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Prenatal Diagnosis Apr 2024Advances in sequencing and imaging technologies enable enhanced assessment in the prenatal space, with a goal to diagnose and predict the natural history of disease, to... (Review)
Review
Advances in sequencing and imaging technologies enable enhanced assessment in the prenatal space, with a goal to diagnose and predict the natural history of disease, to direct targeted therapies, and to implement clinical management, including transfer of care, election of supportive care, and selection of surgical interventions. The current lack of standardization and aggregation stymies variant interpretation and gene discovery, which hinders the provision of prenatal precision medicine, leaving clinicians and patients without an accurate diagnosis. With large amounts of data generated, it is imperative to establish standards for data collection, processing, and aggregation. Aggregated and homogeneously processed genetic and phenotypic data permits dissection of the genomic architecture of prenatal presentations of disease and provides a dataset on which data analysis algorithms can be tuned to the prenatal space. Here we discuss the importance of generating aggregate data sets and how the prenatal space is driving the development of interoperable standards and phenotype-driven tools.
Topics: Pregnancy; Female; Humans; Prenatal Diagnosis; Phenotype; Precision Medicine; Genomics; Algorithms
PubMed: 38242839
DOI: 10.1002/pd.6522 -
BMC Medical Genomics Oct 2023Whole-exome sequencing (WES) significantly improves the diagnosis of the etiology of fetal structural anomalies. This study aims to evaluate the diagnostic value of...
BACKGROUND
Whole-exome sequencing (WES) significantly improves the diagnosis of the etiology of fetal structural anomalies. This study aims to evaluate the diagnostic value of prenatal WES and to investigate the pathogenic variants in structurally abnormal fetuses.
METHODS
We recruited 144 fetuses with structural anomalies between 14 and 2020 and 15 December 2021 in the study. Genetic screening was performed by WES combined with karyotyping and chromosomal microarray analysis. The molecular diagnostic yield of prenatal WES for each type of fetal structural anomaly and the identified pathogenic genes and mutations were reported.
RESULTS
In this study, we retrospectively analyzed the clinical and genetic data of 145 structurally anomalous fetuses. These cases were classified into 9 phenotypic classes based on antenatal ultrasound findings. Thirty-eight pathogenic variants in 24 genes were identified in 35 of the 145 cases, including 14 novel variants in 13 genes (EP300, MYH3, TSC2, MMP9, CPLANE1, INVS, COL1A1, EYA1, TTC21B, MKS1, COL11A2, PDHA1 and L1CAM). Five additional pathogenic variants were classified as incidental findings. Our study showed that the overall diagnosis rate of WES was 28.1% (27/96) in the parent-fetus trio cases and 16.3% (8/49) in the proband-only cases. Fetuses with musculoskeletal anomalies had the highest diagnostic yield (51.4%, 19/37). In addition, FGFR3 and COL1A1 were the most common pathogenic genes.
CONCLUSIONS
Our work expands the mutation spectrum of the genes associated with fetal structural anomalies and provides valuable information for future parental genetic counselling and pregnancy management of the structurally anomalous fetuses.
Topics: Female; Humans; Pregnancy; East Asian People; Exome Sequencing; Fetus; Pregnancy Trimester, First; Prenatal Diagnosis; Retrospective Studies; Ultrasonography, Prenatal; Congenital Abnormalities
PubMed: 37880672
DOI: 10.1186/s12920-023-01697-3 -
Clinica Chimica Acta; International... Jan 2024This review article delves into the rapidly advancing domain of prenatal diagnostics, with a primary focus on the detection and management of chromosomal abnormalities... (Review)
Review
This review article delves into the rapidly advancing domain of prenatal diagnostics, with a primary focus on the detection and management of chromosomal abnormalities such as trisomy 13 ("Patau syndrome)", "trisomy 18 (Edwards syndrome)", and "trisomy 21 (Down syndrome)". The objective of the study is to examine the utilization and effectiveness of novel computational methodologies, such as "machine learning (ML)", "deep learning (DL)", and data analysis, in enhancing the detection rates and accuracy of these prenatal conditions. The contribution of the article lies in its comprehensive examination of advancements in "Non-Invasive Prenatal Testing (NIPT)", prenatal screening, genomics, and medical imaging. It highlights the potential of these techniques for prenatal diagnosis and the contributions of ML and DL to these advancements. It highlights the application of ensemble models and transfer learning to improving model performance, especially with limited datasets. This also delves into optimal feature selection and fusion of high-dimensional features, underscoring the need for future research in these areas. The review finds that ML and DL have substantially improved the detection and management of prenatal conditions, despite limitations such as small sample sizes and issues related to model generalizability. It recognizes the promising results achieved through the use of ensemble models and transfer learning in prenatal diagnostics. The review also notes the increased importance of feature selection and high-dimensional feature fusion in the development and training of predictive models. The findings underline the crucial role of AI and machine learning techniques in early detection and improved therapeutic strategies in prenatal diagnostics, highlighting a pressing need for further research in this area.
