ABSTRACTGenetic technology has advanced dramatically in the past few decades, and its applications and use in caring for and counseling pregnant women has been transformational in the realm of ...prenatal diagnosis. Two of the newer genetic technologies in the prenatal setting are chromosomal microarray and whole-exome sequencing. Chromosomal microarray analysis is a method of measuring gains and losses of DNA throughout the human genome. It can identify chromosomal aneuploidy and other large changes in the structure of chromosomes as well as submicroscopic abnormalities that are too small to be detected by traditional modalities. Prenatal chromosomal microarray analysis is recommended for a patient with a fetus with one or more major structural abnormalities identified on ultrasonographic examination and who is undergoing invasive prenatal diagnosis. Whole-genome sequencing analyzes the entire genome, including noncoding regions (introns) and coding regions (exons). However, because the introns are typically of little clinical relevance, there has been a focus instead on whole-exome sequencing, which examines the coding regions (exons) of the genome. The exons generally have greater clinical relevance and applicability to patient care. However, the routine use of whole-genome or whole-exome sequencing for prenatal diagnosis is not recommended outside of the context of clinical trials.
Birth defects are a major problem threatening the health of children in China. Genetic factors play a major role in birth defect etiology. Molecular diagnosis is the key means for screening, ...diagnosing, and preventing birth defects caused by genetic factors. How to carry out large-scale and cost-effective molecular diagnosis in clinical practice is a major challenge in the prevention and treatment of birth defects in China. This article reviews the current status of birth defects in China, the application of molecular diagnostic technology in birth defect prevention and control, and the challenges in promoting its use, to provide references for clinical practice in birth defect molecular diagnosis.
Filamins are large actin-binding proteins that stabilize delicate three-dimensional actin filament networks and link them to cellular membranes where they integrate cell architectural and signaling ...functions important for cell locomotion. Filamins have been shown to bind to proteins with diverse functions and are implicated in human genetic diseases including malformations of the skeleton, brain, and heart. Mouse models of filamin deficiency have advanced our understanding of the important roles filamins play in embryonic development and disease progression. These studies provide clear evidence that cytoskeletal filamin proteins integrate cell signaling, transcription and organ development. This review focuses on the emerging roles of filamins in cell signaling and transcription, with emphasis on cell motility and organ development.
Background
Routine third‐trimester ultrasound is frequently offered to pregnant women to identify fetuses with abnormal growth. Infrequently, a congenital anomaly is incidentally detected.
Objective
...To establish the prevalence and type of fetal anomalies detected during routine third‐trimester scans using a systematic review and meta‐analysis.
Search strategy
Electronic databases (MEDLINE, Embase and the Cochrane library) from inception until August 2019.
Selection criteria
Population‐based studies (randomised control trials, prospective and retrospective cohorts) reporting abnormalities detected at the routine third‐trimester ultrasound performed in unselected populations with prior screening. Case reports, case series, case‐control studies and reviews without original data were excluded.
Data collection and analysis
Prevalence and type of anomalies detected in the third trimester. We calculated pooled prevalence as the number of anomalies per 1000 scans with 95% confidence intervals. Publication bias was assessed.
Main results
The literature search identified 9594 citations: 13 studies were eligible representing 141 717 women; 643 were diagnosed with an unexpected abnormality. The pooled prevalence of a new abnormality diagnosed was 3.68 per 1000 women scanned (95% CI 2.72–4.78). The largest groups of abnormalities were urogenital (55%), central nervous system abnormalities (18%) and cardiac abnormalities (14%).
Conclusion
Combining data from 13 studies and over 140 000 women, we show that during routine third‐trimester ultrasound, an incidental fetal anomaly will be found in about 1 in 300 scanned women. This information should be taken into account when taking consent from women for third‐trimester ultrasound and when designing and assessing cost of third‐trimester ultrasound screening programmes.
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One in 300 women attending a third‐trimester scan will have a finding of a fetal abnormality.
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One in 300 women attending a third‐trimester scan will have a finding of a fetal abnormality.
