A1, NR2F2, RSPO1, SOX9, WNT2B, WNT4, and WT1. Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.

Analysis of molecular genetic causes of congenital heart defects in children

In 10–20% of cases, congenital heart defects are caused by chromosomal abnormalities and gene mutation. Purpose. The purpose of the study: analysis of the genetic causes of congenital heart defects in children.Materials and Methods. The analysis of the medical history and the results of Genetics and Molecular Research (GMR) in 15 children with congenital heart defects were carried out.Results. Genome-wide DNA sequencing in patients with congenital heart defects revealed deletion 21q22.3 with duplication 4q31.1 ->qter and pathogenic variants in the genes PPP1CB, FN1, PHF6, CITIED2, ARID2, KMT2A, CIT, JAG1, MED13L, ELN, CHRNA3, KCNK9. Conclusion. In the vast majority of cases in the examined children, congenital heart defects were caused by pathogenic gene variants or chromosomal abnormalities. Congenital heart defects are an absolute indication for cytogenetic and molecular genetic examination.

Investigation of the molecular genetic causes of non-syndromic primary ovarian ınsufficiency by next generation sequencing analysis.

The aim of this study is to investigate the molecular genetic causes of non-syndromic primary ovarian insufficiency (POI) cases with the gene panel basedon next generation sequencing analysis and to establish the relationship between genotype and phenotype. Twenty three cases aged 14-40 years followed up with POI were included. Patients with a karyotype of 46, XX, primary or secondary amenorrhea before the age of 40, with elevated FSH (>40 IU/mL) and low AMH levels (<0.03 ng/mL) were included in the study. Molecular genetic analyzes were performed by the next generation sequencing analysis method targeted with the TruSight TM Exome panel. Median age of the cases was 17.8 (14.0-24.3) years, and 12 (52%) cases admitted before the age of 18. Fifteen (65%) patients had consanguineous parents. In2 (8.6%) cases, variants detected were in genes that have been previously proven to cause POI. One was homozygous variant in FIGLA gene and the other was homozygous variant in PSMC3IP gene. Heterozygous variants were detected in PROK2, WDR11 and CHD7 associated with hypogonadotropic hypogonadism, but these variants are insufficient to contribute to the POI phenotype. Genetic panels based on next generation sequencing analysis technologies can be used to determine the molecular genetic diagnosis of POI, which has a highly heterogeneous genetic basis.

The Role of Next-Generation Sequencing in the Management of Patients with Suspected Non-Ischemic Cardiomyopathy after Syncope or Termination of Sudden Arrhythmic Death.

Cardiac arrhythmias and sudden death are frequent in patients with non-ischemic cardiomyopathy and can precede heart failure or additional symptoms where malignant cardiac arrhythmias are mostly the consequence of advanced cardiomyopathy and heart failure. Finding these subgroups and making an early diagnosis could be lifesaving. In our retrospective study, we are presenting arrhythmic types of frequent cardiomyopathies where an arrhythmogenic substrate is less well defined, as in ischemic or structural heart disease. In the period of 2 years, next-generation sequencing (NGS) tests along with standard clinical tests were performed in 208 patients (67 women and 141 men; mean age, 51.2 ± 19.4 years) without ischemic or an overt structural heart disease after syncope or aborted sudden cardiac death. Genetic variants were detected in 34.4% of the study population, with a significant proportion of pathogenic variants (P) (14.4%) and variants of unknown significance (VUS) (20%). Regardless of genotype, all patients were stratified according to clinical guidelines for aggressive treatment of sudden cardiac death with an implantable cardioverter defibrillator (ICD). The P variant identified by NGS serves for an accurate diagnosis and, thus, better prevention and specific treatment of patients and their relatives. Results in our study suggest that targeted sequencing of genes associated with cardiovascular disease is an important addendum for final diagnosis, allowing the identification of a molecular genetic cause in a vast proportion of patients for a definitive diagnosis and a more specific way of treatment. VUS in this target population poses a high risk and should be considered possibly pathogenic in reanalysis.

Addressing Obesity Care in Children With Chronic Health Conditions.