Topics: Pregnancy; Female; Humans; Chromosome Disorders; Artificial Intelligence; Down Syndrome; Prenatal Diagnosis; Chromosome Aberrations; Trisomy 18 Syndrome; Trisomy 13 Syndrome; Chromosomes; Trisomy
PubMed: 38007058
DOI: 10.1016/j.cca.2023.117669 -
Prenatal Diagnosis Aug 2023This 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...
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.
Topics: Female; Humans; Pregnancy; Prenatal Diagnosis; Whole Genome Sequencing; Exome Sequencing; Microarray Analysis; Congenital Abnormalities; Genetic Variation
PubMed: 37355983
DOI: 10.1002/pd.6402 -
Journal of Clinical Ultrasound : JCU Sep 2023Echogenic fetal bowel (EB) is a prenatal ultrasound finding (0.2%-1.4% of all pregnancies) defined as bowel of similar or greater echogenicity than surrounding bone. In... (Review)
Review
Echogenic fetal bowel (EB) is a prenatal ultrasound finding (0.2%-1.4% of all pregnancies) defined as bowel of similar or greater echogenicity than surrounding bone. In fact, the ultrasound assessment is strongly subjective with inter-observer variability. The pathophysiology depends on the underlying condition, apparently related with meconium stasis and hypercellularity. It is often an isolated finding, with possible association with other structural anomalies. About the origin, it was observed in fetuses with cystic fibrosis, congenital infections, thalassemia, intraamniotic bleeding, fetal growth restriction. Fetuses with EB are at increased risk of adverse perinatal outcome, such as intrauterine growth restriction, placental dysfunction and perinatal death, highlighting the need for a thorough antenatal management and post-natal follow-up. It seems to be associated with a plenty of conditions, such as a poor fetal outcome, fetal growth restriction and placental dysfunction. Therefore management requires a multidisciplinary approach with different specialties' involvement and the prognosis is influenced by the underlying pathophysiology. In this complex scenario, the present review aims to define the clinical pathway which should be offered to pregnant women in case of finding of fetal EB ultrasound marker, to rule out any suspected pathological cause.
Topics: Pregnancy; Female; Humans; Pregnancy Outcome; Fetal Growth Retardation; Ultrasonography, Prenatal; Placenta; Prenatal Diagnosis; Echogenic Bowel; Fetus
PubMed: 37553773
DOI: 10.1002/jcu.23528 -
Ultrasound in Obstetrics & Gynecology :... Dec 2023Congenital knee dislocation (CKD) is a rare condition, affecting 1 in 100 000 newborns. Its prenatal diagnosis is challenging and not well described in the literature,... (Review)
Review
OBJECTIVES
Congenital knee dislocation (CKD) is a rare condition, affecting 1 in 100 000 newborns. Its prenatal diagnosis is challenging and not well described in the literature, especially when it appears isolated and not as part of a complex malformation or syndromic pattern. The purpose of this study was to provide a comprehensive review of the available literature on the prenatal diagnosis and postnatal outcome of CKD and to summarize the current evidence on this topic.
METHODS
A systematic review of the literature on the prenatal diagnosis of CKD was performed in PubMed, Scopus and EMBASE. A predefined combination of specific keywords was used, focusing on intrauterine manifestations, diagnostic methods, prenatal behavior, postnatal treatment and neonatal outcome as well as long-term outcome in terms of ambulation, motion and joint stability. The quality of studies was assessed using the National Institutes of Health tool for quality assessment of case series. A summary of results was carried out providing proportions and rates of diagnostic and prognostic features associated with this rare condition.
