Browsing by Author "Miskova, Anna"
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Item Acute Cholecystitis in pregnancy: a case report(2021) Bordo, Zanis; Berzina, Arta; Miskova, Anna; Zeiza, KasparsItem Appearance of Growth Factors, Genes and Their Products in Cases of Human Embryo Tubal and Intrauterine Implantation. Summary of the Doctoral Thesis(Rīga Stradiņš University, 2012) Miskova, Anna; Pilmane, Māra; Rezeberga, DaceThis promotion work deals with the basic points of pregnancy existence, such as embryo implantation, further trophoblast invasion and formation of placenta. It could be possible that fertilized oocyte implantation depends on relation between embryo and endometrial or fallopian tube cells. Molecular signalling at the time of blastocyst nidation could probably be the key to explain normal and abnormal implantation. Growth factors are important for regulation of a variety of cellular processes and typically act as signalling molecules between the cells. The role of growth factors in aetiology of ectopic pregnancy has not been yet clearly established. The aim of this study was to analyze the role of growth factors, their receptors and some genes in human embryo, endometrial and oviduct tissues in a case of uterine or tubal pregnancy. We used biotin–streptavidin method for determination of growth factors and their receptors, Barx1, Msx2 and TUNEL for evaluation of apoptotic cells. The distribution of these factors was detected semi quantitatively. The data was analyzed by nonparametric rank analysis with SPSS Statistic 17 software. A Mann-Whitney U test was used as appropriate for evaluation of significant differences. A p value <0.05 was considered as statistically significant. The Promotion work has been elaborated with ESF project support “Support for doctoral and post-doctoral investigations Riga Stradins University”.Item Augšanas faktoru, gēnu un to produktu sadalījums I trimestrī cilvēka embriju implantācijas gadījumos olvadā un dzemdē. Promocijas darba kopsavilkums(Rīgas Stradiņa universitāte, 2012) Miskova, Anna; Pilmane, Māra; Rezeberga, DaceŠajā promocijas darbā ir aplūkoti un analizēti ļoti nozīmīgi procesi, kas attiecas uz grūtniecības iestāšanās iespējamību un tās saglabāšanu pēc embrija implantācijas ar turpmāko trofoblasta invāziju un funkcionējošas placentas formēšanos. Iespējams, ka blastocistas implantācijas vieta ir atkarīga no izdalīto augšanas faktoru mijiedarbības ar mātes audiem, kas nosaka tiešu implantācijas lokalizāciju un turpmāko embrija attīstību. Augšanas faktori ir nozīmīgi šūnu proliferācijas, migrācijas un diferenciācijas procesos, bet pareiza noteiktu gēnu ekspresija vai „klusēšana” koordinē cilvēka embrija attīstību. Dažādas implantācijas gadījumos augšanas un transkripcijas faktoru sadale ir maz izpētīta, nav noteikta faktoru nozīme olvada grūtniecības morfopatoģenēzē. Dotā darba mērķis bija izpētīt dažādu augšanas faktoru, gēnu un to produktu ekspresijas sadalījumu cilvēka embrija, olvada un endometrija audos pirmajā trimestrī, kā arī augšanas faktoru un gēnu nozīmi nepareizas blastocistas implantācijas patoģenēzē. Darbā tika lietota biotīna – streptavidīna imūnhistoķīmijas metode augšanas faktoru, to receptoru, Msx2, BARX1 un cilvēka defensīna beta 2 sadalījuma noteikteikšanai audos. Apoptozes noteikšanai tika izmantota TUNEL metode. Imūnhistoķīmiski noteikto struktūru relatīvā biežuma apzīmēšanai tika lietota puskvantitatīvās skaitīšanas metode. Iegūto datu puskvantitatīvai izvērtēšanai tika izmantotas neparametriskās statistikas metodes (ar SPSS Statistic 17 datorprogrammas palīdzību): Manna-Vitnija (Mann-Whitney) tests. Rezultāti tika uzskatīti par ticamiem, ja p<0,05. Promocijas darbs veikts ar ESF nacionālās programmas „Atbalsts doktorantūras un pēc doktorantūras pētījumiem medicīnas zinātnēs” atbalstu.Item Augšanas faktoru, gēnu un to produktu sadalījums I trimestrī cilvēka embriju implantācijas gadījumos olvadā un dzemdē. Promocijas darbs(Rīgas Stradiņa universitāte, 