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Current Opinion in Pediatrics Dec 2022Prenatal genetic testing can be divided into two categories: screening and diagnosis. Prenatal genetic screening tests are used to assess carrier status or as a fetal... (Review)
Review
PURPOSE OF REVIEW
Prenatal genetic testing can be divided into two categories: screening and diagnosis. Prenatal genetic screening tests are used to assess carrier status or as a fetal risk assessment for a particular genetic disorder [1]. Prenatal genetic diagnostic testing is used to diagnose particular genetic conditions with as much certainty as possible [1,2]. This review will focus on the diagnostic side of prenatal genetic testing.
RECENT FINDINGS
Next generation sequencing (NGS) has revolutionized prenatal genetic diagnostic testing. NGS methods are becoming more advanced and accurate as more genetic information is being linked to genetic conditions.
SUMMARY
Prenatal genetic diagnostic testing involves clinicians invasively obtaining tissue via amniocentesis or chorionic villus sampling to identify if a fetus has a genetic condition. This testing has traditionally been done through fluorescence in-situ hybridization, karyotype, or chromosomal microarray analysis. However, genetic testing is in a time of rapid technologic expansion and new methods like NGS, which includes targeted gene panels, whole exome sequencing, and whole genome sequencing are being used too. In this time of growth, it is important that providers educate themselves on the research support and indication behind each type of genetic diagnostic test.
Topics: Pregnancy; Female; Humans; Diagnostic Tests, Routine; Chorionic Villi Sampling; Amniocentesis; Genetic Testing; Exome Sequencing; Prenatal Diagnosis
PubMed: 36081360
DOI: 10.1097/MOP.0000000000001174 -
The Journal of Maternal-fetal &... Dec 202315q11.2 microdeletion can lead to syndromes affecting the nervous system. However, 15q11.2 microdeletion has large phenotypic differences and incomplete penetrance,... (Review)
Review Meta-Analysis
OBJECTIVE
15q11.2 microdeletion can lead to syndromes affecting the nervous system. However, 15q11.2 microdeletion has large phenotypic differences and incomplete penetrance, which brings challenges to prenatal diagnosis. We reported 21 cases of 15q11.2 microdeletion fetuses in Eastern China and reviewed literature on the prenatal clinical characteristics related to the deletion variants to provide a basis for prenatal genetic counseling.
METHODS
The clinical data of 21 cases of 15q11.2 microdeletion fetuses collected from June 2018 to September 2021 were retrospectively analyzed, and chromosomal microarray analysis was performed. The reported prenatal clinical features of 15q11.2 microdeletion fetuses were reviewed and summarized. A meta-analysis of 20 studies was performed to test heterogeneity, data integration, and sensitivity on the correlation between 15q11.2 microdeletion and neuropsychiatric diseases.
RESULTS
The median age of the women was 29.5 years. The median gestational age at interventional examination was 24 weeks. All fetuses showed deletion variants of the 15q11.2 fragment, and the median deletion range was approximately 0.48 MB. Ultrasound of five cases showed no abnormalities; however, four of them showed a high risk of Down's syndrome (risk values were 1/184, 1/128, 1/47, and 1/54, respectively). The remaining 16 fetuses showed congenital heart disease (7/16), elevated nuchal translucency (5/16), abnormal brain structure (2/16) and renal disease (2/16). In a literature review of 82 prenatal cases, 44% (36/82) had abnormal ultrasound features, 31% (11/36) showed abnormal nuchal translucency, approximately 28% (10/36) showed abnormal cardiac structure, and 14% (5/36) had brain structural abnormalities. The meta-analysis revealed that the frequency of the 15q11.2 microdeletion mutation in patients with schizophrenia and epilepsy was significantly higher (odds ratio 2.04, 95% confidence interval: 1.78-2.33, < 0.00001; odds ratio 5.23, 95% confidence interval: 2.83-9.67, < 0.00001) than that in normal individuals.
