[Progress in fetal fraction prediction of placental diseases].

Placental diseases may affect the outcome of pregnancy and long-term health of the mother and fetus. Fetal fraction is a key indicator for the success of non-invasive prenatal testing, and has been associated with gestational age, body mass index and fetal chromosomal aneuploidies. Many studies have found that fetal fraction is also related to placenta-derived diseases and may become a new predictor for such diseases. This article has summarized the association between the two, with an aim to provide new ideas for the prediction of placental diseases.

Prenatal and postnatal evaluation of differences of sex development: a user's guide for clinicians and families.

PURPOSE OF REVIEW: Differences of sex development (DSD) are a group of chromosomal, gonadal, and anatomic conditions that are not often diagnosed during pregnancy. Families and clinicians need diagnostic guidance that supports all aspects of the care from the prenatal to postnatal period. RECENT FINDINGS: Noninvasive prenatal screening (NIPS) is obtained by sampling cell-free fetal DNA in the mother's bloodstream in the first trimester. While its primary purpose is to screen for genetic aneuploidies, it is also used to determine the sex of the fetus. When screening ultrasound shows genital anatomy that is discordant with the sex determination by NIPS, a DSD workup is warranted. The use of this relatively new screening tool may result in a higher number of prenatal referrals than in the past. SUMMARY: This review summarizes suggested prenatal counseling, neonatal management, and postnatal workup of the most common DSD diagnoses. All of these diagnoses are rare, but the common features that families face are addressed with particular emphasis on psychosocial support and a measured shared decision-making approach.

[Genetic analysis of a Chinese pedigree affected with Branchio-oculo-facial syndrome and a literature review].

OBJECTIVE: To explore the genetic etiology of a Chinese pedigree affected with Branchio-oculo-facial syndrome (BOFS) and summarize the prenatal phenotype of BOFS patients. METHODS: A pedigree with BOFS which had presented at the Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University in December 2021 was selected as the study subject. Clinical data of the pedigree was collected. The fetus was subjected to routine prenatal ultrasound scan. Trio-whole exome sequencing (trio-WES) was carried out for the fetus and its parents, and candidate variant was verified by Sanger sequencing. Relevant literature was searched from the database to summarize the prenatal phenotype of BOFS patients. RESULTS: Ultrasound exam suggested the fetus had cleft lip and palate. Its father had presented with high palatal arch, prematurely grayed hair, occult cleft lip, congenital preauricular fistula, red-green color blindness and unilateral renal agenesis. Its grandfather also had high palatal arch, prematurely gray hair, protruding ears, congenital preauricular fistula and hearing disorders. Trio-WES revealed that the fetus and its father had both harbored a heterozygous c.890-1G>A variant of the TFAP2A gene. The same variant was not found in its mother. Sanger sequencing confirmed that its grandfather had also harbored the same variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PVS1+PM2_Supporting). Combined with 36 similar cases retrieved from the literature, the prenatal phenotypes of BOFS patients had included growth restriction (25/37), renal abnormalities (10/37), cleft lip and palate (5/37) and oligohydramnios (5/37). CONCLUSION: The c.890-1G>A variant of the TFAP2A gene probably underlay the pathogenesis of BOFS in this pedigree. Discovery of the novel variant has enriched the mutational spectrum of the TFAP2A gene. The common prenatal phenotypes of BOFS have included growth restriction, renal abnormalities, cleft lip and palate and oligohydramnios. Delineation of the intrauterine phenotype of BOFS may facilitate its prenatal diagnosis, clinical diagnosis, treatment and genetic counseling.

[Genetic analysis and prenatal diagnosis for a Chinese pedigree affected with Autosomal dominant polycystic kidney disease].

