Fetal Syndrome Research Articles

Identification of fetal unmodified and 5-hydroxymethylated CG sites in maternal cell-free DNA for non-invasive prenatal testing

BackgroundMassively parallel sequencing of maternal cell-free DNA (cfDNA) is widely used to test fetal genetic abnormalities in non-invasive prenatal testing (NIPT). However, sequencing-based approaches are still of high cost. Building upon previous knowledge that placenta, the main source of fetal circulating DNA, is hypomethylated in comparison to maternal tissue counterparts of cfDNA, we propose that targeting either unmodified or 5-hydroxymethylated CG sites specifically enriches fetal genetic material and reduces numbers of required analytical sequencing reads thereby decreasing cost of a test.MethodsWe employed uTOPseq and hmTOP-seq approaches which combine covalent derivatization of unmodified or hydroxymethylated CG sites, respectively, with next generation sequencing, or quantitative real-time PCR.ResultsWe detected increased 5-hydroxymethylcytosine (5hmC) levels in fetal chorionic villi (CV) tissue samples as compared with peripheral blood. Using our previously developed uTOP-seq and hmTOP-seq approaches we obtained whole-genome uCG and 5hmCG maps of 10 CV tissue and 38 cfDNA samples in total. Our results indicated that, in contrast to conventional whole genome sequencing, such epigenomic analysis highly specifically enriches fetal DNA fragments from maternal cfDNA. While both our approaches yielded 100% accuracy in detecting Down syndrome in fetuses, hmTOP-seq maintained such accuracy at ultra-low sequencing depths using only one million reads. We identified 2164 and 1589 placenta-specific differentially modified and 5-hydroxymethylated regions, respectively, in chromosome 21, as well as 3490 and 2002 Down syndrome-specific differentially modified and 5-hydroxymethylated regions, respectively, that can be used as biomarkers for identification of Down syndrome or other epigenetic diseases of a fetus.ConclusionsuTOP-seq and hmTOP-seq approaches provide a cost-efficient and sensitive epigenetic analysis of fetal abnormalities in maternal cfDNA. The results demonstrated that T21 fetuses contain a perturbed epigenome and also indicated that fetal cfDNA might originate from fetal tissues other than placental chorionic villi. Robust covalent derivatization followed by targeted analysis of fetal DNA by sequencing or qPCR presents an attractive strategy that could help achieve superior sensitivity and specificity in prenatal diagnostics.

Molecular docking and antiviral activities of plant derived compounds against zika virus

Zika virus (ZIKV), a recently emerged pathogen of the genus flavivirus causes Guillain-Barré syndrome and microcephaly in fetus and newborns . Until date, there are no licensed vaccine or approved drug to treat ZIKV infection. Thus, in this study, 5550 phytochemicals retrieved from various databases were subjected for molecular docking in Discovery studio V.4.0 against the ZIKV helicase protein and envelope protein domain III. In addition, in silico ADMET and Density function theory studies were performed to retain the final hit compounds. Further, four of the identified compounds (eleutheroside B, neoandrographolide, apigenin, and madecassic acid) were tested for in vitro cytotoxicity and antiviral activities against ZIKV. Except madecassic acid, the other three compounds reduced ZIKV infection at non-cytotoxic concentrations. Hence, this study encourages the screening of more phytochemicals against druggable targets of ZIKV to identify new promising drug candidates.

VP32.05: Prenatal and postnatal findings of a fetal overgrowth syndrome with complex vascular anomalies: CLOVES Syndrome

VP32.05: Prenatal and postnatal findings of a fetal overgrowth syndrome with complex vascular anomalies: CLOVES Syndrome

VP31.02: Survival rate of Turner syndrome fetuses diagnosed with cystic hygroma

VP31.02: Survival rate of Turner syndrome fetuses diagnosed with cystic hygroma

EARLY MARKERS OF DIAGNOSIS FETAL GROWTH RESTRICTION SYNDROME

The article presents the effectiveness of Dopplerometry for assessing blood flow in large vessels, including the umbilical, uterine artery and middle cerebral artery, 90 women were examined in the second trimester, and 45 women showed signs of placental insufficiency, such as fetal growth restriction syndrome at 28-34 weeks. The results of the study showed that 23 (51.1%) women had signs of subcompensated insufficiency of uteroplacental blood flow, and 11 (24.4%) women showed signs of fetal-placental blood flow. The study of the uteroplacental-fetal blood flow allows early detection of early signs of impairment in the fetoplacental system and its timely correction.