CONCLUSION
More than half of the 15q11.2 microdeletion cases presented no abnormalities in prenatal ultrasound examination. The cases with ultrasound features mainly showed isolated malformations such as elevated nuchal translucency, congenital heart disease, and brain structural abnormalities. Postpartum 15q11.2 microdeletion patients are at an increased risk of suffering from schizophrenia, epilepsy, and other neurological and mental diseases from 15q11.2 microdeletion. Therefore, prenatal diagnosis of 15q11.2 microdeletion not only depends on molecular diagnostic techniques but also requires cautious genetic counseling.
Topics: Adult; Female; Humans; Pregnancy; Fetus; Heart Defects, Congenital; Nuchal Translucency Measurement; Prenatal Diagnosis; Retrospective Studies; Ultrasonography, Prenatal
PubMed: 37770195
DOI: 10.1080/14767058.2023.2262700 -
European Journal of Obstetrics,... Oct 2020Cell-free fetal DNA (cffDNA) can be detected in the maternal circulation from 4 weeks gestation, and is present with cell-free maternal DNA at a level of between 5 % and... (Review)
Review
Cell-free fetal DNA (cffDNA) can be detected in the maternal circulation from 4 weeks gestation, and is present with cell-free maternal DNA at a level of between 5 % and 20 %. Cell-free DNA (cfDNA) can be extracted from a maternal blood sample and, although it is not possible to separate the fetal from the maternal cfDNA, it has enabled non-invasive prenatal diagnosis (NIPD) without the associated miscarriage risk that accompanies invasive testing. NIPD for monogenic diseases was first reported in 2000 and since then there have been many proof of principle studies showing how analysis of cfDNA can provide a definitive diagnosis early in pregnancy for a wide range of single gene diseases. Testing for a number of these diseases has been available in the UK National Health Service (NHS) since 2012. This review highlights the main techniques that are being used for NIPD and discusses the technical limitations of the methods, as well as the advances that are being made to overcome some of the issues. NIPD is technologically challenging for a number of reasons. Firstly, because it requires the detection of low level fetal variants in a high maternal background. For de novo and paternally-inherited variants this has been achieved through the use of techniques such as next-generation sequencing (NGS) and digital PCR to detect variants in the cffDNA that are not present in the maternal cfDNA. However, for maternally-inherited variants this is much more challenging and relies on dosage-based techniques to detect small differences in the levels of mutant and wild-type alleles. Alongside the technical advances that are making NIPD more widely available in both the public healthcare and commercial settings, it is crucial that we continue to monitor the social and ethical impact to ensure that patients are being offered safe and accurate testing.
Topics: Cell-Free Nucleic Acids; Female; Fetus; Humans; Noninvasive Prenatal Testing; Pregnancy; Prenatal Diagnosis; State Medicine
PubMed: 32907778
DOI: 10.1016/j.ejogrb.2020.08.001 -
Journal of Clinical Ultrasound : JCU Feb 2023
Topics: Pregnancy; Female; Humans; Prenatal Diagnosis; Fetus; Magnetic Resonance Imaging
PubMed: 36785502
DOI: 10.1002/jcu.23424 -
Journal of the American Society of... Mar 2022The impact of fetal echocardiography on the diagnosis and outcomes of vascular ring has not been well examined. We hypothesized that prenatal detection of vascular ring...
BACKGROUND
The impact of fetal echocardiography on the diagnosis and outcomes of vascular ring has not been well examined. We hypothesized that prenatal detection of vascular ring has improved over time and that prenatal diagnosis of vascular ring is associated with earlier intervention and favorable outcomes.
METHODS
This is a single-center, retrospective study of the evolution and outcomes of prenatal diagnosis of vascular ring from 2000 to 2020. We compared clinical presentation, timing of surgical intervention, and outcomes between the prenatally and postnatally diagnosed cases during the same study period.