2012) Miskova, Anna; Pilmane, Māra; Rezeberga, DaceŠajā promocijas darbā ir aplūkoti un analizēti ļoti nozīmīgi procesi, kas attiecas uz grūtniecības iestāšanās iespējamību un tās saglabāšanu pēc embrija implantācijas ar turpmāko trofoblasta invāziju un funkcionējošas placentas formēšanos. Iespējams, ka blastocistas implantācijas vieta ir atkarīga no izdalīto augšanas faktoru mijiedarbības ar mātes audiem, kas nosaka tiešu implantācijas lokalizāciju un turpmāko embrija attīstību. Augšanas faktori ir nozīmīgi šūnu proliferācijas, migrācijas un diferenciācijas procesos, bet pareiza noteiktu gēnu ekspresija vai „klusēšana” koordinē cilvēka embrija attīstību. Dažādas implantācijas gadījumos augšanas un transkripcijas faktoru sadale ir maz izpētīta, nav noteikta faktoru nozīme olvada grūtniecības morfopatoģenēzē. Dotā darba mērķis bija izpētīt dažādu augšanas faktoru, gēnu un to produktu ekspresijas sadalījumu cilvēka embrija, olvada un endometrija audos pirmajā trimestrī, kā arī augšanas faktoru un gēnu nozīmi nepareizas blastocistas implantācijas patoģenēzē. Darbā tika lietota biotīna – streptavidīna imūnhistoķīmijas metode augšanas faktoru, to receptoru, Msx2, BARX1 un cilvēka defensīna beta 2 sadalījuma noteikšanai audos. Apoptozes noteikšanai tika izmantota TUNEL metode. Imūnhistoķīmiski noteikto struktūru relatīvā biežuma apzīmēšanai tika lietota puskvantitatīvās skaitīšanas metode. Iegūto datu puskvantitatīvai izvērtēšanai tika izmantotas neparametriskās statistikas metodes (ar SPSS Statistic 17 datorprogrammas palīdzību): Manna-Vitnija (Mann-Whitney) tests. Rezultāti tika uzskatīti par ticamiem, ja p<0,05. Promocijas darbs veikts ar ESF nacionālās programmas „Atbalsts doktorantūras un pēc doktorantūras pētījumiem medicīnas zinātnēs” atbalstu.Item Causes and Genomic Approaches to Female Reproductive Failure. Doctoral Thesis(Rīga Stradiņš University, 2021) Voložonoka, Ludmila; Miskova, Anna; Kempa, IngaClinical recognition of the genetic causes of female reproductive failure using increasingly advancing genetic technologies to preserve patient safety and move towards personalized treatment application is a major challenge of reproductive medicine in the 21st century. The aim of this thesis was to demonstrate a reliable application of advanced genomic techniques in different stages of female reproductive failure in real-life clinical or research scenarios. Several genetic approaches were exploited – starting from the multifactor genetic testing of preimplantation embryos to select the ones free of inherited monogenic conditions and chromosomal aberrations, then following with the analysis of fetal material in case of early pregnancy loss using array comparative genomic hybridization and short tandem repeat analysis to exclude maternal cell contamination, and finally using next generation sequencing technology to analyze genetic landscape leading to preterm delivery in women with cervical insufficiency. The practical work described here was published as three scientific articles now forming three chapters of this thesis. Array comparative genomic hybridization combined with loci-specific genetic testing techniques allowed for a versatile and reliable analysis of preimplantation embryos to select the ones free of genetic conditions analyzed, and in combination with microsatellite analysis it also allowed to access the chromosomal causes of early pregnancy loss while reducing the misdiagnosis caused by maternal cell contamination. Next generation sequencing application allowed to identify the disruptive variants potentially contributive to the development of non-syndromic cervical insufficiency. Pathway enrichment analysis of variant genes from our cohort revealed an increased variation burden in genes playing roles in tissue mechanical and biomechanical properties. Literature analysis allowed to conclude that number of genes can be reliably attributed to female reproductive failure and an increasing number of genes form a pool of good candidates. In order to develop diagnostic gene