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International Journal of Molecular... Jul 2023The central objective of the metamorphosis of discovery science into biomedical applications is to serve the purpose of patients and curtail the global disease burden.... (Review)
Review
The central objective of the metamorphosis of discovery science into biomedical applications is to serve the purpose of patients and curtail the global disease burden. The journey from the discovery of DNA methylation (DNAm) as a biological process to its emergence as a diagnostic tool is one of the finest examples of such metamorphosis and has taken nearly a century. Particularly in the last decade, the application of DNA methylation studies in the clinic has been standardized more than ever before, with great potential to diagnose a multitude of diseases that are associated with a burgeoning number of genes with this epigenetic alteration. Fetal DNAm detection is becoming useful for noninvasive prenatal testing, whereas, in very preterm infants, DNAm is also shown to be a potential biological indicator of prenatal risk factors. In the context of cancer, liquid biopsy-based DNA-methylation profiling is offering valuable epigenetic biomarkers for noninvasive early-stage diagnosis. In this review, we focus on the applications of DNA methylation in prenatal diagnosis for delivering timely therapy before or after birth and in detecting early-stage cancers for better clinical outcomes. Furthermore, we also provide an up-to-date commercial landscape of DNAm biomarkers for cancer detection and screening of cancers of unknown origin.
Topics: Pregnancy; Female; Humans; Infant, Newborn; DNA Methylation; Infant, Premature; Early Detection of Cancer; Prenatal Diagnosis; Biomarkers; Neoplasms; Epigenesis, Genetic
PubMed: 37511475
DOI: 10.3390/ijms241411715 -
European Journal of Obstetrics,... Apr 2024Although the clinical work-up of CMV in pregnancy has gradually become more accurate, counseling for CMV is still challenging. Despite the potential feasibility of... (Review)
Review
Although the clinical work-up of CMV in pregnancy has gradually become more accurate, counseling for CMV is still challenging. Despite the potential feasibility of universal prenatal serological screening, its introduction in prenatal diagnosis continues to raise concerns related to its real cost-effectiveness. Contextually, anticipating the confirmation of fetal infection earlier in pregnancy is one of the most pressing issues to reduce the parental psychological burden. Amniocentesis is still the gold standard and recent data have demonstrated that it could be performed before 20 weeks of gestation, provided that at least 8 weeks have elapsed from the presumed date of maternal seroconversion. New approaches, such as chorionic villus sampling (CVS) and virome DNA, even if not yet validated as confirmation of fetal infection, have been studied alternatively to amniocentesis to reduce the time-interval from maternal seroconversion and the amniocentesis results. Risk stratification for sensorineural hearing loss (SNHL) and long-term sequelae should be provided according to the prognostic predictors. Nevertheless, in the era of valacyclovir, maternal high-dose therapy, mainly for first trimester infections, can reduce the risk of vertical transmission and increase the likelihood of asymptomatic newborns, but it is still unclear whether valacyclovir continues to exert a beneficial effect on fetuses with positive amniocentesis. This review provides updated evidence-based key counseling points with GRADE recommendations.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Perinatology; Valacyclovir; Ultrasonography, Prenatal; Cytomegalovirus Infections; Amniocentesis; Pregnancy Complications, Infectious; Infectious Disease Transmission, Vertical; Counseling
PubMed: 38310675
DOI: 10.1016/j.ejogrb.2024.01.037 -
BMC Medical Genomics Nov 2023With the advancement of molecular technology, fetal talipes equinovarus (TE) is believed to be not only associated with chromosome aneuploidy, but also related to...
BACKGROUND
With the advancement of molecular technology, fetal talipes equinovarus (TE) is believed to be not only associated with chromosome aneuploidy, but also related to chromosomal microdeletion and microduplication. The study aimed to explore the molecular etiology of fetal TE and provide more information for the clinical screening and genetic counseling of TE by Chromosomal Microarray Analysis (CMA).
METHODS
This retrospectively study included 131 fetuses with TE identified by ultrasonography. Conventional karyotyping and SNP array analysis were performed for all the subjects. They were divided into isolated TE group (n = 55) and complex group (n = 76) according to structural anomalies.
