From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease.

NKAP mutations are associated with Hackmann-Di Donato-type X-linked syndromic intellectual developmental disorder (MRXSHD, MIM: #301039). Here, we elucidate the potential prenatal manifestation of NKAP mutation-associated disorder for the first time, alongside revealing the relationship between NKAP mutations and congenital heart defect (CHD) in the Chinese population. An NKAP mutation (NM_024528.4: c.988C>T, p.Arg330Cys) was identified in two foetuses presenting with CHD. Subsequent mechanistic exploration revealed a marked downregulation of NKAP transcription within HEK293T cells transfected with NKAP p.R330C. However, no significant change was observed at the protein level. Moreover, the mutation led to a dysregulation in the transcription of genes associated with cardiac morphogenesis, such as DHRS3, DNAH11 and JAG1. Additionally, our research determined that NKAP p.R330C affected Nkap protein intra-nuclear distribution, and binding with Hdac3. Summarily, our study strengthens NKAP mutations as a cause of CHD and prompts the reclassification of NKAP p.R330C as likely pathogenic, thereby establishing a prospective prenatal phenotypic spectrum that provides new insight into the prenatal diagnosis of CHD. Our findings also provide evidence of NKAP p.R330C pathogenicity and demonstrate the potential mechanism by which p.R330C dysregulates cardiac developmental gene transcription by altering Nkap intra-nuclear distribution and obstructing the interaction between Nkap and Hdac3, thereby leading to CHD.

Prenatal Diagnosis by Trio Clinical Exome Sequencing: Single Center Experience.

Fetal anomalies, characterized by structural or functional abnormalities occurring during intrauterine life, pose a significant medical challenge, with a notable prevalence, affecting approximately 2-3% of live births and 20% of spontaneous miscarriages. This study aims to identify the genetic cause of ultrasound anomalies through clinical exome sequencing (CES) analysis. The focus is on utilizing CES analysis in a trio setting, involving the fetuses and both parents. To achieve this objective, prenatal trio clinical exome sequencing was conducted in 51 fetuseses exhibiting ultrasound anomalies with previously negative results from chromosomal microarray (CMA) analysis. The study revealed pathogenic variants in 24% of the analyzed cases (12 out of 51). It is worth noting that the findings include de novo variants in 50% of cases and the transmission of causative variants from asymptomatic parents in 50% of cases. Trio clinical exome sequencing stands out as a crucial tool in advancing prenatal diagnostics, surpassing the effectiveness of relying solely on chromosomal microarray analysis. This underscores its potential to become a routine diagnostic standard in prenatal care, particularly for cases involving ultrasound anomalies.

Low-pass whole genome sequencing is a reliable and cost-effective approach for copy number variant analysis in the clinical setting.

INTRODUCTION: Next generation sequencing technology has greatly reduced the cost and time required for sequencing a genome. An approach that is rapidly being adopted as an alternative method for CNV analysis is the low-pass whole genome sequencing (LP-WGS). Here, we evaluated the performance of LP-WGS to detect copy number variants (CNVs) in clinical cytogenetics. MATERIALS AND METHODS: DNA samples with known CNVs detected by chromosomal microarray analyses (CMA) were selected for comparison and used as positive controls; our panel included 44 DNA samples (12 prenatal and 32 postnatal), comprising a total of 55 chromosome imbalances. The selected cases were chosen to provide a wide range of clinically relevant CNVs, the vast majority being associated with intellectual disability or recognizable syndromes. The chromosome imbalances ranged in size from 75 kb to 90.3 Mb, including aneuploidies and two cases of mosaicism. RESULTS: All CNVs were successfully detected by LP-WGS, showing a high level of consistency and robust performance of the sequencing method. Notably, the size of chromosome imbalances detected by CMA and LP-WGS were compatible between the two different platforms, which indicates that the resolution and sensitivity of the LP-WGS approach are at least similar to those provided by CMA. DISCUSSION: Our data show the potential use of LP-WGS to detect CNVs in clinical diagnosis and confirm the method as an alternative for chromosome imbalances detection. The diagnostic effectiveness and feasibility of LP-WGS, in this technical validation study, were evidenced by a clinically representative dataset of CNVs that allowed a systematic assessment of the detection power and the accuracy of the sequencing approach. Further, since the software used in this study is commercially available, the method can easily be tested and implemented in a routine diagnostic setting.

