scholarly journals Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Anna Skorczyk-Werner ◽  
Zuzanna Niedziela ◽  
Marcin Stopa ◽  
Maciej Robert Krawczyński
Keyword(s):  
Gene Therapy ◽  
Molecular Genetic ◽  
Retinal Disease ◽  
Severe Form ◽  
Gene Variants ◽  
Genetic Characteristics ◽  
Leber Congenital Amaurosis ◽  
Pathogenic Variants ◽  
Intronic Mutation ◽  
Novel Variants

Abstract Background Leber congenital amaurosis (LCA) is a rare retinal disease that is the most frequent cause of congenital blindness in children and the most severe form of inherited retinal dystrophies. To date, 25 genes have been implicated in the pathogenesis of LCA. As gene therapy is becoming available, the identification of potential treatment candidates is crucial. The aim of the study was to report the molecular basis of Leber congenital amaurosis in 22 Polish families. Methods Single Nucleotide Polymorphism-microarray for LCA genes or Next Generation Sequencing diagnostic panel for LCA genes (or both tests) were performed to identify potentially pathogenic variants. Bidirectional Sanger sequencing was carried out for validation and segregation analysis of the variants identified within the families. Results The molecular background was established in 22 families. From a total of 24 identified variants, 23 were predicted to affect protein-coding or splicing, including 10 novel variants. The variants were identified in 7 genes: CEP290, GUCY2D, RPE65, NMNAT1, CRB1, RPGRIP1, and CRX. More than one-third of the patients, with clinical LCA diagnosis confirmed by the results of molecular analysis, appeared to be affected with a severe form of the disease: LCA10 caused by the CEP290 gene variants. Intronic mutation c.2991+1655A>G in the CEP290 gene was the most frequent variant identified in the studied group. Conclusions This study provides the first molecular genetic characteristics of patients with Leber congenital amaurosis from the previously unexplored Polish population. Our study expands the mutational spectrum as we report 10 novel variants identified in LCA genes. The fact that the most frequent causes of the disease in the studied group of Polish patients are mutations in one out of three genes that are currently the targets for gene therapy (CEP290, GUCY2D, and RPE65) strongly emphasizes the importance of the molecular background analyses of LCA in Polish patients.

Clinical and genetic characteristics of rare pathogenic variants of the CFTR gene in Russian patients with cystic fibrosis

2021 ◽  
Vol 31 (2) ◽  
pp. 148-158
Author(s):  
A. Yu. Voronkova ◽  
Yu. L. Melyanovskaya ◽  
N. V. Petrova ◽  
T. A. Adyan ◽  
E. K. Zhekaite ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Variants ◽  
Pancreatic Insufficiency ◽  
Protein Energy Malnutrition ◽  
Molecular Genetic ◽  
Clinical Manifestations ◽  
Cftr Gene ◽  
Genetic Characteristics ◽  
Missense Variants ◽  
Pathogenic Variants

