A prospective study on rapid exome sequencing as a diagnostic test for multiple congenital anomalies on fetal ultrasound

Objective

Conventional genetic tests (quantitative fluorescent-PCR [QF-PCR] and single nucleotide polymorphism-array) only diagnose ~40% of fetuses showing ultrasound abnormalities. Rapid exome sequencing (rES) may improve this diagnostic yield, but includes challenges such as uncertainties in fetal phenotyping, variant interpretation, incidental unsolicited findings, and rapid turnaround times. In this study, we implemented rES in prenatal care to increase diagnostic yield.

Methods

We prospectively studied 55 fetuses. Inclusion criteria were: (a) two or more independent major fetal anomalies, (b) hydrops fetalis or bilateral renal cysts alone, or (c) one major fetal anomaly and a first-degree relative with the same anomaly. In addition to conventional genetic tests, we performed trio rES analysis using a custom virtual gene panel of ~3850 Online Mendelian Inheritance in Man (OMIM) genes.

Results

We established a genetic rES-based diagnosis in 8 out of 23 fetuses (35%) without QF-PCR or array abnormalities. Diagnoses included MIRAGE (SAMD9), Zellweger (PEX1), Walker-Warburg (POMGNT1), Noonan (PTNP11), Kabuki (KMT2D), and CHARGE (CHD7) syndrome and two cases of Osteogenesis Imperfecta type 2 (COL1A1). In six cases, rES diagnosis aided perinatal management. The median turnaround time was 14 (range 8-20) days.

Conclusion

Implementing rES as a routine test in the prenatal setting is challenging but technically feasible, with a promising diagnostic yield and significant clinical relevance.     

Rapid whole exome sequencing in pregnancies to identify the underlying genetic cause in fetuses with congenital anomalies detected by ultrasound imaging

Objective

The purpose of this study was to explore the diagnostic yield and clinical utility of trio-based rapid whole exome sequencing (rWES) in pregnancies of fetuses with a wide range of congenital anomalies detected by ultrasound imaging.

Methods

In this observational study, we analyzed the first 54 cases referred to our laboratory for prenatal rWES to support clinical decision making, after the sonographic detection of fetal congenital anomalies. The most common identified congenital anomalies were skeletal dysplasia (n = 20), multiple major fetal congenital anomalies (n = 17) and intracerebral structural anomalies (n = 7).

Results

A conclusive diagnosis was identified in 18 of the 54 cases (33%). Pathogenic variants were detected most often in fetuses with skeletal dysplasia (n = 11) followed by fetuses with multiple major fetal congenital anomalies (n = 4) and intracerebral structural anomalies (n = 3). A survey, completed by the physicians for 37 of 54 cases, indicated that the rWES results impacted clinical decision making in 68% of cases.

Conclusions

These results suggest that rWES improves prenatal diagnosis of fetuses with congenital anomalies, and has an important impact on prenatal and peripartum parental and clinical decision making.     

Comprehensive prenatal diagnostics: Exome versus genome sequencing

Objective

This study aimed to assess the diagnostic yield of prenatal genetic testing using trio whole exome sequencing (WES) and trio whole genome sequencing (WGS) in pregnancies with fetal anomalies by comparing the results with conventional chromosomal microarray (CMA) analysis.

Methods

A total of 40 pregnancies with fetal anomalies or increased nuchal translucency (NT ≥ 5 mm) were included between the 12th and 21st week of gestation. Trio WES/WGS and CMA were performed in all cases.

Results

The trio WES/WGS analysis increased the diagnostic yield by 25% in cases with negative CMA results. Furthermore, all six chromosomal aberrations identified by CMA were independently detected by WES/WGS analysis. In total, 16 out of 40 cases obtained a genetic sequence variant, copy number variant, or aneuploidy explaining the phenotype, resulting in an overall WES/WGS diagnostic yield of 40%. WES analysis provided a more reliable identification of mosaic sequence variants than WGS because of its higher sequencing depth.

Conclusions

Prenatal WES/WGS proved to be powerful diagnostic tools for fetal anomalies, surpassing the diagnostic yield of CMA. They have the potential to serve as standalone methods for prenatal diagnosis. The study highlighted the limitations of WGS in accurately detecting mosaic variants, which is particularly relevant when analyzing chorionic villus samples.     

Prenatal diagnosis of congenital head,face, and neck malformations—Is complementary fetal MRI of value?