OBJECTIVE: To explore the clinical phenotype and genetic etiology for a Chinese pedigree affected with Autosomal dominant polycystic kidney disease (ADPKD). METHODS: A pedigree with ADPKD diagnosed at the Department of Gynaecology of the First Affiliated Hospital of Zhengzhou University in December 2020 was selected as the study subject. Clinical data of the pedigree was collected, and whole exome sequencing (WES) was carried out for the proband. Candidate variants were verified by Sanger sequencing of the proband and her relatives. RESULTS: Fetal ultrasonography showed increased volume and parenchymal echogenicity in both kidneys. The fetus was found to harbor c.11098C>T (p.R3700C) and c.11039T>C (p.F3680S) compound heterozygous variants of the PKD1 gene, which were respectively inherited from its mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PM1+PM2_supporting+PP3). CONCLUSION: The c.11098C>T (p.R3700C) and c.11039T>C (p.F3680S) compound heterozygous variants of the PKD1 gene probably underlay the ADPKD in the fetus. Above finding has provided guidance for the genetic counseling and prenatal diagnosis for this pedigree.

Feasibility and Acceptability of Antenatal Hepatitis C Screening: A Pilot Study.

Introduction: Hepatitis C virus (HCV) is not currently included in the United Kingdom routine antenatal screening program, but the latest guidelines from the Centers for Disease Control and Prevention, American Association for the Study of Liver Diseases, and Infectious Diseases Society of America recommend HCV screening for all pregnant women during each pregnancy. The aim of this study was to collect qualitative data on the feasibility and acceptability of antenatal HCV screening in pregnant women at the time of routine antenatal screening at 12 weeks, to estimate patient knowledge about HCV and identify the prevalence of HCV infection in antenatal women. Methods: This was a pilot study targeting a single hospital-based antenatal clinic in Birmingham, initially conducted for eight weeks with a further extension of the study period to enhance recruitment to meet the feasibility target of 500 patients. Data collected included demographic and epidemiological details. Pregnant women attending the antenatal unit were given information regarding HCV and antenatal screening for HCV prior to their initial antenatal visit. During the antenatal visit, research nurses provided further information about the study and HCV infection. Consent was obtained for taking part in the study and testing for HCV using blood samples taken at the same time as other routine antenatal screening blood tests. All women who agreed to participate in the study were asked to complete an acceptability and knowledge questionnaire. All women had HCV antibody testing as the primary screening assay. The test result was communicated in writing to the women and their general practitioner. Confirmatory positive antibody tests were followed up with quantitative HCV PCR and genotype analysis. The outcomes of testing were no evidence of HCV infection and evidence of past HCV infection or current HCV infection. Results: Five hundred and forty-nine women were approached in the antenatal clinic; 30 women refused consent while 29 women were excluded from the study (blood tests not performed after consenting, age less than 18 years, and consent form lost). Four hundred and ninety women were included in the study. The median age of the study population was 29 years (range, 18-46). Knowledge about blood-borne viruses was limited; 75% of women had some understanding about antenatal hepatitis B (HBV) and human immunodeficiency virus (HIV) testing. Previous awareness about hepatitis C was reported by 55%. Ninety-one percent of women found the information they were given about hepatitis C helpful. Ninety-six percent of the women included in this study found the counselling they received about HCV useful and felt that the delivery of this information was carried out in an acceptable manner. Once given information about HCV, 99% felt that universal screening for HCV should be implemented. HCV antibody was negative in 489 women. One patient with a positive HCV antibody (prevalence: 0.2%) had a negative HCV PCR. Conclusion: Routine antenatal screening for HCV is not currently recommended in the UK. Our study suggests that antenatal HCV screening would be both feasible and acceptable to most pregnant women attending antenatal clinics. Though the awareness of HCV was low, with appropriate counselling and communication, 99% of pregnant women were in favor of antenatal screening for HCV. Antenatal screening would identify HCV-positive mothers and allow follow-up of their infants so that any infected mothers and infants could be offered effective curative therapy and prevent the progression of liver disease. The inclusion of HCV antenatal screening would complete the blood-borne virus profile and enhance the WHO target to eliminate HCV in the UK.

Noninvasive prenatal screening and diagnosis of two fetuses with Williams syndrome in a cohort of 19,607 pregnancies.