RESULTS
Among the total of 131 fetuses, karyotype analysis found 12(9.2%) abnormal results, while SNP array found 27 (20.6%) cases. Trisomy 18 was detected most frequently among abnormal karyotypes. The detection rate of SNP array was significantly higher than that of traditional chromosome karyotype analysis (P < 0.05). SNP array detected 15 (11.5%) cases of submicroscopic abnormalities that karyotype analysis did not find. The most common CNV was the 22q11.2 microdeletion. For both analyses, the overall detection rates were significantly higher in the complex TE group than in the isolated TE group (karyotype: P < 0.05; SNP array: P < 0.05). The incremental yield of chromosomal abnormalities in fetuses with unilateral TE (22.0%) was higher than in fetuses with bilateral TE (19.8%), but this difference was not statistically significant (P > 0.05). Abnormal chromosomes were most frequently detected in fetuses with TE plus cardiovascular system abnormalities.
CONCLUSION
Fetal TE is related to chromosomal microdeletion or microduplication. Prenatal diagnosis is recommended for fetuses with TE, and CMA testing is preferred. CMA can improve the detection rate of chromosomal abnormalities associated with fetal TE, especially in pregnancies with complex TE.
Topics: Pregnancy; Female; Humans; Clubfoot; Retrospective Studies; Prenatal Diagnosis; Chromosome Aberrations; Abnormal Karyotype; Microarray Analysis; Fetus; DNA Copy Number Variations
PubMed: 37986075
DOI: 10.1186/s12920-023-01733-2 -
European Radiology Nov 2023To investigate the role of MRI in the diagnosis and classification of fetal microtia.
OBJECTIVE
To investigate the role of MRI in the diagnosis and classification of fetal microtia.
METHODS
Ninety-five fetuses with suspected microtia based on ultrasound and MRI performed within 1 week were enrolled in this study. The diagnosis based on MRI was compared with postnatal diagnosis. Among the microtia cases suspected on the basis of MRI, mild and severe cases were further classified. In addition, external auditory canal (EAC) atresia was evaluated by MRI in 29 fetuses with a gestational age > 28 weeks, and the accuracy of MRI in the diagnosis and classification of microtia was determined.
RESULTS
Of 95 fetuses, 83 were considered to have microtia on the basis of MRI, 81 were confirmed to have microtia, and 14 were found to be normal according to postnatal diagnosis. Among 190 external ears in 95 fetuses, 40 ears were suspected to have mild microtia, and 52 ears were suspected to have severe microtia on the basis of MRI. According to the postnatal diagnosis, mild and severe microtia were confirmed in 43 and 49 ears, respectively. Among the 29 fetuses with a gestational age > 28 weeks, 23 ears were suspected to have EAC atresia according to MRI and 21 ears were ultimately confirmed to have EAC atresia. The accuracy of MRI in diagnosing microtia and EAC atresia was 93.68% and 93.10%, respectively.
CONCLUSION
MRI shows good performance in diagnosing fetal microtia and has the potential to evaluate its severity on the basis of classification and EAC status.
CLINICAL RELEVANCE STATEMENT
This study was aimed at investigating the role of MRI in the diagnosis and classification of fetal microtia. MRI shows good performance and can help evaluate microtia severity and EAC atresia, thus allowing for better clinical management.
KEY POINTS
• MRI is a useful adjunct to prenatal ultrasound. • MRI has a higher accuracy rate than ultrasound in diagnosing fetal microtia. • The accurate classification of fetal microtia and the diagnosis of external auditory canal atresia through MRI may help guide clinical management.
Topics: Pregnancy; Female; Humans; Infant; Congenital Microtia; Ear, External; Prenatal Diagnosis; Fetus; Magnetic Resonance Imaging; Ultrasonography, Prenatal; Retrospective Studies
PubMed: 37311804
DOI: 10.1007/s00330-023-09816-5 -
The Journal of Maternal-fetal &... Dec 2023This study aimed to analyze the ultrasound characteristics of fetal congenital vertical talus (CVT) to provide a detailed basis for the prenatal diagnosis of CVT.