Objectives

The aim of this study was to evaluate the role of fetal magnetic resonance imaging (MRI) as a complement to ultrasound (US) in the prenatal diagnosis of craniofacial anomalies.

Methods

A historical cohort study including all pregnant women who were referred for fetal MRI because of antenatal diagnosis of craniofacial anomalies on screening US. Prenatal diagnostic US, MRI, and postnatal diagnosis were compared for consistencies and discrepancies.

Results

Forty-five pregnant women with 73 suspected fetal craniofacial anomalies diagnosed by US underwent MRI. In 40 out of 73 anomalies (54.8%), US and MRI findings were in complete agreement with postnatal diagnoses. MRI correctly ruled out the diagnosis of 24 anomalies suspected on US and diagnosed four additional pathologies that were not demonstrated by US. Out of the 85 anomalies (suspected by imaging or confirmed postnatally), confident diagnosis could be made by MRI in 68 anomalies (80%), not diagnosed in 10 (11.8%), and over-diagnosed in seven (8.2%). By US, confident diagnosis could be made in 44 anomalies (51.8%), not diagnosed in 11 (12.9%), and over-diagnosed in 30 (35.3%).

Conclusion

MRI is valuable in the antenatal evaluation of fetal craniofacial anomalies and may be useful as an adjunct to US in the prenatal work-up of craniofacial anomalies.     

Isolation of single circulating trophoblasts from maternal circulation for noninvasive fetal copy number variant profiling

Objective

To develop a multi-step workflow for the isolation of circulating extravillous trophoblasts (cEVTs) by describing the key steps enabling a semi-automated process, including a proprietary algorithm for fetal cell origin genetic confirmation and copy number variant (CNV) detection.

Methods

Determination of the limit of detection (LoD) for submicroscopic CNV was performed by serial experiments with genomic DNA and single cells from Coriell cell line biobank with known imbalances of different sizes. A pregnancy population of 372 women was prospectively enrolled and blindly analyzed to evaluate the current workflow.

Results

An LoD of 800 Kb was demonstrated with Coriell cell lines. This level of resolution was confirmed in the clinical cohort with the identification of a pathogenic CNV of 800 Kb, also detected by chromosomal microarray. The mean number of recovered cEVTs was 3.5 cells per sample with a significant reverse linear trend between gestational age and cEVT recovery rate and number of recovered cEVTs. In twin pregnanices, evaluation of zygosity, fetal sex and copy number profiling was performed in each individual cell.

Conclusion

Our semi-automated methodology for the isolation and single-cell analysis of cEVTS supports the feasibility of a cell-based noninvasive prenatal test for fetal genomic profiling.     

Access to prenatal exome sequencing for fetal malformations: A qualitative landscape analysis in the US

Objective

There is increasing evidence supporting the clinical utility of next generation sequencing for identifying fetal genetic disorders. However, there are limited data on the demand for and accessibility of these tests, as well as payer coverage in the prenatal context. We sought to identify clinician perspectives on the utility of prenatal exome sequencing (ES) and on equitable access to genomic technologies for the care of pregnancies complicated by fetal structural anomalies.

Method

We conducted two focus group discussions and six interviews with a total of 13 clinicians (11 genetic counselors; 2 Maternal Fetal Medicine/Geneticists) from U.S. academic centers and community clinics.

Results

Participants strongly supported ES for prenatal diagnostic testing in pregnancies with fetal structural anomalies. Participants emphasized the value of prenatal ES as an opportunity for a continuum of care before, during, and after a pregnancy, not solely as informing decisions about abortions. Cost and coverage of the test was the main access barrier, and research was the main pathway to access ES in academic centers.

Conclusion

Further integrating the perspectives of additional key stakeholders are important for understanding clinical utility, developing policies and practices to address access barriers, and assuring equitable provision of prenatal diagnostic testing.     

Non-invasive prenatal testing (NIPT): Combination of copy number variant and gene analyses using an “in-house” target enrichment next generation sequencing—Solution for non-centralized NIPT laboratory?

Objective

Recent studies have integrated copy number variant (CNV) and gene analysis using target enrichment. Here, we transferred this concept to our routine genetics laboratory, which is not linked to centralized non-invasive prenatal testing (NIPT) facilities.

Method

From a cohort of 100 pregnant women, 22 were selected for the analysis of maternal genomic DNA (gDNA) along with fetal cell-free DNA. Using targeted enrichment, 135 genes were analyzed, combined with aberrations of chromosomes 21, 18, 13, X, and Y. The data were subjected to specificity and sensitivity analyses, and correlated with the results from invasive testing methods.