BACKGROUND: This study aimed to evaluate the efficiency of noninvasive prenatal screening (NIPS) technology in screening for microdeletions in the 7q11.23 region. METHODS: 19,607 pregnant women underwent NIPS in our hospital. Maternal peripheral cell-free foetal DNA (cffDNA) was routinely screened for aneuploidy by cffDNA enrichment and simultaneously analyzed for pathogenic copy number variants (CNVs). The Williams syndrome (WS) 7q11.23 region was targeted in this study. Chromosomal microarray analysis (CMA) was used to verify the screen-positive samples. RESULTS: The mean concentration of cffDNA before and after enrichment increased from 9.44% to 19.32%, with a statistically significant difference. Two out of 19,607 samples tested for CNVs were found to have a heterozygous deletion at the 7q11.23 region, indicating a high risk for WS. CMA results confirmed the 1.5 megabase (Mb) deletions at the 7q11.23 region in amniotic fluid samples. One of the two WS foetuses had a small left ventricle by ultrasound screening, and the other did not have a significant cardiovascular abnormality phenotype. CONCLUSIONS: NIPS screening for Williams syndrome can be achieved by enriching cell-free foetal DNA and improving bioinformatic analysis algorithms.

Awareness of down syndrome screening among educated Muslim women is associated with a favorable attitude toward testing.

OBJECTIVE: There is a general assumption that Muslim women refuse Down syndrome screening, and therefore, many health practitioners do not offer it or briefly discuss it with their participants. This study aims to objectively assess women's awareness, knowledge, and attitudes toward Down Syndrome screening (D.S.S) in a Muslim-majority population. METHODS: We conducted a cross-sectional study among attendees of antenatal clinics at a major university hospital in Saudi Arabia, aiming for a sample size of at least 385 Muslim women. A semi-structured questionnaire assessed awareness of different D.S.S. options and the source of that information (2 items), specific knowledge of D.S.S. (14 items), and attitudes (4 items). The knowledge and attitudes scores were calculated using a five-level agreement Likert-type scale. RESULTS: Among 434 participants, with an even distribution among all age groups and a majority of a college degree holder or higher (71%), 178 (41.0%) reported awareness of D.S.S. Factors associated with increased awareness were maternal age above 40 or those under 30, nulliparity, and extended family history of fetal congenital anomalies (P-value = 0.03,0.015, and 0.017, respectively). Recognized tests were ultrasound measurement of nuchal translucency (71.9%) and first-trimester serum screening (58.4%). The sources of knowledge were obstetricians (53.9%), followed by family and friends (27.0%). The overall mean ± SD knowledge score was 53.9 ± 8.7 out of 70, and the mean attitude score was 17.4 ± 2.9 out of 20. Having 1 or 2 children is associated with a higher knowledge score, and most participants who reported awareness of D.S.S. (51.7%) had a favorable attitude toward screening. CONCLUSION: Awareness of D.S.S. among Muslim women is associated with favorable attitudes towards testing, contradicting the general assumption and highlighting the need for systematic education to increase awareness and subsequent testing uptake.

Molecular diagnostic yield of exome sequencing in a Chinese cohort of 512 fetuses with anomalies.

BACKGROUND: Currently, whole exome sequencing has been performed as a helpful complement in the prenatal setting in case of fetal anomalies. However, data on its clinical utility remain limited in practice. Herein, we reported our data of fetal exome sequencing in a cohort of 512 trios to evaluate its diagnostic yield. METHODS: In this retrospective cohort study, the couples performing prenatal exome sequencing were enrolled. Fetal phenotype was classified according to ultrasound and magnetic resonance imaging findings. Genetic variants were analyzed based on a phenotype-driven followed by genotype-driven approach in all trios. RESULTS: A total of 97 diagnostic variants in 65 genes were identified in 69 fetuses, with an average detection rate of 13.48%. Skeletal and renal system were the most frequently affected organs referred for whole exome sequencing, with the highest diagnostic rates. Among them, short femur and kidney cyst were the most common phenotype. Fetal growth restriction was the most frequently observed phenotype with a low detection rate (4.3%). Exome sequencing had limited value in isolated increased nuchal translucency and chest anomalies. CONCLUSIONS: This study provides our data on the detection rate of whole exome sequencing in fetal anomalies in a large cohort. It contributes to the expanding of phenotypic and genotypic spectrum.

