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Objective: Congenital malformations are frequently diagnosed prenatally even at a viable stage. No adequate registration of incidence and characteristics of late termination of pregnancy (TOP) or abortion for medical reasons exists in Flanders. Methods: Nationwide mortality follow-back survey sent to physicians signing death certificates of all stillbirths for 22 weeks gestation onward (September 2016–December 2017) in Flanders, Belgium. Questions measured whether late TOP preceded stillbirth, and which clinical and sociodemographic characteristics were indicated. Questionnaire data were linked with sociodemographic information from death certificates. Results: Response rate was 56% (203/366). 38% of stillbirths (77/203) concerned late TOP. In 88.3% of late TOPs, physicians classified congenital anomalies of the foetus as serious or very serious (incompatibility with life outside the womb or severe neurological or physical impairment). In 26% of cases, late TOP was first suggested by the physician rather thanspontaneously requested by parents (73%). 88% of late TOPs were discussed in open team meetings. Conclusions: 2/5 stillbirths were preceded by late TOP, indicating severe underreportation by existing registrations and a dire need for adequate registration methods. Although late TOP was most often explicitly requested by parents, in ¼ cases termination was suggested first by physicians. Parents are sometimes hesitant to bring up late TOP themselves, indicating that TOP should always be counselled as an equivalent option.

Maternally inherited 15q11-q13 duplications are generally found to cause more severe neurodevelopmental anomalies compared to paternally inherited duplications. However, this assessment is mainly inferred from the study of patient populations, causing an ascertainment bias towards patients at the more severe end of the phenotypic spectrum. Here, we analyze the low coverage genome-wide cell-free DNA sequencing data obtained from pregnant women during non-invasive prenatal screening (NIPS). We detect 23 15q11-q13 duplications in 333,187 pregnant women (0.0069%), with an approximately equal distribution between maternal and paternal duplications. Maternally inherited duplications are always associated with a clinical phenotype (ranging from learning difficulties to intellectual impairment, epilepsy and psychiatric disorders), while paternal duplications are normal or associated with milder phenotypes (mild learning difficulties and dyslexia). This data corroborates the difference in impact between paternally and maternally inherited 15q11-q13 duplications, contributing to the improvement of genetic counselling. We recommend reporting 15q11-q13 duplications identified during genome-wide NIPS with appropriate genetic counselling for these pregnant women in the interest of both mothers and future children.

Purpose: We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy. Methods: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy. Results: fCES identified the underlying genetic cause in 13% (24/183) of prospective and 29% (35/120) of retrospective cases. In both cohorts, recessive heterozygous compound genotypes were not rare, and trio and simplex variant analysis strategies were complementary to achieve the highest possible diagnostic rate. Limited prenatal phenotypic information led to interpretation challenges. In 2 prospective cases, in-depth analysis allowed expansion of the spectrum of prenatal presentations for genetic syndromes associated with the SLC17A5 and CHAMP1 genes. Conclusion: fCES is diagnostically efficient in fetuses presenting with cerebral, skeletal, urinary, or multiple anomalies. The comparison between the 2 cohorts highlights the importance of providing detailed phenotypic information for better interpretation and prenatal reporting of genetic variants. (C) 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Non-invasive prenatal testing (NIPT) is a screening method for the early detection of foetal aneuploidies in pregnant women. While originally developed for the detection of trisomy 13, 18 and 21, it is becoming clear that NIPT can be used for the identification of rare foetal aneuploidies and mosaic aneuploidy as well. Here we describe a female foetus with trisomy 21 in combination with mosaicism X0/XX, detected during follow-up of an abnormal ultrasound (enlarged NT: 3,3 mm). Microarray analysis and FISH on chorion villi cells confirmed trisomy 21, and mosaicism X0/XX (~29% of cells (n=63)). NIPT convincingly detected the presence of trisomy 21 with a Z-score of 22.9. (Partial) monosomy X on NIPT was revealed by the absence of a clear second X chromosome on the sex plots and the high discrepancy between the foetal fraction of chromosome X and the foetal fraction of chromosome Y. Likely the high seqFF value (16%) helped to more confidently identify these aneuploidies. While the debate as to whether or not aneuploidies of the sex chromosomes should be reported continues, this study shows that these aneuploidies can nevertheless be picked up, and probably other rare genetic abnormalities as well.

An all-wet process based on a novel chemistry has been developed to enable the removal of high-dose implanted photoresist in the presence of exposed metal layers and other materials typical of advanced gate stacks.