Prenatal delineation of a distinct lethal fetal syndrome caused by a homozygous truncating KIDINS220 variant

Kinase D-interacting substrate of 220 kDa (KIDINS220) is a transmembrane protein playing integral role in growth mediating pathways in the nervous and cardiovascular systems. KIDINS220 heterozygous truncating variants that affect the protein's C-terminus have been associated with a phenotype, so far described only in few unrelated children, including spastic paraplegia, intellectual disability, nystagmus, and obesity. More recently, a homozygous, more N-terminal truncating variant in KIDINS220 gene was suggested to be associated with enlarged cerebral ventricles and limb contractures in three fetuses from a consanguineous family. We confirm the latter finding by presenting the first detailed prenatal identification of a fetal phenotype associated with novel homozygous deleterious frameshift variant in KIDINS220 gene in a consanguineous healthy Egyptian couple. History of unexplained seven miscarriages and a similar stillbirth were recorded. Prenatal ultrasonography revealed limb contractions and ventriculomegaly; in addition to previously unreported cerebellar anomalies, cardiac anomalies and hydrops fetalis. These findings represent an expansion of clinical and molecular spectrum associated with KIDINS220 variants and broaden our understanding of genotype-phenotype relationships in lethal congenital contractures syndromes and associated severe abnormal embryological development. More generally, our study adds KIDINS220 to the rare group of genes which may cause disease by either of two distinct mutational mechanisms.

Перинатальний центр м. Києва: Нехай вагітність стане материнством

The article presents the experience of the project on physical and psychological recovery of families after reproductive losses. The concept of fetal loss syndrome was chosen as a principle of the project, which provides both common pathogenetic mechanisms of early and late miscarriage, spontaneous and induced premature birth, which lead to neonatal death, and similar mechanisms of psychological experience of reproductive loss due to the lack of formed connection between parents and child. The main etiological factors of miscarriage, the principles of their diagnosis and the applied algorithm of treatment are considered. In particular, a detailed description of the role of progesterone deficiency in the mechanisms of miscarriage and severe obstetric complications is given, the debatability of the effectiveness of unjustified prescribing of exogenous progesterone, both from a molecular and epidemiological point of view. Attention is paid to thrombophilias of various origins, which is currently one of the recognized factors of miscarriage. The results of the project are presented, which include more than 20 meetings held in 3 years, as a result of which 20 couples were planned to have the next pregnancy and its observation. All 20 cases were completed in the Perinatal Center by timely delivery with the birth of a living healthy child, so all pregnancies became maternity. Keywords: Kyiv Perinatal Center, miscarriage, reproductive losses, pregnancy, thrombophilia, progesterone deficiency, psychology.

GC–MS analysis of seven metabolites for the screening of pregnant women with Down Syndrome fetuses