The variety of clinical manifestations of cystic fibrosis is driven by the diversity of the CFTR gene nucleotide sequence. Descriptions of the clinical manifestations in patients with the newly identified genetic variants are of particular interest.The aim of this study was to describe clinical manifestations of the disease with the newly identified genetic variants.Methods. Data from Registry of patients with cystic fibrosis in the Russian Federation (2018) were used. The data review included three steps — the search for frequent mutations, Sanger sequencing, and the search for extensive rearrangements by MLPA. 38 pathogenic variants were identified that were not previously described in the international CFTR2 database. We selected and analyzed full case histories of 15 patients with 10 of those 38 pathogenic variants: p.Tyr84*, G1047S, 3321delG, c.583delC, CFTRdele13,14del18, CFTRdele19-22, c.2619+1G>A, c.743+2T>A, p.Glu1433Gly, and CFTRdel4-8del10-11.Results. A nonsense variant p.Tyr84* was found in 5 patients (0.08 %). Two missense variants c.3139G>A were found in 2 siblings (0.03 %). The c.4298A>G was found in 1 patient. Other variants were detected in a single patient (0.02 %) each. They included two variants of a deletion with a shift of the reading frame 3321delG and c.583delC, two splicing disorders c.2619+1G>A and c.743+2T>A, three extended rearrangements CFTRdele19-22, CFTRdele13,14del18, and CFTRdel4-8del10-11. The last two variants include 2 rearrangements on one allele, which cause the severe course in two young children. 8 of the 10 variants are accompanied by pancreatic insufficiency (PI). Among patients with p.Tyr84*, one had ABPA, one had liver transplantation, and all had Pseudomonas aeruginosa infection. Nasal polyps were diagnosed in 2 patients with p.Tyr84*, 1 with G1047S, 1 with CFTRdel4-8del10-11, and 1 patient with 3321delG, who also had osteoporosis and cystic fibrosis-related diabetes (CFRD). 2 patients with PI with 3321delG and CFTRdel4-8del10-11 genetic variants, and 1 with PI with p.Glu1433Gly genetic variant had severe protein-energy malnutrition (PEM).Conclusion. Clinical manifestations of previously undescribed CFTR genetic variants were described. 5/10 genetic variants should be attributed to class I, 3/10 – to class 7 of the function classification of pathogenic CFTR gene variants associated with transcription and translation disruptions. Class of the identified missense variants c.3139G>A and c.4298A>G has not been established and requires further functional, cultural, and molecular genetic studies.

Biallelic mutations in USP45, encoding a deubiquitinating enzyme, are associated with Leber congenital amaurosis

2018 ◽  
Vol 56 (5) ◽  
pp. 325-331 ◽  
Author(s):  
Zhen Yi ◽  
Jiamin Ouyang ◽  
Wenmin Sun ◽  
Xueshan Xiao ◽  
Shiqiang Li ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Genetic Defect ◽  
Clinical Analysis ◽  
Severe Form ◽  
Allele Frequencies ◽  
Mice Model ◽  
Zebrafish Model ◽  
Leber Congenital Amaurosis ◽  
Pathogenic Variants ◽  
Biallelic Mutations

BackgroundLeber congenital amaurosis (LCA) is the earliest and most severe form of inherited retinal dystrophies. In approximately 56% of Chinese probands, genetic defects can be detected in known LCA-causing genes. In this study, the objective was to identify pathogenic variants in two unsolved Chinese families with LCA.MethodsTo identify the genetic defect, whole-exome sequencing (WES) and clinical analysis was performed in both probands with LCA as well as in 3011 in-house controls with other hereditary eye diseases. The expression profiles, as well as the phenotype analysis of knockdown zebrafish model and knockout mice model, were performed to investigate the function of USP45 in photoreceptors.ResultsBy analysing WES data based on allele frequencies of in-house controls, population allele frequencies and in silico prediction tools, two rare homozygous mutations in USP45 were identified in two unrelated families. Immunohistochemistry of USP45 in the human and zebrafish retinal sections revealed enriched expression in the inner segments of photoreceptors. The knockdown of usp45 transcript in zebrafish led to abnormal retinal development with effects on photoreceptors, which could be successfully rescued by wild-type usp45 mRNA. Moreover, targeted knockout of Usp45 in mice caused abnormal electroretinography responses, similar to that seen in patients with LCA.ConclusionsOur study implicates that biallelic mutations in USP45 are associated with the occurrence of LCA. Moreover, our results indicate that USP45 is indispensable to the maintenance of photoreceptor function.

scholarly journals RPE65-associated inherited retinal diseases: consensus recommendations for eligibility to gene therapy

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Andrea Sodi ◽  
Sandro Banfi ◽  
Francesco Testa ◽  
Michele Della Corte ◽  
Ilaria Passerini ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Correct Diagnosis ◽  
Clinical Manifestations ◽  
Retinal Disease ◽  
Diagnostic Algorithm ◽  
Steering Committee ◽  
Correct Identification ◽  
Extensive Experience ◽  
Genetic Characteristics ◽  
Consensus Recommendations