Objective To assess live-birth defects after a luteal-phase ovarian-stimulation regimen (LPS) for in vitro fertilization (IVF) and vitrified embryo transfer (ET) cycles. Design Retrospective cohort ...study. Setting Tertiary-care academic medical center. Patient(s) Infants who were born between January 1, 2013 and May 1, 2014 from IVF with intracytoplasmic sperm injection (ICSI) treatments (n = 2,060) after either LPS (n = 587), the standard gonadotropin-releasing hormone–agonist (GnRH-a) short protocol (n = 1,257), or mild ovarian stimulation (n = 216). Intervention(s) The three ovarian-stimulation protocols described and assisted reproductive technology (ART) treatment (IVF or ICSI, and vitrified ET) in ordinary practice. Main Outcome Measure(s) The main measures were: gestational age, birth weight and length, multiple delivery, early neonatal mortality, and birth defects. Associations were assessed using logistic regression by adjusting for confounding factors. Result(s) The final sample included 2,060 live-born infants, corresponding to 1,622 frozen–thawed (FET) cycles, which led to: 587 live-born infants from LPS (458 FET cycles); 1,257 live-born infants from the short protocol (984 FET cycles); and 216 live-born infants from mild ovarian stimulation (180 FET cycles). Birth characteristics regarding gestational age, birth weight and length, multiple delivery, and early neonatal death were comparable in all groups. The incidence of live-birth defects among the LPS group (1.02%) and the short GnRH-a protocol group (0.64%) was slightly higher than in the mild ovarian-stimulation group (0.46%). However, none of these differences reached statistical significance. For congenital malformations, the risk significantly increased for the infertility-duration factor and multiple births; the adjusted odds ratios were 1.161 (95% confidence interval CI: 1.009–1.335) and 3.899 (95% CI: 1.179–12.896), respectively. No associations were found between congenital birth defects and various ovarian-stimulation regimens, maternal age, body mass index, parity, insemination method, or infant gender. Conclusion(s) To date, the data do not indicate an elevated rate of abnormality at birth after LPS, but further study with larger populations is needed to confirm these results. However, infertility itself poses a risk factor for congenital malformation. A higher likelihood of birth defects in multiple births may lead couples to favor elective, single ET; couples undertaking ART should be made aware of the known increased birth defects associated with a twin birth.
Objective
Studies have shown that prenatal exome sequencing (PES) improves diagnostic yield in cases of fetal structural malformation. We have retrospectively analysed PES cases from two of the ...largest fetal medicine centres in the UK to determine the impact of results on management of a pregnancy.
Design
A retrospective review of clinical case notes.
Setting
Two tertiary fetal medicine centres.
Population
Pregnancies with fetal structural abnormalities referred to clinical genetics via a multidisciplinary team.
Methods
We retrospectively reviewed the notes of all patients who had undergone PES. DNA samples were obtained via chorionic villus sampling or amniocentesis. Variants were filtered using patient‐specific panels and interpreted using American College of Medical Genetics guidelines.
Results
A molecular diagnosis was made in 42% (18/43) ongoing pregnancies; of this group, there was a significant management implication in 44% (8/18). A positive result contributed to the decision to terminate a pregnancy in 16% (7/43) of cases. A negative result had a significant impact on management in two cases by affirming the decision to continue pregnancy.
Conclusions
We demonstrate that the results of PES can inform pregnancy management. Challenges include variant interpretation with limited phenotype information. These results emphasise the importance of the MDT and collecting phenotype and variant data. As this testing is soon to be widely available, we should look to move beyond diagnostic yield as a measure of the value of PES.
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Prenatal exome sequencing can aid decision‐making in pregnancy management; review ahead of routine implementation in NHS.
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Prenatal exome sequencing can aid decision making in pregnancy management; review ahead of routine implementation in NHS.