RESULTS
In total, 20 cases were retrieved for analysis, of which 19 were obtained from the identified eligible studies (n = 16) and one was an unpublished case from our center. The median gestational age at prenatal diagnosis, which was made using ultrasound in most cases, was 20 weeks (range, 14-38 weeks). Bilaterality was observed in 11/20 (55%) cases. The condition was isolated in 7/20 (35%) cases and associated with other anomalies in 13/20 (65%) cases. An association was observed with oligohydramnios (4/20 (20%)), and an invasive procedure was performed in 13/20 (65%) cases, including 11 cases with an invasive procedure performed for diagnostic purposes. Genetic testing was normal in all isolated cases for which information was available (4/7), while a genetic syndrome was present in 10/13 (77%) non-isolated cases (Larsen, Noonan, Grebe, Desbuquois or Escobar syndrome). There were seven terminations of pregnancy, of which six were performed in cases with associated anomalies and one in an isolated case, 11 cases of postnatal survival, one case of intrauterine death and one of neonatal death. The fetal and neonatal deaths occurred in cases with associated anomalies or abnormal genetic findings. Postnatal treatment was mostly conservative, with only two reports (18% of the 11 surviving neonates) of surgical intervention, both in cases with associated anomalies. Postnatal follow-up was up to 1 year in most cases, and motor outlook appeared normal in all isolated cases.
CONCLUSIONS
CKD is a rare fetal anomaly with a prenatal diagnosis achievable from the early second trimester, for which a favorable outcome can be expected when no associated anomalies are present. Prenatal diagnosis should include detailed ultrasound assessment and amniocentesis for extensive genetic studies, particularly in non-isolated cases. Early postnatal treatment achieves success in most cases without surgical intervention and leads to a normal motor outlook. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Fetus; Genetic Testing; Prenatal Diagnosis; Renal Insufficiency, Chronic; Retrospective Studies; Ultrasonography, Prenatal
PubMed: 37289939
DOI: 10.1002/uog.26283 -
Prenatal Diagnosis Apr 2024Telehealth is an effective way to increase access to genetic services and can address several challenges, including geographic barriers, a shortage of interpreter... (Review)
Review
Telehealth is an effective way to increase access to genetic services and can address several challenges, including geographic barriers, a shortage of interpreter services, and workforce issues, especially for prenatal diagnosis. The addition of prenatal telegenetics to current workflows shows promise in enhancing the delivery of genetic counseling and testing in prenatal care, providing accessibility, accuracy, patient satisfaction, and cost-effectiveness. Further research is needed to explore long-term patient outcomes and the evolving role of telehealth for prenatal diagnosis. Future studies should address the accuracy of diagnoses, the impact of receiving a diagnosis in a virtual setting, and patient outcomes in order to make informed decisions about the appropriate use of telemedicine in prenatal genetics service delivery.
Topics: Pregnancy; Female; Humans; Telemedicine; Genetic Counseling; Patient Satisfaction; Prenatal Diagnosis
PubMed: 38175174
DOI: 10.1002/pd.6515 -
NeoReviews Nov 2023
Topics: Pregnancy; Female; Humans; Micrognathism; Prenatal Diagnosis; Ultrasonography, Prenatal
PubMed: 37907406
DOI: 10.1542/neo.24-11-e753 -
Ultrasound in Obstetrics & Gynecology :... Jan 2024Type-III vasa previa (VP) is a rare form of VP, not necessarily associated with other placental or vascular anomalies, in which aberrant vessels run from the placenta to... (Review)
Review
OBJECTIVE
Type-III vasa previa (VP) is a rare form of VP, not necessarily associated with other placental or vascular anomalies, in which aberrant vessels run from the placenta to the amniotic membranes, near the internal cervical os, before returning to the placenta. Early diagnosis of Type-III VP is important but technically challenging. The objective of this study was to gather the current available evidence on the perinatal diagnosis and outcome of Type-III VP.
METHODS
A systematic review of the literature on the perinatal diagnosis of atypical Type-III VP was carried out in PubMed, MEDLINE and EMBASE accordingto PRISMA guidelines from inception to March 2023. Data extraction and tabulation were performed by two operators and checked by a third senior author. The quality of the included studies was evaluated using the National Institutes of Health tool for the quality assessment of case-series studies. Our local ultrasound database was searched for previously unreported recent cases. Characteristics of prenatally and postnatally diagnosed Type-III VP, including clinical features and perinatal outcomes, were summarized using descriptive statistics.