Abstract Background This research aimed to establish recommendations on the clinical and genetic characteristics necessary to confirm patient eligibility for gene supplementation with voretigene neparvovec. Methods An expert steering committee comprising an interdisciplinary panel of Italian experts in the three fields of medical specialisation involved in the management of RPE65-associated inherited retinal disease (IRD) (medical retina, genetics, vitreoretinal surgery) proposed clinical questions necessary to determine the correct identification of patients with the disease, determine the fundamental clinical and genetics tests to reach the correct diagnosis and to evaluate the urgency to treat patients eligible to receive treatment with voretigene neparvovec. Supported by an extensive review of the literature, a series of statements were developed and refined to prepare precisely constructed questionnaires that were circulated among an external panel of experts comprising ophthalmologists (retina specialists, vitreoretinal surgeons) and geneticists with extensive experience in IRDs in Italy in a two-round Delphi process. Results The categories addressed in the questionnaires included clinical manifestations of RPE65-related IRD, IRD screening and diagnosis, gene testing and genotyping, ocular gene therapy for IRDs, patient eligibility and prioritisation and surgical issues. Response rates by the survey participants were over 90% for the majority of items in both Delphi rounds. The steering committee developed the key consensus recommendations on each category that came from the two Delphi rounds into a simple and linear diagnostic algorithm designed to illustrate the patient pathway leading from the patient’s referral centre to the retinal specialist centre. Conclusions Consensus guidelines were developed to guide paediatricians and general ophthalmologists to arrive at the correct diagnosis of RPE65-associated IRD and make informed clinical decisions regarding eligibility for a gene therapy approach to RPE65-associated IRD. The guidelines aim to ensure the best outcome for the patient, based on expert opinion, the published literature, and practical experience in the field of IRDs.

scholarly journals An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs

2020 ◽  
Vol 29 (13) ◽  
pp. 2250-2260 ◽  
Author(s):  
Nicola Bedoni ◽  
Mathieu Quinodoz ◽  
Michele Pinelli ◽  
Gerarda Cappuccio ◽  
Annalaura Torella ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Autosomal Recessive Disorder ◽  
Severe Form ◽  
Chromosome 1 ◽  
Whole Genome ◽  
Leber Congenital Amaurosis ◽  
Pathogenic Variants ◽  
Long Read ◽  
Biallelic Mutations

Abstract We investigated the genetic origin of the phenotype displayed by three children from two unrelated Italian families, presenting with a previously unrecognized autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA), as well as some brain anomalies that were visible at the MRI. Autozygome-based analysis showed that these children shared a 4.76 Mb region of homozygosity on chromosome 1, with an identical haplotype. Nonetheless, whole-exome sequencing failed to identify any shared rare coding variants, in this region or elsewhere. We then determined the transcriptome of patients’ fibroblasts by RNA sequencing, followed by additional whole-genome sequencing experiments. Gene expression analysis revealed a 4-fold downregulation of the gene NMNAT1, residing indeed in the shared autozygous interval. Short- and long-read whole-genome sequencing highlighted a duplication involving 2 out of the 5 exons of NMNAT1 main isoform (NM_022787.3), leading to the production of aberrant mRNAs. Pathogenic variants in NMNAT1 have been previously shown to cause non-syndromic Leber congenital amaurosis (LCA). However, no patient with null biallelic mutations has ever been described, and murine Nmnat1 knockouts show embryonic lethality, indicating that complete absence of NMNAT1 activity is probably not compatible with life. The rearrangement found in our cases, presumably causing a strong but not complete reduction of enzymatic activity, may therefore result in an intermediate syndromic phenotype with respect to LCA and lethality.

scholarly journals Molecular genetic features of the development of restrictive cardiomyopathy in Russian children

2021 ◽  
Vol 26 (10) ◽  
pp. 4590
Author(s):  
K. V. Savostyanov ◽  
E. N. Basargina ◽  
E. E. Ryabova ◽  
A. A. Pushkov ◽  
I. S. Zhanin ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Clinical Symptoms ◽  
Massively Parallel Sequencing ◽  
Molecular Genetic ◽  
Restrictive Cardiomyopathy ◽  
Common Mutation ◽  
Genetic Characteristics ◽  
Pathogenic Variants ◽  
Significant Difference ◽  
Restrictive Type