RESULTS
A total of 170 patients were included: 50 with prenatal and 120 with postnatal diagnosis of vascular ring. Prenatal diagnoses included 42 patients (84%) with right aortic arch (RAA), aberrant left subclavian artery (ALSCA), and a left-sided ductus arteriosus and eight (16%) patients with double aortic arch (DAA). The postnatal cohort consisted mainly of 90 patients (75%) with DAA and 22 (18%) with RAA-ALSCA. None of the postnatally diagnosed cases had undergone a fetal echocardiogram. Numbers (percentage) of prenatally diagnosed cases of vascular ring compared with the postnatal cases improved from 4/31 (13%), to 10/29 (34%), to 14/25 (56%), and to 22/35 (69%), respectively, during 2000-2005, 2005-10, 2010-15, and 2015-20 (P = .032). Vascular ring was an isolated abnormality in 84% and 85% of the prenatal and postnatal cohorts, respectively. Compared with the prenatal cohort, postnatally diagnosed patients with an isolated vascular ring were more frequently symptomatic (66% vs 48%, P < .03) and underwent cross-sectional imaging (69% vs 44%, P = .009) and surgery more frequently (79% vs 48%, P = .003). Surgery was performed at a later patient age (18 [2-147] months vs 4.8 [0.5-42] months, P = .01) and was more often associated with residual symptoms (27/81 [33%] vs 1/20 [5%], P = .01) in the postnatal cohort than in the prenatal cohort.
CONCLUSIONS
The diagnosis of vascular ring by fetal echocardiography has improved over time. A significantly higher incidence of RAA-ALSCA in the prenatal compared with the postnatal cohort suggests that patients with this form of vascular ring often do not present to medical attention with significant symptoms postnatally. Prenatal diagnosis of vascular ring was associated with a lower incidence of symptoms, less frequent use of cross-sectional imaging, earlier age at surgical intervention, and lower likelihood of residual symptoms.
Topics: Aorta, Thoracic; Female; Humans; Infant; Pregnancy; Prenatal Diagnosis; Retrospective Studies; Ultrasonography, Prenatal; Vascular Ring
PubMed: 34600045
DOI: 10.1016/j.echo.2021.09.010 -
Journal of Obstetrics and Gynaecology :... Oct 2022We present three new cases and review of the literature on the prenatal diagnosis of Emanuel syndrome (ES). Twenty-one foetuses have been analysed. In all three cases... (Review)
Review
We present three new cases and review of the literature on the prenatal diagnosis of Emanuel syndrome (ES). Twenty-one foetuses have been analysed. In all three cases diagnosed in our department, posterior fossa abnormalities were seen and in one hypoplastic right ventricle was diagnosed at the first trimester scan. Defects of the posterior fossa (62% of foetuses; 13/21) and left diaphragmatic hernia (29% of foetuses; 6/21) are the most frequently reported prenatal findings in ES syndrome. No pattern of specific prenatal ultrasound markers of ES exists. Abnormalities of the posterior fossa are frequent and may be diagnosed as early as in the first trimester of pregnancy. Specific diagnosis can be made only after invasive genetic testing.IMPACT STATEMENT Emanuel syndrome (ES) is a rare genetic disorder. No pattern of specific prenatal ultrasound markers exists. The great majority of cases is diagnosed postnatally and only a few cases of prenatal diagnosis have been published to date. The most frequent structural abnormalities in prenatally detected ES involved central nervous system (80.9%), namely posterior fossa defects (57.1%) and mild ventriculomegaly (23.8%). Other frequent abnormalities include left diaphragmatic hernia (28.6%), renal defects (23.8%) and foetal growth restriction (FGR) (23.8%). Abnormalities of the posterior fossa are the most frequent defects in ES and may be diagnosed as early as in the first trimester of pregnancy. Specific diagnosis can be made only after invasive genetic testing.