RESULTS
Eighteen cases of Type-III VP were included, of which 16 were diagnosed prenatally (14 cases were retrieved from 10 publications and two were unpublished cases from our center) and two were diagnosed postnatally (retrieved from two publications). All prenatal cases were diagnosed on transvaginal ultrasound at a mean gestational age of 29 weeks (median, 31 weeks; range, 19-38 weeks). Conception was achieved with in-vitro fertilization in 4/16 (25.0%) cases. There were no prenatal symptoms in 15/18 (83.3%) cases, while in two (11.1%) cases there was vaginal bleeding and in one (5.6%) preterm labor occurred. In 15/18 (83.3%) cases, at least one placental abnormality was observed, including low-lying insertion (9/17), succenturiate or accessory lobe (1/17), velamentous cord insertion (3/18) and marginal insertion (9/18). All prenatally diagnosed cases were liveborn and were delivered by Cesarean section before rupture of membranes at a median gestational age of 35 weeks (range, 32-38 weeks) without neonatal complications. Emergency Cesarean section was performed in 2/16 (12.5%) cases with a prenatal diagnosis and 1/2 (50.0%) cases with a postnatal diagnosis (P = 0.179). Among those with data available, an Apgar score of ≤ 7 was observed in the prenatally vs postnatally diagnosed group in 5/13 vs 1/1 cases, respectively, at the 1-min evaluation and 3/13 vs 1/1 cases, respectively, at the 5-min evaluation.
CONCLUSIONS
The prenatal diagnosis of Type-III VP is challenging, with few cases reported in the literature; however, it is crucial for minimizing the risk of adverse outcome by enabling early-term elective Cesarean delivery prior to rupture of membranes. Given that clinical manifestations and risk factors are non-specific, and that Type-III VP cannot be excluded when there is a normal cord insertion or a singular placental mass, systematic screening by transvaginal ultrasound in the general pregnant population is recommended, particularly in those with a low-lying or morphologically abnormal placenta and those who conceived using assisted reproductive technology. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Cesarean Section; Placenta; Placenta Diseases; Prenatal Diagnosis; Ultrasonography, Prenatal; Vasa Previa
PubMed: 37470694
DOI: 10.1002/uog.26315 -
BMC Medical Genomics Aug 2023Genodermatoses are a broad group of disorders with specific or non-specific skin-based phenotypes, most of which are monogenic disorders. However, it's a great challenge...
BACKGROUND
Genodermatoses are a broad group of disorders with specific or non-specific skin-based phenotypes, most of which are monogenic disorders. However, it's a great challenge to make a precise molecular diagnosis because of the clinical heterogeneity. The genetic and clinical heterogeneity brings great challenges for diagnosis in dermatology. The whole exome sequencing (WES) not only expedites the discovery of the genetic variations, but also contributes to genetic counselling and prenatal diagnosis.
MATERIALS AND METHODS
Followed by the initial clinical and pathological diagnosis, genetic variations were identified by WES. The pathogenicity of the copy number variations (CNVs) and single-nucleotide variants (SNVs) were evaluated according to ACMG guidelines. Candidate pathogenic SNVs were confirmed by Sanger sequencing in the proband and the family members.
RESULTS
Totally 25 cases were recruited. Nine novel variations, including c.5546G > C and c.1457delC in NF1, c.6110G > T in COL7A1, c.2127delG in TSC1, c.1445 C > A and c.1265G > A in TYR, Xp22.31 deletion in STS, c.908 C > T in ATP2A2, c.1371insC in IKBKG, and nine known ones were identified in 16 cases (64%). Prenatal diagnosis was applied in 6 pregnant women by amniocentesis, two of whom carried positive findings.
CONCLUSIONS
Our findings highlighted the value of WES as a first-tier genetic test in determining the molecular diagnosis. We also discovered the distribution of genodermatoses in this district, which provided a novel clinical dataset for dermatologists.
Topics: Female; Humans; Pregnancy; Exome Sequencing; DNA Copy Number Variations; Skin Diseases; Skin; Prenatal Diagnosis; I-kappa B Kinase; Collagen Type VII
PubMed: 37605172
DOI: 10.1186/s12920-023-01628-2