Aim. To identify the proportion of restrictive cardiomyopathy (RCM), as well as cardiomyopathy (CMP) with a restrictive type of hemodynamics among all cases of genetic CMP and to determine the relative frequencies and spectrum of nucleotide variants in Russian children with RCM, as well as to search for phenogenotypic correlations.Material and methods. The study included 689 children with CMPs. All children underwent a molecular genetic testing of the target regions of 419 genes responsible for various cardiomyopathies and channelopathies using the method of massively parallel sequencing (MPS).Results. In 668 (97,0%) children, pathogenic, likely pathogenic nucleotide variants, as well as nucleotide variants with unknown clinical significance, were identified. Of these, 45 (6,7%) patients were selected to determine the molecular genetic characteristics of RCM, 20 of whom had clinical symptoms and morphofunctional structure of RCMP (3,0%), while the remaining 25 (3,7%) children were diagnosed with another CMP type with a restrictive type of hemodynamics. In total, these patients had 41 nucleotide variants in 15 different genes, while 19 (46,3%) variants were pathogenic, 12 (29,3%) — likely pathogenic, 10 (24,4%) — uncertain clinical significance. Pathogenic and likely pathogenic variants were identified in a total of 38 (84,4%) patients, while in 19 (42,2%) patients, the pathogenic variants described earlier were found. The most common genetic marker of RCM in Russian children was TNNI3 gene mutations. In total, they were identified in 12 (25%) children: with RCP — 8 (40%) patients; with CMP with a restrictive type of hemodynamics — 4 (16%) patients. At the same time, the most common mutation of the TNNI3 gene was the nucleotide variant c.575G>A, leading to the amino acid variant p.R192H, described earlier in patients with RCM and identified by us in three (15%) unrelated children with RCM. In addition, a significant difference was found between the averaged values of N-terminal pro-brain natriuretic peptide in patients with mutations in the MYH7 and TNNI3 genes (0,0039, p<0,05), as well as between the peak flow gradient values in children with mutations in TNNI3 and FLNC genes (0,0016, p<0,05), TNNI3 and MYH7 genes (0,039, p<0,05).Conclusion. The results of this study indicate a significant genetic heterogeneity of RCM in Russian children and the need for further research aimed at finding genotype-phenotype associations in order to predict the course of the disease and select the proper therapy.

scholarly journals SARS-CoV-2 spike protein gene variants with N501T and G142D mutation dominated infections in minks in the US

2021 ◽  
Author(s):  
Hugh Y. Cai ◽  
Allison Cai
Keyword(s):  
Protein Gene ◽  
Human Infection ◽  
Spike Protein ◽  
Gene Variants ◽  
The Novel ◽  
Genetic Characteristics ◽  
Novel Variants ◽  
The Us

AbstractLarge number of minks were infected with SARS-CoV-2 virus containing the spike protein Y453F mutation in Europe, causing zoonosis concerns. To evaluate the genetic characteristics of the US and Canadian mink-derived SARS-CoV-2 sequences, we analyzed all animal-derived (977), all Canadian (19,529) and US (173,277) SARS-CoV-2 sequences deposited in GISAID from December 2019 to March 12, 2021, and identified 2 dominant novel variants, the N501T-G142D variant and N501T-G142D-F486L variant, in the US mink-derived SARS-CoV-2 sequences. These variants were not found in minks from Canada or other countries. The Y453F mutation was not identified in the mink-derive sequences in the US and Canada. The N501T mutation occurred two months earlier in the human than in the minks in the US, and the novel N501T-G142D variant and N501T-G142D-F486L variant were found in human prior to minks. The result of this study indicates that the novel variants may have evolved during human infection and then transmitted to mink populations in the US.

scholarly journals Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8

2018 ◽  
Vol 103 (3) ◽  
pp. 390-397 ◽  
Author(s):  
Kaoru Fujinami ◽  
Rupert W Strauss ◽  
John (Pei-Wen) Chiang ◽  
Isabelle S Audo ◽  
Paul S Bernstein ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Stargardt Disease ◽  
Genetic Characteristics ◽  
Mild Phenotype ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Significant Difference ◽  
Novel Variants ◽  
The Usa ◽  
Subsequent Comparison