Obesity care in pediatric populations has entered a new era. The recent discovery of molecular genetic causes for abnormal weight gain, development of antiobesity medications, mounting data on the robust efficacy and favorable safety profile of bariatric surgery, and implementation of clinical guidelines fill a long-standing gap in the care of children affected by obesity, one of the most challenging pediatric diseases. However, these novel clinical approaches do not appear to have reached every individual who is in need, particularly children with chronic health conditions (CHCs), raising important questions for equitable medical care. In this study, we discuss specific etiologies, challenges, and ideas for future directions in diagnosing and managing obesity in children with CHCs. Although this article is not intended to be utilized as clinical guidelines, it underscores potential practical solutions for the current issues.

Modern approaches to the treatment of spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease. The cause of the disease is the presence of mutations in the SMN1 gene, which leads to a decrease in the expression of the SMN protein. Decreased functional activity of the SMN protein contributes to the degeneration of motor neurons. Understanding the molecular genetic cause of spinal muscular atrophy made it possible to develop and start using Nusinersen, Onasemnogene Abeparvovec and Risdiplam drugs in clinical practice for the treatment of this disease. The main approaches to the treatment of SMA are either modifying the splicing of the SMN2 gene, which, due to a point mutation in exon 7, is unable to express the full-length SMN protein, or viral delivery of a functional copy of the SMN1 gene.&#x0D; Approved drugs differ in peculiarities of use, which are associated, in particular, with the route of administration, adverse reactions and restrictions of use, including restrictions associated with the socio-economic burden of patients with SMA.&#x0D; The development and use of domestic products for the treatment of SMA with a comparable clinical effect and at a lower price would reduce the cost of drug therapy for severe forms of the disease.

Searching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learning.

One of the most common congenital metabolic disorders is familial hypercholesterolemia. Familial hypercholesterolemia is a condition caused by a type of genetic defect leading to a decreased rate of removal of low-density lipoproteins from the bloodstream and a pronounced increase in the blood level of total cholesterol. This disease leads to the early development of cardiovascular diseases of atherosclerotic etiology. Familial hypercholesterolemia is a monogenic disease that is predominantly autosomal dominant. Rare pathogenic variants in the LDLR gene are present in 75-85 % of cases with an identified molecular genetic cause of the disease, and variants in other genes (APOB, PCSK9, LDLRAP1, ABCG5, ABCG8, and others) occur at a frequency of < 5 % in this group of patients. A negative result of genetic screening for pathogenic variants in genes of the low-density lipoprotein receptor and its ligands does not rule out a diagnosis of familial hypercholesterolemia. In 20-40 % of cases, molecular genetic testing fails to detect changes in the above genes. The aim of this work was to search for new genes associated with the familial hypercholesterolemia phenotype by modern high-tech methods of sequencing and machine learning. On the basis of a group of patients with familial hypercholesterolemia (enrolled according to the Dutch Lipid Clinic Network Criteria and including cases confirmed by molecular genetic analysis), decision trees were constructed, which made it possible to identify cases in the study population that require additional molecular genetic analysis. Five probands were identified as having the severest familial hypercholesterolemia without pathogenic variants in the studied genes and were analyzed by whole-genome sequencing on the HiSeq 1500 platform (Illumina). The whole-genome sequencing revealed rare variants in three out of five analyzed patients: a heterozygous variant (rs760657350) located in a splicing acceptor site in the PLD1 gene (c.2430-1G>A), a previously undescribed single-nucleotide deletion in the SIDT1 gene [c.2426del (p.Leu809CysfsTer2)], new missense variant c.10313C>G (p.Pro3438Arg) in the LRP1B gene, and single-nucleotide deletion variant rs753876598 [c.165del (p.Ser56AlafsTer11)] in the CETP gene. All these variants were found for the first time in patients with a clinical diagnosis of familial hypercholesterolemia. Variants were identified that may influence the formation of the familial hypercholesterolemia phenotype.