Results

The sensitivity/specificity was determined for the CNV analysis of chromosomes: 21 (80%/75%), 18 (-/82%), 13 (100%/67%), and Y (100%/100%). The gene detection was valid for maternal gDNA. However, for cell-free fetal DNA, it was not possible to determine the boundary between an artifact and a real sequence variant.

Conclusion

The target enrichment method combining CNV and gene detection seems feasible in a regular laboratory. However, this method can only be responsibly optimized with a sufficient number of controls and further validation on a strong bioinformatic background. The present results showed that NIPT should be performed in specialized centers, and that its introduction to isolated laboratories may not provide valid data.     

Multicenter clinical experience with non-invasive cell-free DNA screening for monosomy X and related X-chromosome variants

Objective

We aimed to investigate how the presence of fetal anomalies and different X chromosome variants influences Cell-free DNA (cfDNA) screening results for monosomy X.

Methods

From a multicenter retrospective survey on 673 pregnancies with prenatally suspected or confirmed Turner syndrome, we analyzed the subgroup for which prenatal cfDNA screening and karyotype results were available. A cfDNA screening result was defined as true positive (TP) when confirmatory testing showed 45,X or an X-chromosome variant.

Results

We had cfDNA results, karyotype, and phenotype data for 55 pregnancies. cfDNA results were high risk for monosomy X in 48/55, of which 23 were TP and 25 were false positive (FP). 32/48 high-risk cfDNA cases did not show fetal anomalies. Of these, 7 were TP. All were X-chromosome variants. All 16 fetuses with high-risk cfDNA result and ultrasound anomalies were TP. Of fetuses with abnormalities, those with 45,X more often had fetal hydrops/cystic hygroma, whereas those with “variant” karyotypes had different anomalies.

Conclusion

Both, 45,X or X-chromosome variants can be detected after a high-risk cfDNA result for monosomy X. When there are fetal anomalies, the result is more likely a TP. In the absence of fetal anomalies, it is most often an FP or X-chromosome variant.     

Couples experiences of receiving uncertain results following prenatal microarray or exome sequencing: A mixed-methods systematic review

Background

Tests in pregnancy such as chromosomal microarray analysis and exome sequencing are increasing diagnostic yield for fetal structural anomalies, but have greater potential to result in uncertain findings. This systematic review investigated the experiences of prospective parents about receiving uncertain results from these tests.

Methods

A systematic search of three electronic databases was conducted. Data extraction was performed for studies that met the eligibility and quality criteria. Results were synthesised following the principles of thematic analysis.

Results

Fourteen studies (10 qualitative, 4 quantitative) were included. Findings were grouped into three overarching themes. Sources of uncertainty included the testing procedure, the diagnosis and prognosis, and health professionals' own uncertainty. The clinical impact of the uncertainty included parents struggling to make clinical decisions with the information available, the emotional impact included decisional-regret, shock, worry and feeling overwhelmed. To manage the uncertainty, parents sought support from healthcare professionals, friends, family, the internet and other parents as well as remaining hopeful.

Conclusions

Prospective parents experience a myriad of uncertainties in the prenatal setting, which must be handled sensitively. Future research should explore optimal ways of managing uncertainty to minimise harm. Recommendations are made for discussing uncertainty during pre- and post-test counseling.     

Prenatal diagnosis of the Hunter syndrome and the introduction of a new fluorimetric enzyme assay

Prenatal diagnosis of the Hunter syndrome (mucopolysaccharidosis type II; MPS II) is preferably achieved by the assay of iduronate-2-sulphate sulphatase (IDS) in uncultured chorionic villi (CV) as this allows early (12th week), rapid (2–3 days) and reliable results. We summarize the results of 174 prenatal analyses in the past 30 years, using various methods such as radiolabelled sulphate incorporation in amniotic fluid (AF) cells, glycosaminoglycan (GAG)-electrophoresis in AF and IDS assay in CV, CV-cells, AF and AF-cells. Twenty-seven fetuses with MPS II were diagnosed after finding clearly abnormal results in pregnancies with a male fetus; very low IDS activity has also been measured in some pregnancies with a (heterozygous) female fetus, emphasizing the need to combine enzyme assay with fetal sex determination. IDS activity has until recently been assessed by a cumbersome radioactive enzyme assay. Here we describe the use of a novel fluorigenic 4-methylumbelliferyl substrate, which allows a sensitive, rapid and convenient assay of IDS activity and reliable early prenatal diagnosis. This novel IDS assay was validated in retrospective analyses of 14 CV, CV-cell, AF and AF-cell samples from affected pregnancies in addition to prospective prenatal diagnosis in eight pregnancies at risk with one MPS II-affected fetus. Copyright © 2002 John Wiley & Sons, Ltd.     