OBJECTIVE
This study aimed to analyze the ultrasound characteristics of fetal congenital vertical talus (CVT) to provide a detailed basis for the prenatal diagnosis of CVT.
METHODS
We retrospectively analyzed the ultrasonographic findings of fetuses with CVT confirmed by X-ray, surgery, or autopsy from 2010 to 2020. Clinical characteristics and ultrasonographic findings of CVT, including foot morphology, ossification center of the calcaneus and talus, associated deformities, and chromosomal test results, were recorded.
RESULTS
Thirteen patients diagnosed with CVT by prenatal ultrasound were confirmed postpartum. Nine cases were bilateral, and four were unilateral. Under two-dimensional ultrasound, 13/13 cases had abnormal foot morphology, and 10 of 13 cases (76.9%) showed that the ossification center of the talus moved downward, and the calcaneus moved laterally. Under three-dimensional ultrasound, 11 cases (84.6%) presented a "rocking chair" appearance, and two cases did not obtain satisfactory three-dimensional image due to oligohydramnios and fetal position. In this group of cases, two cases (15.4%) were isolated CVT, and the other 11 cases (84.6%) were complicated with other abnormalities. Eleven cases of non-isolated CVT and 1 case of isolated CVT were induced, and another patient with isolated CVT had undergone postnatal surgery, which had been followed up for 8 years and recovered well.
CONCLUSIONS
The combination of fetal foot morphology, ossification center position of the calcaneus and talus, and three-dimensional ultrasound can provide a reliable diagnosis of CVT. Furthermore, we should pay more attention to the evaluation of other systemic and chromosomal abnormalities in CVT cases.
Topics: Female; Humans; Pregnancy; Flatfoot; Retrospective Studies; Prenatal Diagnosis; Talus; Ultrasonography, Prenatal
PubMed: 36948222
DOI: 10.1080/14767058.2023.2192323 -
Current Opinion in Pediatrics Oct 2023The aim of this study was to provide pediatric providers with a review of the diagnosis and management of fetal cardiac disease in the current era. (Review)
Review
PURPOSE OF REVIEW
The aim of this study was to provide pediatric providers with a review of the diagnosis and management of fetal cardiac disease in the current era.
RECENT FINDINGS
Prenatal detection of congenital heart disease (CHD) has improved but is still imperfect. In experienced hands, fetal echocardiography can detect severe CHD as early as the first trimester and a majority of more subtle conditions in the second and third trimesters. Beyond detection, a prenatal diagnosis allows for lesion-specific counseling for families as well as for development of a multidisciplinary perinatal management plan, which may involve in-utero treatment. Given the diversity of cardiac diagnoses and the rarity of some, collaborative multicenter fetal cardiac research has gained momentum in recent years.
SUMMARY
Accurate diagnosis of fetal cardiac disease allows for appropriate counseling, pregnancy and delivery planning, and optimization of immediate neonatal care. There is potential for improving fetal CHD detection rates. Fetal interventions are available for certain conditions, and fetal and pediatric cardiac centers have developed management plans specific to the expected postnatal physiology.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Child; Ultrasonography, Prenatal; Fetus; Heart Defects, Congenital; Fetal Diseases; Prenatal Diagnosis; Multicenter Studies as Topic
PubMed: 37466056
DOI: 10.1097/MOP.0000000000001274 -
International Journal of Gynaecology... Jul 2024Duplex kidney is a relatively frequent form of urinary system abnormality. This study aimed to elucidate the value of chromosomal microarray analysis (CMA) and whole...
OBJECTIVE
Duplex kidney is a relatively frequent form of urinary system abnormality. This study aimed to elucidate the value of chromosomal microarray analysis (CMA) and whole exome sequencing (WES) for duplex kidney and the perinatal outcomes of duplex kidney fetuses.
METHODS
This retrospective cohort study included 63 patients with duplex kidney diagnosed using antenatal ultrasound between August 2013 and January 2023. We reviewed the clinical characteristics, genetic test results, and pregnancy outcomes of the patients.