Molecular genetic diagnostics for inherited retinal dystrophies in the clinical setting

ObjectifÉvaluer le succès du dépistage génétique de la dystrophie rétinienne héréditaire (DRH) à des fins diagnostiques en milieu clinique. NatureAnalyse de cohorte rétrospective. ParticipantsUn total de 446 participants consécutifs de diverses origines ethniques vivant dans l'Ouest canadien. MéthodesLes données cliniques, notamment les antécédents familiaux, ont été recueillies auprès des participants qui ont fait l'objet d'un examen ophtalmique complet, suivi d'une analyse de leurs dossiers médicaux. On a offert un dépistage génétique réunissant un panel de 351 gènes aux patients chez lesquels on soupçonnait la présence d'une DRH entre le 1er mars 2019 et le 28 février 2022. Le principal paramètre de mesure était l'effet du dépistage génétique sur le diagnostic clinique. RésultatsLe dépistage génétique a donné lieu à un diagnostic moléculaire certain dans 249 cas sur 446 (55,8 %), à un résultat nettement négatif dans 90 cas sur 446 (20,1 %) et à un diagnostic incertain dans 108 cas sur 446 (24,2 %). On a identifié de manière concluante des variants pathogènes dans 69 gènes, les gènes le plus souvent touchés étant ABCA4 (31 variants), USH2A (25 variants) et RPGR (19 variants). Le groupe diagnostic incertain comprenait vraisemblablement des variants autosomiques dominants encore inconnus ou un variant pathogène comprenant un variant dans le même gène dont la signification est incertaine en ce qui touche le phénotype récessif. Fait à noter, on a obtenu un diagnostic moléculaire génétique incertain dans une proportion pouvant atteindre 47,3 % des participants est-asiatiques qui présentaient une dystrophie de la rétine externe. ConclusionsLa présente étude constitue la plus importante revue sur le dépistage moléculaire génétique des DRH au Canada. L'obtention de résultats négatifs ou incertains dans environ 45 % des cas témoigne du besoin criant en matière de recherche sur les causes moléculaires génétiques des DRH, particulièrement lorsqu'il s'agit d'interpréter un variant dont la signification est incertaine au sein de minorités ethniques.

Genetic counselling and gene analysis in patients with hereditary ocular diseases

Purpose. Non-syndromic hereditary ocular diseases can lead to severe functional limitations of vision at all ages. Therefore, molecular genetic research into the causes of hereditary ocular diseases is of paramount importance. Due to the increasingly optimised pathophysiologically adapted treatments and gene therapy options, a rapid determination of the genetic cause of hereditary ocular diseases is neces- sary, also to increase the chances of treatment at early stages of the disease. In this context, the authors retrospectively analysed the database of the “rare diseases” consultation hour of the PraxisKlinik Augenärzte Halle, which has been in existence since 2016, for patients with a suspected hereditary ophthalmological disease after molecular genetic diagnostics, counselling and therapy options. Material and Methods. 367 index patients were treated dur- ing the period under consideration. In 221 (60.2 %) of them, the molecular genetic cause of the underlying disease could be found. In addition to a large group of patients with cor- neal dystrophies (304 patients, detection rate 61.2 %), we treated 23 index patients with hereditary retinal diseases (detection rate 69.6 %), 28 index patients with complex mal- formations (detection rate 50 %) and 15 index patients with optic atrophies (detection rate 33.4 %). In addition to the ophthalmological-clinical examination and diagnostics, ge- nealogical analysis and molecular genetic testing were always performed. Results. On the basis of 3 case studies with a molecularly ge- netically proven hereditary retinal disease (X-linked recessive inherited juvenile retinoschisis, hemizygous missense muta- tion in the RS1 gene; enhanced S-Cone syndrome, compound heterozygous mutation in the RS2E3 gene; oculocutaneous albinism, homozygous mutation in the TYR gene), the inher- itance, the clinical picture, the course and the therapeutic and rehabilitative options were explained. Conclusion. Ophthalmogenetic counselling and diagnostics in cases of suspected hereditary eye diseases are crucial for a prompt and a sufficient possible therapy and optical reha- bilitation in affected families. Thorough history analysis and diagnostics can optimise the detection rate and provide rapid and sufficient patient care. Keywords hereditary retinal disease, homozygous mutation, ophthal- mogenetics, juvenile retinischisis, oculocutaneous albinism

Роль молекулярно-генетического исследования в диагностике наследственного полипозного синдрома

To determine the molecular genetic cause of the disease in a patient with colon oligopolyposis, whole exome sequencing was performed. The c.333+5G/C variant was detected in the BMPR1A gene. The functional significance of the found variant was elucidated, which demonstrated exon elongation at the mRNA level. This made it possible to confirm the diagnosis of juvenile polyposis in the patient. Keywords: oligopolyposis, NGS, BMPR1A gene, mRNA, cDNA, reverse transcription.