panels and facilitate genetic advancement inclusion in the clinical practice of female reproduction, a standardized clinical gene-disease validity assessment of the identified genes has to be performed and best practice guidelines have to be composed.Item Causes and Genomic Approaches to Female Reproductive Failure. Summary of the Doctoral Thesis(Rīga Stradiņš University, 2021) Voložonoka, Ludmila; Miskova, Anna; Kempa, IngaClinical recognition of the genetic causes of female reproductive failure using increasingly advancing genetic technologies to preserve patient safety and move towards personalized treatment application is a major challenge of reproductive medicine in the 21st century. The aim of this thesis was to demonstrate a reliable application of advanced genomic techniques in different stages of female reproductive failure in real-life clinical or research scenarios. Several genetic approaches were exploited – starting from the multifactor genetic testing of preimplantation embryos to select the ones free of inherited monogenic conditions and chromosomal aberrations, then following with the analysis of fetal material in case of early pregnancy loss using array comparative genomic hybridization and short tandem repeat analysis to exclude maternal cell contamination, and finally using next generation sequencing technology to analyze genetic landscape leading to preterm delivery in women with cervical insufficiency. The practical work described here was published as three scientific articles now forming three chapters of this thesis. Array comparative genomic hybridization combined with loci-specific genetic testing techniques allowed for a versatile and reliable analysis of preimplantation embryos to select the ones free of genetic conditions analyzed, and in combination with microsatellite analysis it also allowed to access the chromosomal causes of early pregnancy loss while reducing the misdiagnosis caused by maternal cell contamination. Next generation sequencing application allowed to identify the disruptive variants potentially contributive to the development of non-syndromic cervical insufficiency. Pathway enrichment analysis of variant genes from our cohort revealed an increased variation burden in genes playing roles in tissue mechanical and biomechanical properties. Literature analysis allowed to conclude that number of genes can be reliably attributed to female reproductive failure and an increasing number of genes form a pool of good candidates. In order to develop diagnostic gene panels and facilitate genetic advancement inclusion in the clinical practice of female reproduction, a standardized clinical gene-disease validity assessment of the identified genes has to be performed and best practice guidelines have to be composed.Item Clinical Case of Pregnancy and Follow-Up of Bartter Syndrome (Type II) with a Novel Mutation(2020-05-18) Lūse, Laura; Vedmedovska, Natālija; Rasnača, Kristīne; Kovale, Sabīne; Rezeberga, Dace; Jansone, Gita; Miskova, Anna; Department of Obstetrics and Gynaecology; Department of PaediatricsBackground: Bartter syndrome is a rare autosomal recessive inherited salt wasting tubulopathy, it`s incidence proportion is 1.2 cases per 1.000.000 live births. The present case - report discusses a clinical case of an antenatal Bartter syndrome (type II) with a novel mutation and it`s course from antenatal presentation to 6 months postpartum.Case Presentation: The case-report discusses a clinical case of an antenatal Bartter syndrome (type II) with a novel homozygous missense variant mutation in KCNJ1 gene: c.554C>T (p. Pro185Leu). Symptoms presented from 24 weeks of pregnancy as premature labour threats, maternal dyspnoea and severe polyhydramnios (amniotic fluid index 36 cm). Therapeutic interventions included use of indomethacin, dexamethasone, micronized progesterone and three consequent amnioreductions. Pregnancy was prolonged until 32 weeks and induced due to severe reoccurring polyhydramnios, progressing maternal dyspnoea