Fetal de novo heterozygous variant in the isocitrate dehydrogenase 1 gene associated with growth restriction,skeletal, cerebral and vascular anomalies

Germline pathogenic variants in isocitrate dehydrogenase 1 (IDH1) can lead to a rare neurodevelopmental disorder called metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, including severe skeletal and cerebral anomalies. To the best of our knowledge, no prenatal case of an IDH1 pathogenic variant has been reported in literature. Somatic sequence variants in IDH1/2 genes are described in distinct cancers, premalignant diseases and rare inherited metabolic disorders. Amniocentesis and further genetic testing including trio exome sequencing were performed due to suspicious findings on a second trimester routine prenatal ultrasound examination. The fetus was found to have growth restriction, cerebral abnormalities (ex vacuo hydrocephalus, cerebellar and vermian hypoplasia, corpus callosum dysgenesis), brachycephaly, narrow chest, persistent left superior vena cava, liver calcifications, hyperechogenic bowel, short tubular bones and joint contractures. A de novo heterozygous variant in the IDH1 gene was detected via trio exome sequencing. The prenatal diagnosis of a de novo pathogenic variant in IDH1 in a fetus with the described phenotype, obtained through trio exome sequencing, helped parents and providers with an informed decision making about pregnancy management.     

Perinatal outcomes and genomic characteristics of fetal copy number variants: An individual record linkage study of 713 pregnancies

Objective

To determine the perinatal outcomes of fetuses diagnosed with a pathogenic copy number variant (CNV) or variant of uncertain significance (VUS); and to characterize these variants in terms of testing indication, genomic location, size, and inheritance.

Methods

Retrospective study of singleton pregnancies with a pathogenic CNV or VUS from a single laboratory during 2012–2018. Probabilistic record linkage between the prenatal diagnosis dataset and perinatal outcome data for births from 20 weeks gestation was performed. If no birth record was found, this implied a pregnancy loss <20 weeks.

Results

We included 6945 prenatal microarray results; a pathogenic CNV was detected in 230 (3.3%, 95% CI: 2.9%–3.8%) and a VUS in 483 (7.0%, 95% CI: 6.4%–7.6%). Of pregnancies with a pathogenic CNV, 20.0% (95% CI: 15.3%–25.6%) had a live birth, 3.0% (95% CI: 1.5%–6.2%) had a perinatal death (stillbirth or neonatal death), and 77% (95% CI: 71.1%–81.9%) had no birth record. Of those with a VUS, 64.4% (95% CI: 60.0%–68.5%) had a live birth, 1.8% (95% CI: 1.0%–3.5%) had a perinatal death, and no birth record was found for 33.7% (95% CI: 29.7%–38.1%). Most pathogenic CNVs (61.1%) were <7 Mb in size. The most common microdeletion syndromes were DiGeorge, Wolf-Hirschhorn, and Cri-du-chat syndromes.

Conclusion

This study provides an overview of perinatal outcomes and frequency of recurrent CNVs observed in the prenatal microarray era.     

Prenatal diagnosis of Myhre syndrome with a heterozygous pathogenic variant in SMAD4 gene presented with thick nuchal translucency and cardiac abnormalities

Prenatal testing was performed in a 39-year-old Chinese pregnant woman referred for increased nuchal translucency measuring 5.7 mm. Non-invasive prenatal testing and SNP array study on amniotic fluid samples were normal. Whole exome sequencing (WES) was initiated further as the fetus had pericardial effusion of 1.2 mm, thickened myocardium over the right ventricular lateral wall and aberrant right subclavian artery. A detailed fetal echocardiogram also revealed persistent left superior vena cava and dilated coronary sinus at 20 weeks. From whole exome sequencing of the trio, a de novo heterozygous variant NM_005359.5(SMAD4): c.1499T>C (p.Ile500Thr) was detected. This pathogenic variant has been reported in the postnatal case cohort of Myhre syndrome. This condition is characterized by facial dysmorphism, intellectual disability, hearing loss, skeletal abnormalities and potential life threatening respiratory or cardiovascular manifestations. Termination of pregnancy was performed at 23 weeks. Small chins, pre-axial polydactyly, brachydactyly and clinodactyly were noted in the abortus. Ultrasound findings of increased nuchal translucency, thickened myocardium and pericardial effusion prompted further genetic evaluation for the prenatal diagnosis of Myhre syndrome by whole exome sequencing.     