Worrying increase in the risk of vertical transmission of syphilis in Croatia, 2020 to 2024.

Four infants potentially exposed to syphilis infection in utero, meeting World Health Organization surveillance criteria of congenital syphilis (CS), were diagnosed in Croatia between September 2020 and January 2024. We conducted a retrospective analysis of epidemiological, clinical and laboratory data of these cases to assess compliance with surveillance case definitions. As only one confirmed CS case has been reported in Croatia in over 2 decades, these reports signal an increased risk of syphilis vertical transmission and warrant strengthening antenatal screening.

Pregnancies with 'double-positive' multiple marker screening results: a population-based study in Ontario, Canada.

BACKGROUND: Multiple marker screening is offered to pregnant individuals in many jurisdictions to screen for trisomies 21 and 18. On occasion, the result is 'double-positive'-a screening result that is unexpectedly positive for both aneuploidies. Although this occurs rarely, the paucity of available evidence about the outcomes of these pregnancies hinders patient counselling. This study aimed to investigate the association of double-positive results with preterm birth and other adverse perinatal outcomes. METHODS: We conducted a population-based retrospective cohort study of pregnancies with an estimated date of delivery from September 1, 2016, to March 31, 2021, using province-wide perinatal registry data in Ontario, Canada. Pregnancies with double-positive screening results where trisomies 21 and 18 were ruled-out were compared to pregnancies with screen negative results for both aneuploidies. We used modified Poisson regression models with robust variance estimation to examine the association of double positive results with preterm birth and secondary outcomes. RESULTS: From 429 540 pregnancies with multiple marker screening, 863 (0.2%) had a double-positive result; trisomies 21 and 18 were ruled out in 374 pregnancies, 203 of which resulted in a live birth. Among the pregnancies in the double-positive group resulting in a live birth, the risk of preterm birth was increased compared to pregnancies with a screen negative result: adjusted risk ratio (aRR) 2.6 (95%CI 2.0-3.6), adjusted risk difference (aRD) 10.5% (95%CI 5.4-15.7). In a sensitivity analysis excluding all diagnosed chromosomal abnormalities, the risk of preterm birth remained elevated to a similar degree: aRR 2.6 (95%CI 1.9-3.7), aRD 10.0% (95%CI 4.8-15.3). The risk of other adverse perinatal outcomes was also higher, including the risk of chromosomal abnormalities other than trisomies 21 and 18: aRR 81.1 (95%CI 69.4-94.8), aRD 34.0% (95%CI 29.2-38.8). Pregnancies with double-positive results were also less likely to result in a live birth, even when excluding all diagnosed chromosomal abnormalities; and at increased risk of adverse perinatal outcomes for those resulting in a live birth. CONCLUSION: Although rare, double-positive multiple marker screening results are associated with an increased risk of preterm birth and other adverse perinatal outcomes, even when excluding all identified chromosomal abnormalities.

Genetic counseling of mosaic and non-mosaic tetrasomy 9p at prenatal diagnosis.

Genetic counseling of mosaic and non-mosaic tetrasomy 9p remains difficult because of the possible associated congenital abnormalities, cytogenetic discrepancy in various tissues, true-positive and false-positive diagnosis in non-invasive prenatal testing (NIPT), uniparental disomy (UPD) 9, tissue-limited mosaicism, perinatal progressive decrease of the aneuploid cell line, phenotypic normal carriers and possible favorable fetal outcome in the cases with mosaic tetrasomy 9p at amniocentesis. This article presents a comprehensive review of various counseling issues concerning mosaic and non-mosaic tetrasomy 9p at prenatal diagnosis, and the information provided is very useful for genetic counseling under such circumstances.

Prenatal diagnosis and outcome of congenital dacryocystoceles.