and inability to perform next amnioreduction. Labour was complicated by severe placental abruption and new born – boy was referred to neonatal intensive care unit. Neonatal period was complicated by electrolyte abnormalities: hyponatremia, hypochloremic metabolic alkalosis, transient hyperkalaemia that gradually developed into hypokalaemia, hypercalcemia and elevated rennin and aldosterone levels characteristic to type II Bartter syndrome. At 6 months (corrected age 4 months) he is gaining weight within normal ranges and his psychomotor development is ahead of his corrected age, without any need for daily medications.Conclusion: The present case report describes the clinical course of a Bartter syndrome is of high importance, due to the reason that it shows clinical course of patient with novel mutation and offers one of the ways how to manage the disease. The described novel mutation may have favourable prognosis for neonate. The pregnancy should be managed as high-risk pregnancy with expertise in perinatal diagnostics and interventions. Early recognition, and interventions, are and essential to prolong a pregnancy and lessen prematurity complications.Item Immunohistochemical distribution of IGF-1, bFGF and their receptors in decidual, embryonic and tubal human pregnancy tissue(2011) Miskova, Anna; Pilmane, Māra; Rezeberga, Dace; Department of Morphology; Institute of Anatomy and Anthropology; Department of Obstetrics and GynaecologyEmbryo implantation is a complicated process involving mother and conceptus cells differentiation, proliferation and invasion that are essential for successful pregnancy. Almost every cell in the human body is affected by IGF-1 that is one of the most potent natural activators of cell growth and multiplication, and also a potent inhibitor of the programmed cell death. bFGF, acting via its receptor FGFR1, is one of the factors involved in mediating the angiogenesis, proteolysis and apoptosis during the implantation. OBJECTIVE: To establish pregnancy inducted difference of appearance of bFGF, IGF-1 and their receptors in the embryonic, decidual and tubal tissue. STUDY DESIGN: In this study 14 tubal pregnancy and 10 decidual tissue samples were evaluated immunohistochemically in order to define the distribution of bFGF, FGFR1, IGF-1, IGF-1R. RESULTS: The Mann-Whitney U test was used as appropriate for the evaluation of significant differences. FGFR1 appearance dominated on bFGF in the decidual (z=2.539, p=0.01), tubal (z=2.539, p=0.01) and embryonic (z=2.539, p=0.01) tissue. IGF-1 and IGF-1R appearance in the decidual, tubal and embryonic tissue was not statistically different. It was the same as IGF-1 and IGF-1R expression in gravid endometrium, but in the ectopic implantation site IGF-1R was particularly absent (z=1.935, p=0.05), only mesothelium and some epithelial cells stained. CONCLUSION: IGF-1, IGF-1R, bFGF and FGFR1 are widely appearing growth factors in actively developing and differentiating of the human embryonic tissue during the first trimester. Both endometrial and fallopian tube tissues express more FGFR1 than bFGF that testify the stimulation of compensatory adaptation of the organ during pregnancy. IGF-1 and IGF-1R richly appear in gravid endometrium. IGF-1 is widely distributed in both the mother and the embryo tissues but only some of them are IGF-1R marked in a case of ectopic pregnancy. The deficit of IGF-1R in the fallopian tube might be a result of cell growth restriction and the impaired process of trophoblast invasion.Item Impact of Intraoperative Factors on the Development of Postpartum Septic Complications(2023-09) Andzane, Diana; Miskova, Anna; Krone, Antra; Rezeberga, Dace; Department of Clinical Skills and Medical Technologies; Department of Obstetrics and GynaecologyBackground and Objectives: Triclosan-coated sutures (antibacterial sutures) can reduce the risk of postoperative surgical site infection. This study aimed to investigate the effect of intraoperative factors, including antibacterial