Noninvasive prenatal screening for cystic fibrosis using circulating trophoblasts: Detection of the 50 most common disease-causing variants

Objectives

Cystic fibrosis (CF) is one of the most common severe autosomal recessive disorders. Prenatal or preconception CF screening is offered in some countries. A maternal blood sample in early pregnancy can provide circulating trophoblasts and offers a DNA source for genetic analysis of both the mother and the fetus. This study aimed to develop a cell-based noninvasive prenatal test (NIPT) to screen for the 50 most common CF variants.

Methods

Blood samples were collected from 30 pregnancies undergoing invasive diagnostics and circulating trophoblasts were harvested in 27. Cystic fibrosis testing was conducted using two different methods: by fragment length analysis and by our newly developed NGS-based CF analysis.

Results

In all 27 cases, cell-based NIPT provided a result using both methods in agreement with the invasive test result.

Conclusion

This study shows that cell-based NIPT for CF screening provides a reliable result without the need for partner- and proband samples.     

Prenatal ultrasound finding of atypical genitalia: Counseling,genetic testing and outcomes

Objective

To report uptake of genetic counseling (GC) and prenatal genetic testing after the finding of atypical genitalia on prenatal ultrasound (US) and the clinical and genetic findings of these pregnancies.

Methods

A retrospective cohort study (2017–2019) of atypical fetal genitalia in a large expert center for disorders/differences of sex development. We describe counseling aspects, invasive prenatal testing, genetic and clinical outcome of fetuses apparently without [group 1, n = 22 (38%)] or with [group 2, n = 36 (62%)] additional anomalies on US.

Results

In group 1, 86% of parents opted for GC versus 72% in group 2, and respectively 58% and 15% of these parents refrained from invasive testing. Atypical genitalia were postnatally confirmed in 91% (group 1) and 64% (group 2), indicating a high rate of false positive US diagnosis of ambiguous genitalia. Four genetic diagnoses were established in group 1 (18%) and 10 in group 2 (28%). The total genetic diagnostic yield was 24%. No terminations of pregnancy occurred in group 1.

Conclusions

For optimal care, referral for an expert fetal US scan, GC and invasive diagnostics including broad testing should be offered after prenatal detection of isolated atypical genitalia.     

Prenatal diagnosis of bilateral anophthalmia: Identifying de novo SOX2 variant

A 26 year old nulligravida presented at 24 weeks gestation for the second opinion of abnormal fetal profile and mid-face views on ultrasound at another institution. A detailed fetal anatomic ultrasound at our facility revealed the absence of fetal lens and globes bilaterally consistent with bilateral anophthalmia (HP: 0000528) without other anomalies. Karyotype and chromosomal microarray analysis were completed from amniocentesis sample. After these results, duo exome testing with paternal sequencing was completed from proband amniotic fluid sample and parental blood samples. A pathogenic variant in SOX2 (NM_003106.3: c.513C>G p.(Tyr171*Ter)) with heterozygous autosomal dominant inheritance resulted. On duo exome testing with paternal segregation analysis, the variant was found to be consistent with likely sporadic de novo inheritance. The SOX2 variant reported is consistent with the fetal phenotype in this case. While germline mosaicism could exist, this identified variant provided the family with a likely explanation for this proband's finding. This ultrasound and genetic testing allowed the family to make decisions related to planning in current and future pregnancies.     

Investigation into the genetics of fetal congenital lymphatic anomalies

Objective

Congenital lymphatic anomalies (LAs) arise due to defects in lymphatic development and often present in utero as pleural effusion, chylothorax, nuchal and soft tissue edema, ascites, or hydrops. Many LAs are caused by single nucleotide variants, which are not detected on routine prenatal testing.

Methods

Demographic data were compared between two subcohorts, those with clinically significant fetal edema (CSFE) and isolated fetal edema. A targeted variant analysis of LA genes was performed using American College of Medical Genetics criteria on whole exome sequencing (WES) data generated for 71 fetal edema cases who remained undiagnosed after standard workup.