Topics: Female; Pregnancy; Humans; Ultrasonography, Prenatal; Prenatal Diagnosis; Chromosome Disorders; Hernia, Diaphragmatic
PubMed: 36048922
DOI: 10.1080/01443615.2022.2114331 -
The Canadian Journal of Cardiology Jul 2022In the current era, most single-ventricle heart disease (SVHD) is diagnosed prenatally by means of fetal echocardiography. Disparities exist, however, by socioeconomic... (Review)
Review
In the current era, most single-ventricle heart disease (SVHD) is diagnosed prenatally by means of fetal echocardiography. Disparities exist, however, by socioeconomic status and remote location, which require further attention. Prenatal diagnosis affords the opportunity to counsel expectant parents regarding the life-long course of children with SVHD, including the stages of single-ventricle palliation and challenges of the Fontan circulation; to discuss pregnancy management options; and to optimise delivery planning and perinatal care. Prognosis may be refined by specific features on the fetal echocardiogram, such as ventricular morphology, total anomalous pulmonary venous return, and atrioventricular valve regurgitation. Expectant mothers should be referred for evaluation of extracardiac anomalies and/or a genetic syndrome, which also significantly affect outcome. Fetuses with SVHD should be cared for by a multidisciplinary team and ideally delivered at term at or near a cardiac surgical center. Serial echocardiograms refine the anticipated postnatal physiology to optimise transitional care, including the need for prostaglandin or urgent atrial septal intervention in fetuses with hypoplastic left heart syndrome. In selected patients, there may be a role for fetal cardiac intervention to improve mortality or achieve a biventricular circulation after birth. Together, these strategies enhance the preoperative status of the neonate. Recent advances in fetal cardiovascular magnetic resonance imaging have focused on studying the relationships between cardiovascular physiology and fetal growth and development. These novel techniques allow for the exploration of the physiologic effects of SVHD on the brain and open avenues for the investigation of neuroprotective therapies.
Topics: Child; Echocardiography; Female; Fetal Heart; Fetus; Fontan Procedure; Humans; Hypoplastic Left Heart Syndrome; Infant, Newborn; Pregnancy; Prenatal Diagnosis; Retrospective Studies; Ultrasonography, Prenatal
PubMed: 35429589
DOI: 10.1016/j.cjca.2022.04.003 -
Current Opinion in Obstetrics &... Apr 2020Congenital gastrointestinal anomalies are common findings with relatively established methods of treatment. However, the genetic cause of how these defects occur and how... (Review)
Review
PURPOSE OF REVIEW
Congenital gastrointestinal anomalies are common findings with relatively established methods of treatment. However, the genetic cause of how these defects occur and how that may impact a child's lifelong care is less established. Genetic testing has improved significantly in recent years, yet reviews documenting prenatal genetic counseling and testing guidelines have not been comprehensively updated.
RECENT FINDINGS
Congenital anomalies of the foregut, such as tracheoesophageal fistula carry a high association with genetic disorders, both in isolation and syndromic forms. Duodenal atresia remains highly associated with Trisomy 21 but is not enriched in other genetic conditions. Disorders of the midgut, such as omphalocele often have a genetic cause and may require both cytogenetic and panel testing to obtain a diagnosis. The etiologic basis of hindgut malformations remain largely unknown, though imperforate anus as well as Hirschprung's disease have been associated with many micro deletion syndromes as well as in association with other birth defects as part of larger syndromes.
SUMMARY
Prenatal diagnostic genetic testing through amniocentesis or chorionic villus sampling can be offered to every patient who wants to learn genetic information about their fetus. Cytogenetic testing, such as microarray is a first tier test to assess cause for these conditions and can provide meaningful answers. When a gastrointestinal anomaly is identified in association with an additionally affected organ system next-generation sequencing and defect-specific genetic testing panels can be necessary to understand cause as well as prognosis to best prepare families for the medical management that lies ahead.
Topics: Female; Gastrointestinal Tract; Genetic Counseling; Genetic Testing; Humans; Pregnancy; Prenatal Diagnosis
PubMed: 32039977
DOI: 10.1097/GCO.0000000000000613 -
Ultrasound in Obstetrics & Gynecology :... Aug 2022Outcome of common arterial trunk (CAT) depends mainly on truncal valve function, presence of coronary artery abnormalities and presence of interrupted aortic arch. The...