sutures, on the risk of postpartum septic complications. Materials and Methods: The prospective study included patients who underwent caesarean section. The exclusion criterion was chorioamnionitis. The investigation group patient’s (n = 67) uterus and fascial sheath of the abdominal wall were sutured with triclosan-coated polyglactin 910 sutures during surgery. The control group consisted of 98 patients using uncoated polyglactin 910 sutures only. The patients were contacted by phone after the 30th postoperative day. Results: No significant difference was found between the investigation group and the control group in the development of postpartum endometritis (11.7% in the investigation group vs. 8.4% in the control group, p = 0.401), wound infection (6.3% vs. 3.6%, p = 0.444) or patients experienced any septic complication (15.9% vs. 12%, p = 0.506). Postpartum endometritis was more common in patients who underwent instrumental uterine examination during the surgery (23.8% vs. 18%, p = 0.043). A moderately strong correlation was found for haemoglobin level on the third–fourth postoperative day with the development of postpartum septic complications, p < 0.001, Pearson coefficient −0.319. Post-caesarean delivery septic complications were not statistically more common in patients with blood loss greater than 1 L. The incidence of post-caesarean endometritis was 13.4%, and wound infection was 4.8% in this study’s hospital, having five to six thousand deliveries per year. Conclusions: Using antibacterial sutures during caesarean section does not affect the incidence of postpartum septic complications. Instrumental uterine examination during caesarean section increases the risk of post-caesarean endometritis and is, therefore, not recommended. Haemoglobin level on the 3rd–4th postoperative day, rather than the estimated blood loss during surgery, affects the development of postpartum septic complications.Item Management of Pregnancy with Cervical Shortening: Real-Life Clinical Challenges(2023-03-26) Kornete, Anna; Voložonoka, Ludmila; Zolovs, Maksims; Rota, Adele; Kempa, Inga; Gailīte, Linda; Rezeberga, Dace; Miskova, Anna; Department of Obstetrics and Gynaecology; Scientific Laboratory of Molecular Genetics; Statistics UnitBackground and Objectives: Preterm birth is the leading cause of neonatal mortality worldwide and may be responsible for lifelong morbidities in the survivors. Cervical shortening is one of the common pathways to preterm birth associated with its own diagnostic and management challenges. The preventive modalities that have been tested include progesterone supplementation and cervical cerclage and pessaries. The study aimed to assess the management strategies and outcomes in a group of patients with a short cervix during pregnancy or cervical insufficiency. Materials and Methods: Seventy patients from the Riga Maternity Hospital in Riga, Latvia, were included in the prospective longitudinal cohort study between 2017 and 2021. Patients were treated with progesterone, cerclage, and/or pessaries. The signs of intra-amniotic infection/inflammation were assessed, and antibacterial therapy was given when the signs were positive. Results: The rates of PTB were 43.6% (n = 17), 45.5% (n = 5), 61.1% (n = 11), and 50.0% (n = 1) in progesterone only, cerclage, pessary, and cerclage plus pesssary groups, respectively. The progesterone therapy was associated with a reduced preterm birth risk (x2(1) = 6.937, p = 0.008)), whereas positive signs of intra-amniotic infection/inflammation significantly predicted the risk of preterm birth (p = 0.005, OR = 3.82, 95% [CI 1.31–11.11]). Conclusions: A short cervix and bulging membranes, both indicators of intra-amniotic infection/inflammation, are the key risk factors in preterm birth risk predictions. Progesterone supplementation should remain at the forefront of preterm birth prevention. Among patients with a short cervix and especially complex anamnesis, the preterm rates remain high. The successful management of