BACKGROUND: Cytomegalovirus infection is the most common perinatal viral infection which can lead to severe long-term medical conditions. Antenatal identification of maternal Cytomegalovirus infections with proven fetal transmission and potential postnatal clinical sequelae remains a major challenge in perinatology. There is a need to improve the prenatal counseling offered to patients and guide future clinical management decisions in cases of proven primary Cytomegalovirus infection. OBJECTIVE: To evaluate the accuracy of fetal ultrasound for predicting sequelae in fetuses infected with congenital cytomegalovirus after maternal primary infection. STUDY DESIGN: We conducted a prospective observational study between 1996 and 2012 in pregnant women with serological evidence of primary cytomegalovirus infection and proven vertical transmission to the fetus, based on viral load in the amniotic fluid. Fetal ultrasound was performed in all patients. Pregnancy termination was presented as an option for infected fetuses. Hearing and neurological clinical assessments were performed for all neonates with Cytomegalovirus-positive urine samples. RESULTS: Sixty-seven patients (69 fetuses) with proven vertical transmission were included in this study, including 64 singleton and three twin pregnancies. Eight fetuses were lost to follow-up. Of the remaining 61 fetuses, Termination of the pregnancy was performed for 26, including 11 with fetal ultrasound anomalies. Autopsy provided histological evidence of fetal Cytomegalovirus infection in all cases. In the 15 terminated fetuses without ultrasound anomalies, histological evidence of damage caused by fetal infection was detected in 13 cases. Among the 35 live-born infants, 12 had fetal ultrasound anomalies suggestive of congenital infection. Of these 12 infants, six had normal clinical evaluations, whereas six presented with either hearing and/or neurological anomalies, classified as severe in four cases. Among the 23 live-born infants with normal prenatal ultrasound, five developed hearing impairments and one showed mild neurological developmental delay. CONCLUSIONS: Fetal ultrasound anomalies were detected in 37.7% of pregnant women with primary Cytomegalovirus infection acquired in early pregnancy and proven fetal infection, and were confirmed by autopsy or postnatal clinical evaluation in 73.9%. Autopsy or postnatal clinical evaluation also detected Cytomegalovirus-related anomalies in 55% of infants with normal fetal ultrasound evaluations.

Molecular testing of FMR1 (CGG)n expanded repeats remains hard to tackle given the limitations of sizing PCR in detecting large and uninformative alleles, resulting in a significant number of samples that require confirmation through laborious southern blot analysis. Abbott recently developed a TP-PCR in combination with a sizing PCR to facilitate the Fragile X diagnostic testing workflow. This study aimed at comparing Abbott FraXa sizing PCR and TP-PCR versus in-house sizing PCR and southern blot in order to evaluate the sizing accuracy and detection sensitivity of normal, intermediate, premutation and mutation alleles. Over 100 samples of different sources (approximately 50% whole blood, 40% chorion villi and 10% amniocytes) and a panel of artificially mimicked mosaic samples were evaluated. Signal intensity and sizing accuracy met expectations in the normal to small premutation range with a deviation of ± 1 repeat regardless the sample source or DNA extraction method used. The sizing 'long run' greatly improved the detection capacity and sizing accuracy of longer range (large premutation to full mutation) fragments, although inspection of raw data is recommended. TP-PCR allowed discrimination between normal/intermediate and premutation/mutation alleles. However, premutation and mutation TP-PCR signal patterns were very similar, therefore requiring the Abbott sizing PCR to distinguish them. Mosaic detection in sizing- and TP-PCR ranged from 20% to 10% depending on the repeat range mixture used. Our results corroborate the suggested Abbott workflow of using FraXa TP-PCR as a first line screening platform in combination with the sizing PCR as second line test.

This study evaluated a large set of blinded, previously analyzed prenatal DNA samples with a novel, CGG triplet-repeat primed (TP)–PCR assay (Amplidex FMR1 PCR Kit; Asuragen, Austin, TX). This cohort of 67 fetal DNAs contained 18 full mutations (270 to 1100 repeats, including 1 mosaic), 12 premutations (59 to 150 repeats), 9 intermediate mutations (54 to 58 repeats), and 28 normal samples (17 to 50 repeats, including 3 homozygous female samples). TP-PCR accurately identified FMR1 genotypes, ranging from normal to full- mutation alleles, with a 100% specificity (95% CI, 85.0% to 100%) and a 97.4% sensitivity (95% CI, 84.9% to 99.9%) in comparison with Southern blot analysis results. Exact sizing was possible for a spectrum of normal, intermediate, and premutation (up to 150 repeats) alleles, but CGG repeat numbers >200 are only identified as full mutations. All homozygous alleles were correctly resolved. The assay is also able to reproducibly detect a 2.5% premutation and a 3% full-mutation mosaicism in a normal male background, but a large premutation in a full male mutation background was masked when the amount of the latter was >5%. Implementation of this TP-PCR will significantly reduce reflex testing using Southern blot analyses. Additional testing with methylation-informative techniques might still be needed for a few cases with (large) premutations or full mutations.

Robertsonian translocation carriers are at increased risk for infertility, spontaneous abortions, or chromosomally unbalanced offspring. Reproductive counseling of these carriers is challenging. We performed a retrospective analysis of all prenatal diagnoses from Robertsonian translocation carriers during the time period January 1, 1992 through December 31, 2007. Data on the carriers and the results of their prenatal analyses were retrieved as well as data on their previous pregnancies. We identified 28 female and 20 male carriers of Robertsonian translocations and results on 79 prenatal samples were obtained. Among female carriers, 10.3% of chorionic villus sampling and 5.9% of amniocentesis results were unbalanced, whereas for male carriers, this was 3.6% and 0%, respectively. When considering all pregnancies involving carriers, 52.7% of those to female carriers and 61.8% of those to male carriers led to the birth of a healthy child. Male carriers in whom the translocation was ascertained because of infertility or recurrent miscarriages appear to be at higher risk, whereas carriers in whom ascertainment was because of a family history are at lower risk. We conclude that pregnancies of Robertsonian translocation carriers are at increased risk for chromosomal imbalance, and prenatal chromosomal testing should be discussed. More than half of the pregnancies led to the birth of a healthy child, but prediction of which couples will be successful in obtaining a pregnancy with or without assisted reproductive technologies and/or embryo selection remains difficult. The reason for ascertainment of the translocation should be taken into account when counseling these couples. The possibility of preimplantation genetic diagnosis should also be discussed with the couples.