RESULTS
Among the 63 cases based on the inclusion criteria, the CMA detected seven (11.1%) clinically significant variants and nine variants of uncertain significance (VUS), and the pathogenic/likely pathogenic (P/LP) copy number variations (CNVs) in the recurrent region that were associated with prenatal duplex kidney included 17q12, 17p13.3, and 22q11.2. No significant disparity was observed in the CMA detection rate between the unilateral and bilateral groups, or between the isolated and non-isolated groups. WES identified three (50%) P/LP single-gene variants in six fetuses with duplex kidney. We detected the following pathogenic genes in the duplex kidney fetuses: KMT2D, SMPD4, and FANCI. Pregnancy termination in cases where clinically significant variants were detected by genetic testing was different in statistical significance from that in cases with negative results (9/10, 90.0% vs 8/48, 16.7%, P < 0.001).
CONCLUSION
This study elucidated the value of CMA and WES for fetal duplex kidney, proving that CMA and WES may be useful tools in prenatal diagnosis and genetic counseling.
Topics: Humans; Female; Pregnancy; Retrospective Studies; Adult; Kidney; Ultrasonography, Prenatal; Exome Sequencing; Pregnancy Outcome; Prenatal Diagnosis; DNA Copy Number Variations; Urogenital Abnormalities; Genetic Testing; Microarray Analysis
PubMed: 38189110
DOI: 10.1002/ijgo.15344 -
Prenatal Diagnosis Apr 2024To evaluate the prenatal diagnosis of closed dysraphism (CD) and its correlation with postnatal findings and neonatal adverse outcomes.
OBJECTIVE
To evaluate the prenatal diagnosis of closed dysraphism (CD) and its correlation with postnatal findings and neonatal adverse outcomes.
METHODS
A retrospective cohort study including pregnancies diagsnosed with fetal CD by prenatal ultrasound (US) and magnetic resonance imaging (MRI) at a single tertiary center between September 2011 and July 2021.
RESULTS
CD was diagnosed prenatally and confirmed postnatally in 12 fetuses. The mean gestational age of prenatal imaging was 24.2 weeks, in 17% the head circumference was ≤fifth percentile and in 25% the cerebellar diameter was ≤fifth percentile. US findings included banana sign in 17%, and lemon sign in 33%. On MRI, posterior fossa anomalies were seen in 33% of cases, with hindbrain herniation below the foramen magnum in two cases. Mean clivus-supraocciput angle (CSA) was 74°. Additional anomalies outside the CNS were observed in 50%. Abnormal foot position was demonstrated prenatally in 17%. Neurogenic bladder was present in 90% of patients after birth.
CONCLUSION
Arnold Chiari II malformation and impaired motor function can be present on prenatal imaging of fetuses with CD and may be associated with a specific type of CD. Prenatal distinction of CD can be challenging. Associated extra CNS anomalies are frequent and the rate of neurogenic urinary tract dysfunction is high.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Infant; Retrospective Studies; Prenatal Diagnosis; Arnold-Chiari Malformation; Magnetic Resonance Imaging; Spinal Dysraphism; Ultrasonography, Prenatal; Nervous System Malformations
PubMed: 38013494
DOI: 10.1002/pd.6454 -
International Journal of Molecular... Jul 2023Hemophilia A (HA), a rare recessive X-linked bleeding disorder, is caused by either deficiency or dysfunction of coagulation factor VIII (FVIII) resulting from... (Review)
Review
Hemophilia A (HA), a rare recessive X-linked bleeding disorder, is caused by either deficiency or dysfunction of coagulation factor VIII (FVIII) resulting from deleterious mutations in the F8 gene encoding FVIII. Over the last 4 decades, the methods aimed at determining the HA carrier status in female relatives of HA patients have evolved from phenotypic studies based on coagulation tests providing merely probabilistic results, via genetic linkage studies based on polymorphic markers providing more accurate results, to next generation sequencing studies enabling highly precise identification of the causative F8 mutation. In parallel, the options for prenatal diagnosis of HA have progressed from examination of FVIII levels in fetal blood samples at