patients with cervical shortening lies between the consensus-based approach for screening, follow-up, and treatment on the one side and personalising medical therapy on the other.Item Performance comparison of two whole genome amplification techniques in frame of multifactor preimplantation genetic testing(2018-08-01) Volozonoka, Ludmila; Perminov, Dmitry; Korņejeva, Liene; Alkšere, Baiba; Novikova, Natālija; Pīmane, Evija Jokste; Blumberga, Arita; Kempa, Inga; Miskova, Anna; Gailīte, Linda; Fodina, Violeta; Scientific Laboratory of Molecular Genetics; Department of Obstetrics and GynaecologyPurpose: To compare multiple displacement amplification and OmniPlex whole genome amplification technique performance during array comparative genome hybridization (aCGH), Sanger sequencing, SNaPshot and fragment size analysis downstream applications in frame of multifactor embryo preimplantation genetic testing. Methods: Preclinical workup included linked short tandem repeat (STR) marker selection and primer design for loci of interest. It was followed by a family haplotyping, after which an in vitro fertilization preimplantation genetic testing (IVF-PGT) cycle was carried out. A total of 62 embryos were retrieved from nine couples with a confirmed single gene disorder being transmitted in their family with various inheritance traits—autosomal dominant (genes—ACTA2, HTT, KRT14), autosomal recessive (genes—ALOX12B, TPP1, GLB1) and X-linked (genes—MTM1, DMD). Whole genome amplification (WGA) for the day 5 embryo trophectoderm single biopsies was carried out by multiple displacement amplification (MDA) or polymerase chain reaction (PCR)-based technology OmniPlex and was used for direct (Sanger sequencing, fragment size analysis, SNaPshot) and indirect mutation assessment (STR marker haplotyping), and embryo aneuploidy testing by array comparative genome hybridization (aCGH). Results: Family haplotyping revealed informative/semi-informative microsatellite markers for all clinical cases for all types of inheritance. Indirect testing gave a persuasive conclusion for all embryos assessed, which was confirmed through direct testing. The overall allele dropout (ADO) rate was higher for PCR-based WGA, and MDA shows a better genomic recovery scale. Five euploid embryos were subjected to elective single embryo transfer (eSET), which resulted in four clinical pregnancies and birth of two healthy children, which proved free of disease causative variants running in the family postnataly. Conclusions: A developed multifactor PGT protocol can be adapted and applied to virtually any genetic condition and is capable of improving single gene disorder preimplantation genetic testing in a patient-tailored manner thus increasing pregnancy rates, saving costs and increasing patient reliability.Item Sievietes reproduktīvās mazspējas iemesli un genomiskās pieejas to risināšanai. Promocijas darba kopsavilkums(Rīgas Stradiņa universitāte, 2021) Voložonoka, Ludmila; Miskova, Anna; Kempa, IngaSievietes reproduktīvās mazspējas iemesli un genomiskās pieejas to risināšanai Sievietes reproduktīvās mazspējas ģenētisko cēloņu identificēšana, izmantojot mūsdienīgas ģenētiskās tehnoloģijas, vienlaikus saglabājot pacientu drošību un virzoties uz personalizētas ārstēšanas lietošanu, ir reproduktīvās medicīnas izaicinājums 21. gadsimtā. Darba mērķis bija demonstrēt genomisko tehnoloģiju lietojumu dažādos sievietes reproduktīvās mazspējas etapos reālos klīniskajos vai pētījumu apstākļos. Tika lietotas vairākas genomiskās metodoloģijas – pirmsimplantācijas embriju testēšanai, lai atlasītu embrijus bez iedzimtas monogēnas patoloģijas un hromosomālajām aberācijām, salīdzinošā genoma hibridizācija uz mikročipiem un mikrosatelītu analīze augļa hromosomu analīzei pārtraukušās grūtniecības materiālā, nosakot mātes šūnu kontaminācijas klātbūtni paraugā, un, visbeidzot, nākamās paaudzes sekvencēšana dzemdes kakla nepietiekamības izraisītu priekšlaicīgu dzemdību ģenētiskās etioloģijas raksturošanai. Paveiktais praktiskais