Down Syndrome is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. Metabolomics is identification and quantification of small-molecule metabolites (molecular weight <1000 Da) in tissues, cells and physiological fluids within a certain period time. Metabolites are intermediate products of various types of biochemical reactions that participate in bonding metabolic pathways. In this study, metabolites such as 2-Hydroxybutyric acid, 3-Hydroxybutyric acid, β-Hydroxyisovaleric acid, Uracil, Glutamic acid, Maltose and Melezitose were chosen as the possible determinants/markers for the prenatal screening of Down Syndrome. Quantitative analysis of the metabolites conducted by GCMS method using 5 % phenyl / 95 % dimethylpolysiloxane (30 m ×0.25 mm, 0.25 μm film thickness) capillary column. The oven temperature was held constant at 60 °C for 1 min and ramped at 10 °C /min to 200 °C then ramped at 30 °C/min to 320 °C and hold for 6 min before cool-down, as helium mobile phase and flow rate of 2.8 mL/min and adding Myristic acid-d27 as an internal standard. Our method was validated by parameters of system suitability, stability, linearity, sensitivity, accuracy, precision, selectivity, robustness and ruggedness. The developed and validated method was applied to plasma samples taken from pregnant women with Down Syndrome (study group) and euploid fetuses (healthy group). The levels of these seven metabolites are statistically different (p < 0.05 for all) between the groups. It can be concluded that these relevant metabolites might be used for the prenatal screening of Down Syndrome.

Genome-wide miRNA profiling in plasma of pregnant women with down syndrome fetuses

Down syndrome (DS) is one of the most common causes of intellectual disability and new approaches allowing its rapid and effective prenatal detection are being explored. In this study, we investigated the diagnostic potential of plasma microRNAs (miRNAs). This study builds upon our previous study in DS placentas, where seven miRNAs were found to be significantly up-regulated. A total of 70 first-trimester plasma samples from pregnant women were included in the present study (35 samples with DS fetuses; 35 with euploid fetuses). Genome-wide miRNA profiling was performed in the pilot study using Affymetrix GeneChip™ miRNA 4.1 Array Strips (18 samples). Selected miRNAs were then analysed in the validation study using quantitative reverse transcription PCR (RT-qPCR; 52 samples). Based on the current pilot study results (12 miRNAs), our previous research on chorionic villi samples (7 miRNAs) and the literature (4 miRNAs), a group of 23 miRNAs was selected for the validation study. Although the results of the pilot study were promising, the validation study using the more sensitive RT-qPCR technique and a larger group of samples revealed no significant differences in miRNA profiles between the compared groups. Our results suggest that testing of the first-trimester plasma miRNAs is probably not suitable for non-invasive prenatal testing (NIPT). Different results could be theoretically achieved at later gestational ages; however, such a result probably would have limited use in clinical practice.

Prevalence of Fetomaternal Indications of Therapeutic Abortions in Yazd Province

Background: Therapeutic abortion is defined as intentional termination of pregnancy in order to save the mother’s life and health or when the fetus has an abnormality incompatible with normal life.The aim of this study was to evaluate causes of issuance of therapeutic abortion in women referred to the Yazd province Legal Medicine Organization to terminate the pregnancy. Methods: In this cross sectional study, all the applications for therapeutic abortions from March 2014 to March 2016 approved by the legal medicine organization of Yazd province were included and recorded. The data was analyzed by SPSS software. Results: From 333 permissions for abortion during three years ,299 cases (89.8%) were issued for the reason of fetal indications and 34 cases (10.2%) for maternalindications. The most prevalent fetal abnormalities indicated for abortion were central nervous system disorders (especially Anencephaly and Spina Bifida); Hydrops Fetalis and Down syndrome, respectively and the most frequent maternal disorders were cardiovascular diseases. Conclusion: The current study shows that therapeutic abortions due to fetal abnormalities are increasing. It seems that educating health professionals and people and increasing their awareness about preventing fetal abnormalities and also contraception in women with maternal diseases indicated for abortion could be an effective way to reduce the rate of abortion.