Diagnosis and treatment of Wilson disease: An update

Wilson’s illness is an autosomal dominant impairment of copper metabolism that results from the lack of or dysfunction of a copper-transporting P-type ATPase, which is expressed on chromosome 13. This ATPase is a component of the trans-Golgi network and is carried by hepatocytes. It transports copper into the secretory route where it is combined with ceruloplasmin and excreted as bile. Affected people gradually develop copper accumulation in the liver since the only pathway for copper excretion in physiological settings is through biliary clearance. Hepatocytes experience cell death when their storage capacity is exceeded, which causes hemolysis, copper leakage into the plasma, and tissue deposition. Children might experience rapid liver failure, silent cirrhosis, or chronic hepatitis. Among the neuropsychiatric symptoms induced by copper overload in the central nervous system that are frequently seen in young people are dystonia, tremors, temperamental disorders, and cognitive deficiencies. Test results showing lower ceruloplasmin levels in serum, elevated urine copper concentration, and elevated intrahepatic copper percentage indicate Wilson’s illness. Because there are more than 100 distinct mutations and most people are compound heterozygotes, molecular genetic analysis is difficult. Copper treatment with penicillamine is a successful therapy for the vast number of patients, and liver transplantation is beneficial in situations of chronic liver failure. The molecular genetic causes of Wilson’s disease have shed new light on the mechanisms governing cellular copper homeostasis.

Hereditary etiology of non-syndromic sensorineural hearing loss in the Republic of North Ossetia-Alania.

More than 50% of congenital hearing loss is hereditary, in which the majority form is non-syndromic. In this study we estimate the most prevalent pathogenic genetic changes in an Ossetian cohort of patients. This is useful for local public health officials to promote genetic counseling of affected families with regard to high allele frequencies of prevalent pathogenic variants and assortative mating in the community of people with hearing loss. In this study, genetic heterogeneity of hereditary non-syndromic sensorineural hearing loss (NSNHL) in a cohort of 109 patients and an assessment of the frequency of two GJB2 gene pathogenic variants in a cohort of 349 healthy individuals from the populations of the Republic of North Ossetia-Alania (RNO-Alania) were assessed. The molecular genetic cause of NSNHL in the GJB2 gene in RNO-Alania was confirmed in ~30% of the cases, including ~27% in Ossetians. In Russian patients, the most frequent variant is GJB2:c.35delG (~83%). The GJB2:c.358_360delGAG variant was found to be the most frequent among Ossetians (~54%). Two genetic variants in GJB2, c.35delG and c.358_360delGAG, accounted for 91% of GJB2 pathogenic alleles in the Ossetian patients. A search for large genome rearrangements revealed etiological cause in two Ossetian patients, a deletion at the POU3F4 gene locus associated with X-linked hearing loss (type DFNX2). In another Ossetian patient, a biallelic pathogenic variant in the MYO15A gene caused hearing loss type DFNB3 was identified, and in one Russian family a heterozygous MYH14 gene variant associated with dominant NSNHL was found. Thus, the informative value of the diagnosis was ~37% among all patients with NSNHL from RNO-Alania and ~32% among the Ossetians. These estimates correspond to the literature data on the fraction of recessive genetic forms of hearing loss within the affected population. The importance of this study consists not only in the estimation of the most prevalent pathogenic genetic changes in the Ossetian cohort of patients which could be useful for the public health but also in the genetic counselling of the affected families with regard to the high allele frequencies of revealed pathogenic variants as well as to the assortative mating in community of people with hearing loss.