Results

CSFE cases had poor outcomes, including preterm delivery, demise, and maternal preeclampsia. Pathogenic and likely pathogenic variants were identified in 7% (5/71) of cases, including variants in RASopathy genes, RASA1, SOS1, PTPN11, and a novel PIEZO1 variant. Variants of uncertain significance (VOUS) were identified in 45% (32/71) of cases. In CSFEs, VOUS were found in CELSR1, EPHB4, TIE1, PIEZO1, ITGA9, RASopathy genes, SOS1, SOS2, and RAF1.

Conclusions

WES identified pathogenic and likely pathogenic variants and VOUS in LA genes in 51% of fetal edema cases, supporting WES and expanded hydrops panels in cases of idiopathic fetal hydrops and fluid collections.     

Turner syndrome-omphalocele association: Incidence,karyotype, phenotype and fetal outcome

Objective

Omphalocele is known to be associated with genetic anomalies like trisomy 13, 18 and Beckwith–Wiedemann syndrome, but not with Turner syndrome (TS). Our aim was to assess the incidence of omphalocele in fetuses with TS, the phenotype of this association with other anomalies, their karyotype, and the fetal outcomes.

Method

Retrospective multicenter study of fetuses with confirmed diagnosis of TS. Data were extracted from a detailed questionnaire sent to specialists in prenatal ultrasound.

Results

680 fetuses with TS were included in this analysis. Incidence of small omphalocele in fetuses diagnosed ≥12 weeks was 3.1%. Including fetuses diagnosed before 12 weeks, it was 5.1%. 97.1% (34/35) of the affected fetuses had one or more associated anomalies including increased nuchal translucency (≥3 mm) and/or cystic hygroma (94.3%), hydrops/skin edema (71.1%), and cardiac anomalies (40%). The karyotype was 45,X in all fetuses. Fetal outcomes were poor with only 1 fetus born alive.

Conclusion

TS with 45,X karyotype but not with X chromosome variants is associated with small omphalocele. Most of these fetuses have associated anomalies and a poor prognosis. Our data suggest an association of TS with omphalocele, which is evident from the first trimester.     

Non-invasive fetal genotyping for maternal alleles with droplet digital PCR: A comparative study of analytical approaches

Objectives

To develop a flexible droplet digital PCR (ddPCR) workflow to perform non-invasive prenatal diagnosis via relative mutation dosage (RMD) for maternal pathogenic variants with a range of inheritance patterns, and to compare the accuracy of multiple analytical approaches.

Methods

Cell free DNA (cfDNA) was tested from 124 archived maternal plasma samples: 88 cases for sickle cell disease and 36 for rare Mendelian conditions. Three analytical methods were compared: sequential probability ratio testing (SPRT), Bayesian and z-score analyses.

Results

The SPRT, Bayesian and z-score analyses performed similarly well with correct prediction rates of 96%, 97% and 98%, respectively. However, there were high rates of inconclusive results for each cohort, particularly for z-score analysis which was 31% overall. Two samples were incorrectly classified by all three analytical methods; a false negative result predicted for a fetus affected with sickle cell disease and a false positive result predicting the presence of an X-linked IDS variant in an unaffected fetus.

Conclusions

ddPCR can be applied to RMD for diverse conditions and inheritance patterns, but all methods carry a small risk of erroneous results. Further evaluation is required both to reduce the rate of inconclusive results and explore discordant results in more detail.     

Exomphalos without other prenatally detected anomalies: Perinatal outcomes from 22 years of population-based data

Objective

To ascertain the perinatal outcomes for an apparently isolated exomphalos detected by prenatal ultrasound.

Method

Our dataset captures cases from 614 321 births in the Wessex region of England and the Channel Isles on all cases of pre- or postnatally diagnosed exomphalos from 1994 to 2015. Ascertainment was >95%.

Results

Three hundred and thirty five cases were reported to the register: 28 (8%) were not detected prenatally, 18 (6%) had already died in utero, 169 (55%) cases were found to have additional anomalies on first tertiary ultrasound scan and one case was lost to follow-up. Therefore 119 (39%) cases had an apparently isolated exomphalos. Of the 119 cases with only an exomphalos detected on first tertiary ultrasound scan, 25 (21%) had a chromosome abnormality. Of those with a normal or untested karyotype, 61% were confirmed to be an isolated anomaly after birth, 13% had an additional heart abnormality, 9% had Beckwith-Wiedemann syndrome and 11% had additional problems diagnosed postnatally.

Conclusion

Our large population-based dataset with an average of 1 year's postnatal follow-up suggests that more than one-third of apparently isolated prenatal cases of exomphalos will have an additional finding detected after birth. These data should help assist clinicians in their prenatal counseling.