Hydrops fetalis and neonatal abdominal compartment syndrome continuum from immature gastric teratoma: a case report

BackgroundHydrops fetalis as well as abdominal compartment syndrome (ACS) are conditions that are associated with high mortality rates. A rare case of immature gastric teratoma causing fetal hydrops and subsequent ACS is presented. The related pathophysiologic mechanisms are discussed, and the importance of timely recognition and appropriate interventions are highlighted.Case presentationThe male patient was born preterm, weighing 3.9 kg., by Cesarean section. Prior prenatal ultrasounds were normal, but a scan done just before delivery had findings indicating polyhydramnios, fetal ascites, and meconium peritonitis. Upon delivery, the patient had respiratory distress, anasarca and a massively distended abdomen. Resuscitation measures, including ventilatory support, were instituted. Imaging studies showed ascites as well as a large, complex intra-abdominal lesion with calcifications. In the succeeding hours, anuria persisted, anasarca worsened, the abdomen became more distended, and inotrope requirements increased. The occurrence of ACS, from what was presumed to be a retroperitoneal teratoma, was therefore considered. Laparotomy was done on the 28th hour of life, with en bloc excision of a massive tumor and attached section of the greater curvature of the stomach. Passage of urine occurred intra-operatively, and the patient was soon after weaned off inotropes and ventilator support. The histopathologic result was immature gastric teratoma. No chemotherapy was given, and the patient’s serum AFP is at normal levels 15 months following surgery.ConclusionThe presence of a massive intra-abdominal lesion can result in the pathophysiologic continuum of hydrops fetalis and neonatal ACS. The early recognition of such an association can enable appropriate expectant management of similarly affected neonates, including emergent decompression laparotomy.

Пренатальная диагностика оро-фацио-дигитального синдрома I типа у плода с частичной моносомией Хр22.2

Представлен первый случай пренатальной диагностики оро-фацио-дигитального синдрома I типа (OMIM 311200) у плода с частичной моносомией Хр22.2. Причиной оро-фацио-дигитального синдрома I типа являются мутации в гене OFDI, случаи заболевания вследствие хромосомных микроделеций, затрагивающих ген OFDI встречаются редко. При ультразвуковом исследовании плода во втором триместре беременности выявлены врожденный порок развития головного мозга и множественные эхографические маркеры хромосомной и синдромальной патологии. Биологический образец плода (пуповинная кровь) получен в 21 неделю гестации посредством кордоцентеза. Молекулярно-цитогенетический анализ ДНК, выделенной из лимфоцитов пуповинной крови плода, с применением матричной сравнительной геномной гибридизации выявил частичную моносомию региона Хр22.2, размером 2,6 млн п.н.: arr[hg19] Xp22.2(11135472_13798048)×1. Наличие перестройки, а также ее de novo происхождение, подтверждено количественной ПЦР в режиме реального времени. The first case of prenatal diagnosis of type I oro-facio-digital syndrome (OMIM 311200) in fetus with partial monosomy Xp22.2 is presented. The cause of type I oro-facio-digital syndrome is mutations in the OFDI gene, cases of disease due to chromosomal microdeletions affecting the OFDI gene are rare. Ultrasound examination of the fetus in the second trimester of pregnancy revealed congenital defect of brain development and multiple echographic markers of chromosomal and syndrome pathology. An umbilical cord blood was obtained in 21 weeks of gestation by cordocentesis. aCGH revealed partial monosomy Xp22.2 at 2.6 Mb in size: arr [hg19] Xp22.2(11135472_13798048) × 1. The presence of microdeletion, as well as its de novo origin, was confirmed by the quantitative real time PCR. The use of high-resolution molecular cytogenetic analysis significantly expands the possibilities of syndrome monogenic pathology diagnosis in the prenatal period.

Изучение ассоциации полиморфных локусов генов фолатного цикла с развитием синдрома задержки роста плода 2-3 степени

Изучение ассоциации полиморфных локусов генов фолатного цикла с развитием синдрома задержки роста плода 2-3 степени

Apert syndrome in a first trimester fetus with diaphragmatic hernia

Apert syndrome (AS) is one of the most commonly described craniosynostosis syndromes. Prenatal diagnosis of left diaphragmatic hernia on malformed fetus with AS at 11+5 week’s of gestation is presented. This is the fourth report of AS in association with diaphragmatic hernia. The diagnosis of AS was confirmed by a molecular analysis of FGFR2, which showed a heterozygous Ser252Trp mutation.