weeks 20-22 of pregnancy to genetic analysis of fetal DNA extracted from chorionic villus tissue at weeks 11-14 of pregnancy. In some countries, in vitro fertilization (IVF) combined with preimplantation genetic diagnosis (PGD) has gradually become the procedure of choice for HA carriers who wish to prevent further transmission of HA without the need to undergo termination of pregnancies diagnosed with affected fetuses. In rare cases, genetic analysis of a HA carrier might be complicated by skewed X chromosome inactivation (XCI) of her non-hemophilic X chromosome, thus leading to the phenotypic manifestation of moderate to severe HA. Such skewed XCI may be associated with deleterious mutations in X-linked genes located on the non-hemophilic X chromosome, which should be considered in the process of genetic counseling and PGD planning for the symptomatic HA carrier. Therefore, whole exome sequencing, combined with X-chromosome targeted bioinformatic analysis, is highly recommended for symptomatic HA carriers diagnosed with skewed XCI in order to identify additional deleterious mutations potentially involved in XCI skewing. Identification of such mutations, which may profoundly impact the reproductive choices of HA carriers with skewed XCI, is extremely important.
Topics: Humans; Pregnancy; Female; Hemophilia A; Factor VIII; Prenatal Diagnosis; Genetic Carrier Screening; Mutation; Heterozygote
PubMed: 37511607
DOI: 10.3390/ijms241411846 -
American Journal of Obstetrics &... Jan 2024Polycystic renal disease is a frequent congenital anomaly of the kidneys, but research using chromosomal microarray analysis and exome sequencing in fetuses with... (Review)
Review
BACKGROUND
Polycystic renal disease is a frequent congenital anomaly of the kidneys, but research using chromosomal microarray analysis and exome sequencing in fetuses with polycystic renal disease remains sparse, with most studies focusing on the multisystem or genitourinary system.
OBJECTIVE
This study aimed to assess the detection rate of detectable genetic causes of fetal polycystic renal disease at different levels, novel disease-causing variants, and genotype-phenotype correlations.
STUDY DESIGN
This study included 220 fetal polycystic renal disease cases from January 2014 to June 2022. Cases were divided into the following 3 groups: isolated multicystic dysplastic kidneys, nonisolated multicystic dysplastic kidneys, and suspected polycystic kidney disease group. We reviewed data on maternal demographics, ultrasonographic results, chromosomal microarray analysis/exome sequencing results, and pregnancy outcomes.
RESULTS
In our cohort, chromosomal microarray analysis identified 19 (8.6%) fetuses carrying chromosomal abnormalities, and the most common copy number variation was 17q12 microdeletion (7/220; 3.2%). Furthermore, 94 families chose to perform trio-exome sequencing testing, and 21 fetuses (22.3%) were found to harbor pathogenic/likely pathogenic variants. There was a significant difference in the live birth rate among the 3 groups (91/130 vs 46/80 vs 1/10; P<.001). Among 138 live birth cases, 106 (78.5%) underwent postnatal ultrasound review, of which 95 (89.6%) had a consistent prenatal-postnatal ultrasound diagnosis.
CONCLUSION
For both isolated and nonisolated polycystic renal disease, our data showed high detection efficiency with both testing tools. The detection of novel pathogenic variants expands the known disease spectrum of polycystic renal disease-associated genes while enriching our understanding of the genotype-phenotype correlation. Therefore, we consider it feasible to perform chromosomal microarray analysis+exome sequencing testing in fetal polycystic renal disease. Moreover, prenatal-postnatal ultrasound concordance was greater, the live birth rate was higher, and prognosis was better when known genetic disorders were excluded, indicating that genetic testing results significantly influenced pregnancy decisions.
Topics: Pregnancy; Female; Humans; Multicystic Dysplastic Kidney; DNA Copy Number Variations; Prenatal Diagnosis; Polycystic Kidney Diseases; Fetus
PubMed: 37984685
DOI: 10.1016/j.ajogmf.2023.101228