OBJECTIVE: To determine the incidence and present our experience with prenatal diagnosis and postnatal outcome of dacryocystocele. MATERIAL AND METHODS: All cases of congenital dacryocystocele diagnosed in our center between 2020 and 2022 were identified in our database to establish the incidence of these defects. The medical records were then reviewed for gestational age, gender, size, and side of dacryocystocele and postnatal outcome. RESULTS: A total of 26 cases with dacryocystoceles were found at a mean gestation age of 30 weeks (range, 29-33 weeks). The overall incidence was 1.35%, there was an obvious female predominance (73%), 69% of cases were unilateral and 31% were bilateral. There were no serious associated anomalies. The postnatal outcome was obtained in 88% of cases (23/26), in 39% (9 out of 23) cases the dacryocystocele was confirmed postnatally, and in 7 (77%) of these it was complicated by dacryocystitis. The spontaneous resolution was more likely in the right-sided lesions, and this was statistically significant. The treatment in cases with dacryocystitis involved massage and local antibiotics and was successful in 71% of cases. 2 cases (29%) suffer from recurrent dacryocystitis and are followed up with recurrent probing and local antibiotics. No breathing difficulties were described postnatally in our study group. CONCLUSION: The overall prenatal incidence of dacryocystocele was 1.35%. The outcome is favorable, 61% of dacryocystoceles in our study resolved spontaneously and in no case postnatal breathing complications were reported. Dacryocystitis was common in persisting cases but was usually treated successfully by massage and antibiotics. The right-sided dacryocystoceles are more likely to resolve spontaneously than left-sided, and this was the only significant factor predicting persistence.

Clinical and genetic analysis of two phenotypically normal families carrying 4p16.1 microduplications.

OBJECTIVE: To help determine the pathogenicity of 4p16.1 microduplications, we reported two asymptomatic families carrying this variation. CASE REPORT: We present the prenatal diagnosis and genetic analysis of two normal families with 4p16.1 microduplications. CONCLUSION: This paper highlights two families with clinically asymptomatic 4p16.1 microduplications that assisted in determining the pathogenicity of this fragment. The findings can be used as a reference for genetic counseling in cases of similar abnormalities encountered during future prenatal diagnosis.

Potential candidate maternal serum miRNAs for the diagnosis of fetal congenital heart disease.

Congenital heart disease (CHD) is one of the most significant birth defects leading to infant mortality worldwide. Circulating microRNAs (miRNAs) are emerging as novel biomarkers for the detection of cardiovascular diseases. In this study, we aimed to investigate the role of maternal serum miRNAs expression as biomarkers in the diagnosis and prediction of children with CHD. High-throughput sequencing of peripheral blood from pregnant women with abnormal and normal fetal hearts identified 1939 differentially expressed miRNAs, the first 11 of which were selected as predictive biomarkers of CHD. The expression of miRNAs in more clinical samples was then quantitatively verified by reverse transcriptase polymerase chain reaction and the correlation between abnormal miRNAs and CHD was analyzed. Two miRNAs (hsa-miR-3195 and hsa-miR-122-5p) were found to be significantly down-regulated in pregnant women with fetal CHD. By further bioinformatics analysis, we predicted that hsa-miR-3195 and hsa-miR-122-5p could induce CHD by influencing biometabolic processes. hsa-miR-3195 and hsa-miR-122-5p may serve as novel non-invasive biomarkers for prenatal detection of fetal CHD.

Detection of genomic variants by genome sequencing in foetuses with central nervous system abnormalities.