darbs tika publicēts trijos zinātniskajos rakstos, kas veido trīs darba sadaļas. Salīdzinošā genoma hibridizācija uz mikročipiem apvienojumā ar lokusa ģenētiskās testēšanas metodēm deva iespēju veikt pirmsimplantācijas analīzi, lai atlasītu embrijus bez testētās patoloģijas, savukārt kombinācijā ar mikrosatelītu analīzi ļāva noteikt hromosomālās patoloģijas izraisošas agrīnas grūtniecības pārtraukšanos, vienlaikus mazinot mātes šūnu kontaminācijas izraisītas kļūdainas diagnozes iespēju. Lietojot nākamās paaudzes sekvencēšanu, tika identificēti gēnu varianti, kas potenciāli veicina nesindromiskas dzemdes kakla nepietiekamības attīstību. Gēnu ceļu bagātināšanas analīze atklāja palielinātu gēnu variācijas slogu gēnos, kas nodrošina audu mehānisko un biomehānisko izturību. Literatūras analīze ļauj secināt, ka gēnu skaits ar zināmu ietekmi uz sievietes reproduktīvās mazspējas attīstību nepārtraukti aug un aizvien lielāks gēnu skaits veido labu kandidātu kopu, kas gaida replikācijas pētījumus. Diagnostisko gēnu paneļu klīniskajai izveidei un lietošanai un ģenētisko sasniegumu iekļaušanai sievietes reprodukcijas klīniskajā praksē nepieciešama standartizēta identificēto gēnu klīniskās validitātes novērtēšana un labās prakses vadlīniju izstrāde.Item A systematic review and standardized clinical validity assessment of genes involved in female reproductive failure(2022-04-22) Volozonoka, Ludmila; Miskova, Anna; Kornejeva, Liene; Kempa, Inga; Bargatina, Veronika; Gailite, Linda; Scientific Laboratory of Molecular Genetics; Department of Obstetrics and GynaecologyGenetic testing is becoming increasingly required at almost every stage of failed female reproduction/infertility. Nonetheless, clinical evidence for the majority of identified gene-disease relationships is ill-defined, thus leading to difficult gene variant interpretation and poor translation of existing knowledge into clinics. We aimed to identify the genes that have ever been implicated in monogenic female reproductive failure in humans and to classify the identified gene-disease relationship pairs using a standardized clinical validity assessment. A PubMed search following PRISMA guidelines was conducted on 20 September 2021 aiming to identify studies pertaining to genetic causes of phenotypes of female reproductive failure. The clinical validity of identified gene-disease pairs was assessed using standardized criteria, counting whether sufficient genetic and experimental evidence has been accumulated to consider a single gene 'characterized' for a single Mendelian disease. In total, 1256 articles were selected for the data extraction; 183 unique gene-disease pairs were classified spanning the following phenotypes: hypogonadotropic hypogonadism, ovarian dysgenesis, premature ovarian failure/insufficiency, ovarian hyperstimulation syndrome, empty follicle syndrome, oocyte maturation defect, fertilization failure, early embryonic arrest, recurrent hydatidiform mole, adrenal disfunction and Mullerian aplasia. Twenty-four gene-disease pairs showed definitive evidence, 36 - strong, 19 - moderate, 81 - limited and 23 - showed no evidence. Here, we provide comprehensive, systematic and timely information on the genetic causes of female infertility. Our classification of genetic causes of female reproductive failure will facilitate the composition of up-to-date guidelines on genetic testing in female reproduction, the development of diagnostic gene panels and the advancement of reproductive decision-making.Item Unravelling the genetic landscape of cervical insufficiency : Insights into connective tissue dysfunction and hormonal pathways(2024-09) Voložonoka, Ludmila; Bārdiņa, Līvija; Kornete, Anna; Krūmiņa, Zita; Rots, Dmitrijs; Minkauskienė, Meilė; Rota, Adele; Strelcoviene, Zita; Vilne, Baiba; Kempa, Inga; Miskova, Anna; Gailīte, Linda; Rezeberga, Dace; Rīga Stradiņš UniversityBACKGROUND: The intricate molecular pathways and genetic factors that underlie the pathophysiology of cervical insufficiency (CI) remain