Zika virus is a mosquito-transmitted flavivirus and was first linked to congenital microcephaly caused by a large outbreak in northeastern Brazil. Although the Zika virus epidemic is now in decline, ...pregnancies in large parts of the Americas remain at risk because of ongoing transmission and the potential for new outbreaks. This review presents why Zika virus is still a complex and worrisome public health problem with an expanding spectrum of birth defects and how Zika virus and related viruses evade the immune response to injure the fetus. Recent reports indicate that the spectrum of fetal brain and other anomalies associated with Zika virus exposure is broader and more complex than microcephaly alone and includes subtle fetal brain and ocular injuries; thus, the ability to prenatally diagnose fetal injury associated with Zika virus infection remains limited. New studies indicate that Zika virus imparts disproportionate effects on fetal growth with an unusual femur-sparing profile, potentially providing a new approach to identify viral injury to the fetus. Studies to determine the limitations of prenatal and postnatal testing for detection of Zika virus–associated birth defects and long-term neurocognitive deficits are needed to better guide women with a possible infectious exposure. It is also imperative that we investigate why the Zika virus is so adept at infecting the placenta and the fetal brain to better predict other viruses with similar capabilities that may give rise to new epidemics. The efficiency with which the Zika virus evades the early immune response to enable infection of the mother, placenta, and fetus is likely critical for understanding why the infection may either be fulminant or limited. Furthermore, studies suggest that several emerging and related viruses may also cause birth defects, including West Nile virus, which is endemic in many parts of the United States. With mosquito-borne diseases increasing worldwide, there remains an urgent need to better understand the pathogenesis of the Zika virus and related viruses to protect pregnancies and child health.
During the Schmallenberg virus (SBV) epidemic, the European Food Safety Authority (EFSA) collected data on SBV occurrence across Europe in order to provide an assessment of spread and impact. By May ...2013, twenty-nine countries were reporting to EFSA and twenty-two countries had reported cases of SBV. The total number of SBV herds reported was 13,846 and the number of SBV laboratory confirmed herds was 8730. The surveillance activities were based on the detection of SBV clinical cases (either adults or newborns). Malformation in newborns was the most commonly reported clinical sign of SBV-infection. All countries were able to provide the date when the first suspicion of SBV in the herd was reported and nineteen could report the location of the herd at a regional level. This allowed the spread of SBV in Europe to be measured both temporally and spatially. The number of SBV confirmed herds started to increase in December 2011 and two peaks were observed in 2012 (February and May). Confirmed herds continued to be reported in 2012 and into 2013. An increase during winter 2012 and spring 2013 was again observed, but the number of confirmed herds was lower than in the previous year. SBV spread rapidly throughout Europe from the initial area of detection. SBV was detected above the latitude of 60° North, which exceeds the northern expansion observed during the bluetongue virus serotype 8 epidemic in 2006–2009. The impact of SBV was calculated as ratio of the number of herds with at least one malformed SBV positive foetus and the total number of herds in this region. The 75th percentile of the malformations ratio in the various affected countries for the whole reporting period was below 1% and 3% for cattle and sheep herds, respectively. International data collection on emerging diseases represents a challenge as the nature of available data, data quality and the proportion of reported cases may vary widely between affected countries. Surveillance activities on emerging animal diseases are often structured only for case detection making the estimation of infection/diseases prevalence and the investigation of risk factors difficult. The impact of the disease must be determined to allow risk managers to take appropriate decisions. Simple within-herd impact indicators suitable for emerging disease outbreaks should be defined that could be measured as part of routine animal health surveillance programmes and allow for rapid and reliable impact assessment of emerging animal health diseases.
Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial ...proportion of them unexplained. Some of these cases have been shown to result from DNA methylation defects at a single locus (epi-variants), while others can exhibit syndrome-specific DNA methylation changes across multiple loci (epi-signatures). Here, we investigate the clinical diagnostic utility of genome-wide DNA methylation analysis of peripheral blood in unresolved ND/CAs. We generate a computational model enabling concurrent detection of 14 syndromes using DNA methylation data with full accuracy. We demonstrate the ability of this model in resolving 67 individuals with uncertain clinical diagnoses, some of whom had variants of unknown clinical significance (VUS) in the related genes. We show that the provisional diagnoses can be ruled out in many of the case subjects, some of whom are shown by our model to have other diseases initially not considered. By applying this model to a cohort of 965 ND/CA-affected subjects without a previous diagnostic assumption and a separate assessment of rare epi-variants in this cohort, we identify 15 case subjects with syndromic Mendelian disorders, 12 case subjects with imprinting and trinucleotide repeat expansion disorders, as well as 106 case subjects with rare epi-variants, a portion of which involved genes clinically or functionally linked to the subjects’ phenotypes. This study demonstrates that genomic DNA methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases and highlights the potential value of epigenomic testing in the routine clinical assessment of ND/CAs.
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