OBJECTIVE: Clinical validity of genome sequencing (GS) (>30×) has been preliminarily verified in the post-natal setting. This study is to investigate the potential utility of trio-GS as a prenatal test for diagnosis of central nervous system (CNS) anomalies. METHODS: We performed trio-based GS on a prospective cohort of 17 foetuses with CNS abnormalities. Single nucleotide variation (SNV), small insertion and deletion (Indel), copy number variation (CNV), structural variant (SV), and regions with absence of heterozygosity (AOH) were analyzed and classified according to ACMG guidelines. RESULTS: Trio-GS identified diagnostic findings in 29.4% (5/17) of foetuses, with pathogenic variants found in SON, L1CAM, KMT2D, and ASPM. Corpus callosum (CC) and cavum septum pellucidum (CSP) abnormalities were the most frequent CNS abnormalities (47.1%, 8/17) with a diagnostic yield of 50%. A total of 29.4% (5/17) foetuses had variants of uncertain significance (VUS). Particularly, maternal uniparental disomy 16 and a de novo mosaic 4p12p11 duplication were simultaneously detected in one foetus with abnormal sulcus development. In addition, parentally inherited chromosomal inversions were identified in two foetuses. CONCLUSION: GS demonstrates its feasibility in providing genetic diagnosis for foetal CNS abnormalities and shows the potential to expand the application to foetuses with other ultrasound anomalies in prenatal diagnosis.

Prenatal diagnosis and molecular cytogenetic analyses of a homozygous Robertsonian translocation family with novel mosaic Robertsonian fission karyotype.

BACKGROUND: Approximately one person in 1000 is a Robertsonian translocation carrier. Errors in the formation of eggs (or more rarely of sperms) may be the cause of Robertsonian translocation. Most Robertsonian translocation carriers are healthy and have a normal lifespan, but do have an increased risk of offsprings with trisomies and pregnancy loss. The fitness of Robertsonian translocation carriers is reduced, but can provide material for evolution. MATERIALS AND METHODS: We have done prenatal diagnosis and molecular cytogenetic analyses on this homozygous Robertson translocation family. We report a homozygous Robertson translocation family with previously undescribed mosaic Robertsonian fission karyotype. RESULTS: We identified six Robertsonian translocation carriers in this family. Four were heterozygous translocation carriers of 45,XX or XY,der(14;15)(q10;q10), one was a homozygous translocation carrier of a 44,XY,der(14;15)(q10;q10),der(14;15)(q10;q10), and one was a previously undescribed Robertsonian fission carrier of 45,XN,der(14;15)(q10;q10)[42]/46,XN[58] with normal phenotype. CONCLUSION: We reported a previously undescribed mosaic Robertsonian fission karyotype. The homozygosity of Robertsonian translocation for speciation may be a potential mechanism of speciation in humans. In theory, the carriers of homologous Robertsonian translocation cannot produce normal gametes, but Robertson fission made it possible for them to produce normal gametes.

Population-based prevalence of congenital defects in a routine sentinel site-based surveillance system in the Western Cape, South Africa.

BACKGROUND: Lack of data on the burden and scope of congenital disorders (CDs) in South Africa undermines resource allocation and limits the ability to detect signals from potentially teratogenic pregnancy exposures. METHODS: We used routine electronic data in the Western Cape Pregnancy Exposure Registry (PER) to determine the overall and individual prevalence of CD identified on neonatal surface examination at birth in the Western Cape, South Africa, 2016-2022. CD was confirmed by record review. The contribution of late (≤24 months) and antenatal diagnoses was assessed. We compared demographic and obstetric characteristics between women with/without pregnancies affected by CD. RESULTS: Women with a viable pregnancy (>22 weeks gestation; birth weight ≥ 500 g) (n = 32,494) were included. Of 1106 potential CD identified, 56.1% were confirmed on folder review. When internal and minor CD were excluded the prevalence of major CD identified on surface examination at birth was 7.2/1000 births. When missed/late diagnoses on examination (16.8%) and ultrasound (6.8%) were included, the prevalence was 9.2/1000 births: 8.9/1000 livebirths and 21.5/1000 stillbirths. The PER did not detect 21.5% of major CD visible at birth. Older maternal age and diabetes mellitus were associated with an increased prevalence of CD. Women living with/without HIV (or the timing of antiretroviral therapy, before/after conception), hypertension or obesity did not significantly affect prevalence of CD. CONCLUSIONS: A surveillance system based on routine data successfully determined the prevalence of major CD identified on surface examination at birth at rates slightly higher than in equivalent studies. Overall rates, modeled at ~2%, are likely underestimated. Strengthening routine neonatal examination and clinical record-keeping could improve CD ascertainment.