largely unknown and understudied. METHODS: We sequenced exomes from 114 patients in Latvia and Lithuania, diagnosed with a short cervix, CI, or a history of CI in previous pregnancies. To probe the well-known link between CI and connective tissue dysfunction, we introduced a connective tissue dysfunction assessment questionnaire, incorporating Beighton and Brighton scores. The phenotypic data obtained from the questionnaire was correlated with the number of rare damaging variants identified in genes associated with connective tissue disorders (in silico NGS panel). SKAT, SKAT-O, and burden tests were performed to identify genes associated with CI without a priori hypotheses. Pathway enrichment analysis was conducted using both targeted and genome-wide approaches. RESULTS: No patient could be assigned monogenic connective tissue disorder neither genetically, neither clinically upon clinical geneticist evaluation. Expanding our exploration to a genome-wide perspective, pathway enrichment analysis replicated the significance of extracellular matrix-related pathways as important contributors to CI's development. A genome-wide burden analysis unveiled a statistically significant prevalence of rare damaging variants in genes and pathways associated with steroids (p-adj = 5.37E-06). Rare damaging variants, absent in controls (internal database, n = 588), in the progesterone receptor (PGR) (six patients) and glucocorticoid receptor (NR3C1) (two patients) genes were identified within key functional domains, potentially disrupting the receptors' affinity for DNA or ligands. CONCLUSION: Cervical insufficiency in non-syndromic patients is not attributed to a single connective tissue gene variant in a Mendelian fashion but rather to the cumulative effect of multiple inherited gene variants highlighting the significance of the connective tissue pathway in the multifactorial nature of CI. PGR or NR3C1 variants may contribute to the pathophysiology of CI and/or preterm birth through the impaired progesterone action pathways, opening new perspectives for targeted interventions and enhanced clinical management strategies of this condition.Item Uterine rupture - clinical analysis of a case series in Riga Maternity Hospital(2018) Smilga, Santa; Miskova, Anna; Rezeberga, Dace; Department of Obstetrics and GynaecologyItem Whole Genome Amplification in Preimplantation Genetic Testing in the Era of Massively Parallel Sequencing(2022-05-01) Voložonoka, Ludmila; Miskova, Anna; Gailīte, Linda; Scientific Laboratory of Molecular Genetics; Department of Obstetrics and GynaecologySuccessful whole genome amplification (WGA) is a cornerstone of contemporary preimplantation genetic testing (PGT). Choosing the most suitable WGA technique for PGT can be particularly challenging because each WGA technique performs differently in combination with different downstream processing and detection methods. The aim of this review is to provide insight into the performance and drawbacks of DOP-PCR, MDA and MALBAC, as well as the hybrid WGA techniques most widely used in PGT. As the field of PGT is moving towards a wide adaptation of comprehensive massively parallel sequencing (MPS)-based approaches, we especially focus our review on MPS parameters and detection opportunities of WGA-amplified material, i.e., mappability of reads, uniformity of coverage and its influence on copy number variation analysis, and genomic coverage and its influence on single nucleotide variation calling. The ability of MDA-based WGA solutions to better cover the targeted genome and the ability of PCR-based solutions to provide better uniformity of coverage are highlighted. While numerous comprehensive PGT solutions exploiting different WGA types and adjusted bioinformatic pipelines to detect copy number and single nucleotide changes are available, the ones exploiting MDA appear more advantageous. The opportunity to fully analyse the targeted genome is influenced by the MPS parameters themselves rather than the solely chosen WGA.