OBJECTIVES
Outcome of common arterial trunk (CAT) depends mainly on truncal valve function, presence of coronary artery abnormalities and presence of interrupted aortic arch. The main objective of this study was to evaluate the accuracy of prenatal diagnosis of CAT by analyzing prenatal vs postnatal assessment of: (1) anatomic subtypes and (2) truncal valve function. The secondary objective was to assess the potential impact of prenatal diagnosis of CAT on postnatal mortality and morbidity by comparing prenatally vs postnatally diagnosed patients.
METHODS
This was a retrospective analysis of all CAT patients diagnosed either prenatally, with postnatal or fetopsy confirmation, or postnatally, from 2011 to 2019 in a single tertiary center. Cohen's kappa statistic was used to evaluate agreement between pre- and postnatal assessment of anatomic subtypes according to Van Praagh and of truncal valve function. Mortality and morbidity variables were compared between prenatally vs postnatally diagnosed CAT patients.
RESULTS
A total of 84 patients (62 liveborn with prenatal diagnosis, 16 liveborn with postnatal diagnosis and six terminations of pregnancy with fetopsy) met the inclusion criteria. The accuracy of prenatal diagnosis of CAT anatomic subtype was 80.3%, and prenatal and postnatal concordance for subtype diagnosis was only moderate (κ = 0.43), with no patient with CAT Type A3 (0/4) and only half of patients with CAT Type A4 (8/17) being diagnosed prenatally. Fetal evaluation of truncal valve function underestimated the presence (no agreement; κ = 0.09) and severity (slight agreement; κ = 0.19) of insufficiency. However, four of five cases of postnatally confirmed significant truncal valve stenosis were diagnosed prenatally, with fair agreement for both presence and severity of stenosis (κ = 0.38 and 0.24, respectively). Mortality was comparable in patients with and those without prenatal diagnosis (log-rank P = 0.87). CAT patients with fetal diagnosis underwent earlier intervention (P < 0.001), had shorter intubation time (P = 0.047) and shorter global hospital stay (P = 0.01).
CONCLUSIONS
The accuracy of prenatal diagnosis of CAT is insufficient to tailor neonatal management and to predict outcome. Fetal assessment of truncal valve dysfunction appears unreliable due to perinatal transition. Improvement is necessary in the fetal diagnosis of anatomic subtypes of CAT requiring postnatal prostaglandin infusion. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Constriction, Pathologic; Female; Heart Defects, Congenital; Humans; Pregnancy; Prenatal Diagnosis; Retrospective Studies; Truncus Arteriosus, Persistent; Ultrasonography, Prenatal
PubMed: 35118719
DOI: 10.1002/uog.24873 -
The Journal of Maternal-fetal &... Jan 2022To report our experience in early prenatal diagnosis of six cases of tricuspid valve dysplasia (TVD) and to delineate echocardiographic features.
OBJECTIVE
To report our experience in early prenatal diagnosis of six cases of tricuspid valve dysplasia (TVD) and to delineate echocardiographic features.
METHODS
This was a retrospective study which included all the women who attended our clinic for early fetal screening sonography, between 2001 and 2018. The ultrasound screening was done at 11-16 weeks of gestation, and included an anatomic fetal scan and Doppler imaging. The diagnosis of TVD was done based on sonographic features visualized on four chamber view and color mapping of the valve. Complete fetal echocardiography was carried out to rule out additional heart malformations.
RESULTS
Out of 34,933 early prenatal transvaginal ultrasound screening examinations, six cases of TVD were diagnosed. Five of the pregnancies were terminated as per parental request, and one fetus was delivered at term and died shortly after birth. In three fetuses a chromosomal analysis was performed, one had trisomy 21, one had an abnormal CGH, and the third had a normal karyotype. In two fetuses an autopsy was performed and the diagnosis of TVD was confirmed in both.
CONCLUSION
Early prenatal detection of TVD is possible and may aid in parental counseling. Larger studies, examining the outcome of TVD should be considered.
Topics: Female; Gestational Age; Humans; Pregnancy; Prenatal Diagnosis; Retrospective Studies; Tricuspid Valve; Ultrasonography, Prenatal
PubMed: 31990249
DOI: 10.1080/14767058.2020.1718643