Prenatal phenotype of a homozygous nonsense MPDZ variant in a fetus with severe congenital hydrocephalus.

The fetal phenotype of MPDZ-associated congenital hydrocephalus type 2 with or without brain or eye anomalies (HYC2) (OMIM 615219) is not well described in the literature. The present case shows not previously published clinical fetal features that are detected during routine second trimester ultrasound screening at 21 weeks of gestation such as bilateral ventriculomegaly, lean cavum septum pellucidum, suspicion of hypoplastic corpus callosum, and suspicion of gyration disorder with normal fossa posterior. Combination of clinical features and a gene panel for congenital malformation syndromes detected a homozygous, likely pathogenic nonsense variant in the MPDZ gene. HYC2 is a rare autosomal recessive disorder with prenatal onset. Clinical presentation is highly variable, varying from stillbirth and severe neurodevelopmental problems with death in infancy to adult patients. Other reported associated congenital anomalies are mainly heart defects and ophthalmologic abnormalities. The present case so far is the first prenatally well described case of HYC2 in an ongoing pregnancy.

Population screening for 15q11-q13 duplications: corroboration of the difference in impact between maternally and paternally inherited alleles.

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.

Searching for a sense of closure: parental experiences of recontacting after a terminated pregnancy for congenital malformations.

Rapid advances in genetic testing have improved the probability of successful genetic diagnosis. For couples who undergo a termination of pregnancy (TOP) due to foetal congenital malformations, these techniques may reveal the underlying cause and satisfy parents' need to know. The aim of this qualitative descriptive research study was to explore couples' experience of being recontacted after a congenital malformation-related TOP, as well as their reasons for participation. A retrospective cohort of 31 eligible candidates was recontacted for additional genetic testing using a standardized letter followed by a telephone call. Fourteen participants (45%) were included. Data were collected through semi-structured interviews at a hospital genetics department (UZ Brussel). Interviews were audiotaped, transcribed and analysed using thematic analysis. We found that despite the sometimes considerable length of time that passed since TOP, participants were still interested in new genetic testing. They appreciated that the initiative originated from the medical team, describing it as a "sensitive" approach. Both intrinsic (providing answers for themselves and their children) and extrinsic motivators (contributing to science and helping other parents) were identified as important factors for participation. These results show that participants often remain interested in being recontacted for new genetic testing such as whole genome sequencing, even after several years. As such, the results of this study can offer guidance in the more general current debate on recontacting patients in the field of genetics.

Pregnancy termination at a viable stage in daily clinical practice: A nationwide mortality follow-back study in Flanders, Belgium.

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 than spontaneously 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 » 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.

Implementation of fetal clinical exome sequencing: Comparing prospective and retrospective cohorts.

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.

A prenatal case of lissencephaly with cerebellar hypoplasia: New mutation in RELN gene.

Reelinopathies cause a distinctive lissencephaly type associated with cerebellar hypoplasia. To help further management, we wanted to report here the first prenatal diagnosis due to a homozygous inherited reelinopathy.

Primary maternal cytomegalovirus infections: accuracy of fetal ultrasound for predicting sequelae in offspring.

BACKGROUND: Cytomegalovirus infection is the most common perinatal viral infection that 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: We sought 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 from 1996 through 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: A total of 67 patients (69 fetuses) with proven vertical transmission were included in this study, including 64 singleton and 3 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, 6 had normal clinical evaluations, whereas 6 presented with either hearing and/or neurological anomalies, classified as severe in 4 cases. Among the 23 live-born infants with normal prenatal ultrasound, 5 developed hearing impairments and 1 showed mild neurological developmental delay. CONCLUSION: 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.

Reliable and sensitive detection of fragile X (expanded) alleles in clinical prenatal DNA samples with a fast turnaround time.

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.

Pregnancy outcome in carriers of Robertsonian translocations.

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.

Tailored Composite Polymer-Metal Nanoparticles by Miniemulsion Polymerization and Thiol-ene Functionalization.

A simple and modular synthetic approach, based on miniemulsion polymerization, has been developed for the fabrication of composite polymer-metal nanoparticle materials. The procedure produces well-defined composite structures consisting of gold, silver or MnFe(2)O(4) nanoparticles (∼10 nm in diameter) encapsulated within larger spherical nanoparticles of poly(divinylbenzene) (∼100 nm in diameter). This methodology readily permits the incorporation of multiple metal domains into a single polymeric particle, while still preserving the useful optical and magnetic properties of the metal nanoparticles. The morphology of the composite particles is retained upon increasing the inorganic content, and also upon redispersion in organic solvents. Finally, the ability to tailor the surface chemistry of the composite nanoparticles and incorporate steric stabilizing groups using simple thiol-ene chemistry is demonstrated.