Perinatal outcomes of infants with congenital limb malformations: an observational study from a tertiary referral center in Central Europe

BackgroundCongenital limb malformations are rare, and their perinatal outcomes are not well described. This study analyzed the perinatal outcomes of infants with congenital limb malformations.MethodsAll infants with congenital limb malformations who underwent prenatal assessment and delivery at our tertiary referral center from 2004 through 2017 were retrospectively identified. Neonatal outcome parameters were assessed, and the predictors of worse perinatal outcomes were determined.ResultsOne hundred twenty-four cases of congenital limb malformations were identified, of which 104 (83.9%) were analyzed. The upper limb was affected in 15 patients (14.4%), the lower limb in 49 (47.1%), and both limbs in 40 (38.5%) patients. A fetal syndrome was identified in 66 patients (63.5%); clubfoot and longitudinal reduction defects were the most frequent malformations. In total, 38 patients (36.5%) underwent termination, seven (6.7%) had stillbirth, and 59 (56.7%) had live-born delivery. Rates of preterm delivery and transfer to the Neonatal Intensive Care Unit were 42.4 and 25.4%, respectively. Localization of the malformation was a determinant of perinatal outcome (P = .006) and preterm delivery (P = .046).ConclusionsCongenital limb malformations frequently occur bilaterally and are associated with poor perinatal outcomes, including high rates of stillbirth and preterm delivery. Multidisciplinary care and referral to a perinatal center are warranted.

Analysis of 21 723 Pregnant Women's First Trimester Screening for Down Syndrome in Sichuan Province

To compare the effect of different first-trimester screening programmes for Down syndrome in Sichuan Province. We retrospectively collected the data of singleton pregnancies that were screened by serum biochemistry markers combined with nuchal translucency screening tests in the first trimester in Prenatal Diagnosis Center of West China Second University Hospital of Sichuan University from January 2011 to December 2017. The fetal chromosome results were obtained by amniocentesis or by telephone follow-up. The screening effect of maternal age, nuchal translucency thickness, maternal serum biochemistry markers and combined screening in the first trimester were analyzed. Among the 21 723 singleton pregnancies, 33 cases were diagnosed as Down syndrome, and 19 cases were diagnosed as trisomy 18 sex chromosome abnormalities were found in 4 cases, and other chromosome abnormalities were found in 8 cases. For the combined screening, the detection rate of Down syndrome was 72.73%, and the false positive rate was 2.49%; the detection rate of trisomy 18 syndrome was 73.68% with the false positive rate of 0.39%. With a 5% false positive rate, maternal age, nuchal translucency thickness, serum biochemistry markers and combined screening would respectively detect 15.15%, 57.58%, 60.61% and 87.88% of Down syndrome fetuses. Compared with the other three screening programmes, the combined screening can effectively screen fetuses with Down syndrome and other chromosomal abnormalities.

Forehead and facial heights in Down syndrome and normal fetuses in the midtrimester of pregnancy

Forehead and facial heights in Down syndrome and normal fetuses in the midtrimester of pregnancy

Сравнительная характеристика новорожденных с «поздней недоношенностью» и доношенных новорожденных детей с синдромом задержки развития плода

Сравнительная характеристика новорожденных с «поздней недоношенностью» и доношенных новорожденных детей с синдромом задержки развития плода

Патогенетические механизмы и основные подходы допплеровской диагностики перинатальной централизации кровообращения при синдроме задержки роста плода

Патогенетические механизмы и основные подходы допплеровской диагностики перинатальной централизации кровообращения при синдроме задержки роста плода

Alkoholowy zespół płodowy (FAS) jako wyzwanie naszych czasów

The article addresses the issue of an alcoholic fetal syndrome (FAS). It explains the notion and the characteristic of FAS. A diagnosis of FAS and associated human development disorders was developed. It was also an attempt to construct a program for therapy and prevention of FAS.