Background/aimsTo describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease 1 (STGD1) studies (ProgStar) and to determine geographic differences based on the allele frequency.Methods345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and in silico analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele.Results211 likely pathogenic variants were identified in the total cohort, including missense (63%), splice site alteration (18%), stop (9%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15%), p.G863A (7%) and c.5461-10 T>C (5%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants.ConclusionsThere is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants.

scholarly journals Molecular Therapies for Choroideremia

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 738 ◽  
Author(s):  
Jasmina Cehajic Kapetanovic ◽  
Alun R. Barnard ◽  
Robert E. MacLaren
Keyword(s):  
Gene Therapy ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
Retinal Disease ◽  
Phase Iii ◽  
Nonsense Suppression ◽  
Inherited Retinal Disease ◽  
Molecular Therapies ◽  
Restoration Strategies

Advances in molecular research have culminated in the development of novel gene-based therapies for inherited retinal diseases. We have recently witnessed several groundbreaking clinical studies that ultimately led to approval of Luxturna, the first gene therapy for an inherited retinal disease. In parallel, international research community has been engaged in conducting gene therapy trials for another more common inherited retinal disease known as choroideremia and with phase III clinical trials now underway, approval of this therapy is poised to follow suit. This chapter discusses new insights into clinical phenotyping and molecular genetic testing in choroideremia with review of molecular mechanisms implicated in its pathogenesis. We provide an update on current gene therapy trials and discuss potential inclusion of female carries in future clinical studies. Alternative molecular therapies are discussed including suitability of CRISPR gene editing, small molecule nonsense suppression therapy and vision restoration strategies in late stage choroideremia.

scholarly journals Two Novel Compound Heterozygous Pathogenic Variants in P2YR12 gene

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1154-1154
Author(s):  
Arnaud Dupuis ◽  
Doris Böckelmann ◽  
Patricia Laeuffer ◽  
Katharina Neubauer ◽  
Christian Gachet ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Platelet Aggregation ◽  
Molecular Genetic ◽  
Index Patient ◽  
Molecular Genetic Analysis ◽  
Compound Heterozygous ◽  
Twin Brother ◽  
Pathogenic Variants ◽  
Fibrinogen Binding ◽  
Novel Variants

Abstract Introduction: P2Y12 receptor (P2Y12R) defect is a rare hemorrhagic disorder characterized by mild to moderate bleeding diathesis with easy bruising, mucosal bleedings, and excessive post-operative hemorrhage. It is due to mutations of the P2YR12 gene resulting in impairment of platelet responses to adenosine 5'-diphosphate (ADP) and subsequently to any other agonist as ADP is secreted from the dense granules during platelet activation. The P2Y12R plays a key role in platelet aggregation by amplifying the platelet activation process which is necessary to ensure appropriate primary hemostasis. The activation of the P2Y12R by ADP results in inhibition of adenylyl cyclase (AC) and in activation of phosphoinositide 3-kinase (PIK3), which amplifies and sustains the platelet aggregation response. To date only 12 pathogenic variants in the P2YR12 gene are listed in the Human Gene Mutation Database (HGMD®) (10 missense/nonsense mutations and 2 small deletions). Seven missense mutations are described in the literature in patients suffering from bleeding disorders of various severity. Autosomal recessive (homozygous and compound heterozygous pathogenic variants) as well as autosomal dominant (only one heterozygous pathogenic variant) inheritance has been reported. Patients and Methods: We investigated an 8 year old index patient who came to our outpatient clinic to investigate an increased bleeding tendency. He suffered from easy bruising and reported increased bleeding after tonsillectomy. His twin brother was also affected regarding bleeding disorder. Their father suffered sometimes from epistaxis, their mother and three older siblings were clinically unaffected. Platelet functions were assessed by light transmission aggregometry using citrated PRP. Membrane glycoprotein quantification, fibrinogen binding, von Willebrand factor (VWF) binding and the VASP assay were performed by flow cytometry. Molecular genetic analysis (Sanger sequencing) was performed for all exons including UTR regions and splice sites of the P2RY12-gene (NM_002788.4) for the twins and their parents. Results: The index patient and his brother showed normal values for platelet count, aPTT, INR, FXIII and VWF parameters. Both twins showed impaired platelet aggregation after stimulation with collagen, ADP and epinephrine. For both the index patient and his twin brother ADP (4-20 µM and 4-10 µM respectively) induced aggregation was markedly reduced and rapidly reversible. Flow cytometry revealed severely decreased fibrinogen binding for the index patient and his twin brother after stimulation with ADP (0.25-5.0 μmol/l) compared to control platelets. For CD42a/b (GP Ib/IX-complex), CD41 (GP IIb/IIIa-complex), ristocetin-induced VWF-binding, CD62- and CD63-expression, normal values were measured. The VASP assay revealed a strong defect with a PRI value of patient's platelets as low as 1.2% and 1% respectively (normal range > 69%). Molecular genetic analysis revealed two novel variants in the P2YR12 coding sequence (Tab.1). Conclusion: We have identified two novel variants in the P2YR12 gene with pathogenic predictions in a compound heterozygous state in twin brothers suffering from a chronic bleeding disorder. Flow cytometry analyses (fibrinogen binding) and VASP analyses are valuable tools to diagnose a platelet ADP-receptor defect. Table Table. Disclosures No relevant conflicts of interest to declare.

Clinical application of polymorphic variants of the genes ESR1 and CYP2D6*4 in patients with breast and endometrial cancer

2017 ◽  
pp. 132-138
Author(s):  
O.V. Paliychuk ◽  
◽  
L.Z. Polishchuk ◽  
Z.I. Rossokha ◽  
◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endometrial Cancer ◽  
Hormone Therapy ◽  
Molecular Genetic ◽  
Cancer Syndrome ◽  
Genetic Characteristics ◽  
Multiple Tumors ◽  
Receptor Status ◽  
Genetic Examination ◽  
The Impact

The objective: determining gene polymorphism features ERS1, CYP2D6 in patients with breast cancer (RHZ) and endometrial cancer (EC) and the impact assessment studied genetic characteristics compared to receptor status (immunohistochemical determination of expression levels of ER, PR) tumors and the results of the treatment. Patients and methods. article presents the results of complex clinical, morphological, clinical-genealogical, and molecular-genetic examination of 28 females: 19 patients with breast cancer (BC), 9 patients with endometrial cancer (EC), including 5 patients with primary-multiple tumors (PMT) with and without tumor pathology aggregation in families. Results. The It was determined that in patients’ families malignant tumors of breast, uterine body and/or ovaries prevail that corresponds to Lynch type II syndrome (family cancer syndrome). Molecular-genetic examination of genomic DNA of peripheral blood and histological sections for the presence of SNPs of ESR and CYP2D6*4 genes comparing with the results of immunohistochemical study of tumors for receptors ER and PR status have not found associations between these characteristics; although among EC patients the occurrence of genotypes 397ТТ and 351АА was significantly higher comparing with BC patients (55.55% and 10.5% for genotype 397ТТ,and 15.8% for genotype 351АА, respectively). At the same time the patients with BC and primary-multiple tumors (PMT) of female reproductive system organs (FRSO) that carried mutations in BRCA1 in all the cases demonstrated positive ER and PR receptor status and adverse combinations of polymorphous variants of the genes ESR1 (397СС, 397ТС) and CYP2D6*4 (1846G, 1846GA), suggesting combined effect of these factors on the development of malignant neoplasias of FRSO in families with positive family cancer history. In BC patients, receiving standard hormone therapy with tamoxifen, those, who had genotype 1846GG of the gene CYP2D6*4, in 3 patients (15.8%) of 19 (100%) patients disease recurrence was diagnosed. Conclusion. The obtained results allow clinical use of the assessment of polymorphism frequency of the genes ESR1 and CYP2D6*4 for selection of individual hormone therapy regimens schemes for BC patients, to increase efficacy of dispensary observation after finishing of special therapy for such patients, and also personalization of complex and combined treatment regimens. Key words: breast cancer, endometrial cancer, family cancer syndrome, single nucleotide polymorphisms (SNPs) of the genes ESR1, CYP2D6*4.

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