Emphasizing the need for preconceptional, prenatal genetic counseling and comprehensive genetic testing in consanguinity: challenges and experience.

Preconception and prenatal genetic counseling is a well-established means of risk assessment in many parts of the world, and in recent years, an emerging concept in India. Likelihood of an offspring having autosomal recessive disorder increases based on the degree of consanguinity. Hence, genetic testing of the couple for the identification of carrier status for disease-causing variants is crucial. The purpose of this study is to understand the frequency of genetic abnormalities in consanguineous marriages by using a comprehensive genetic testing algorithm where in karyotyping, FISH, exome sequencing and microarray are used sequentially to determine the genetic etiology based on the clinical presentation and to evaluate the need and benefits of preconceptional and prenatal genetic counseling. This retrospective study includes 66 couples having consanguinity referred for genetic counseling and testing. Of the 66 couples, 58 underwent comprehensive genetic testing which included Karyotyping, Fluorescence in Situ Hybridization (FISH), Microarray and Exome sequencing based on their clinical presentation. The analyses revealed a genetic abnormality in approximately 31% and chromosomal polymorphic variations & variants of uncertain significance in 17% of the couples. Counseling in these couples helped in identifying the carrier status and enabled them to take an informed decision in subsequent pregnancies. These findings reiterate the acute need for preconception and prenatal genetic counseling services in India.

Characterizing neuroinflammation and identifying prenatal diagnostic markers for neural tube defects through integrated multi-omics analysis.

BACKGROUND: Neural Tube Defects (NTDs) are congenital malformations of the central nervous system resulting from the incomplete closure of the neural tube during early embryonic development. Neuroinflammation refers to the inflammatory response in the nervous system, typically resulting from damage to neural tissue. Immune-related processes have been identified in NTDs, however, the detailed relationship and underlying mechanisms between neuroinflammation and NTDs remain largely unclear. In this study, we utilized integrated multi-omics analysis to explore the role of neuroinflammation in NTDs and identify potential prenatal diagnostic markers using a murine model. METHODS: Nine public datasets from Gene Expression Omnibus (GEO) and ArrayExpress were mined using integrated multi-omics analysis to characterize the molecular landscape associated with neuroinflammation in NTDs. Special attention was given to the involvement of macrophages in neuroinflammation within amniotic fluid, as well as the dynamics of macrophage polarization and their interactions with neural cells at single-cell resolution. We also used qPCR assay to validate the key TFs and candidate prenatal diagnostic genes identified through the integrated analysis in a retinoic acid-induced NTDs mouse model. RESULTS: Our analysis indicated that neuroinflammation is a critical pathological feature of NTDs, regulated both transcriptionally and epigenetically within central nervous system tissues. Key alterations in gene expression and pathways highlighted the crucial role of STATs molecules in the JAK-STAT signaling pathway in regulating NTDs-associated neuroinflammation. Furthermore, single-cell resolution analysis revealed significant polarization of macrophages and their interaction with neural cells in amniotic fluid, underscoring their central role in mediating neuroinflammation associated with NTDs. Finally, we identified a set of six potential prenatal diagnostic genes, including FABP7, CRMP1, SCG3, SLC16A10, RNASE6 and RNASE1, which were subsequently validated in a murine NTDs model, indicating their promise as prospective markers for prenatal diagnosis of NTDs. CONCLUSIONS: Our study emphasizes the pivotal role of neuroinflammation in the progression of NTDs and underlines the potential of specific inflammatory and neural markers as novel prenatal diagnostic tools. These findings provide important clues for further understanding the underlying mechanisms between neuroinflammation and NTDs, and offer valuable insights for the future development of prenatal diagnostics.

Utilization of a SNP microarray to detect uniparental disomy: Implications and outcomes.

PURPOSE: To examine the utility of single-nucleotide polymorphisms (SNP) microarray analysis to detect uniparental disomy (UPD) by utilizing trios and duos (for which only 1 parent is available). METHODS: We established Mendelian Inheritance Error (MIE) values associated with either UPD or biparental inheritance in a cohort of 124 patients. In duos, the percentage of proband heterozygous (AB) SNPs contributed from the parent submitted was also used to detect UPD. RESULTS: Examination of 25 trios revealed UPD with a MIE = 0.02 +/- 0.02 and a range of 0.01 to 0.23 for the contributing parent and a MIE = 8.76 +/- 1.68 with a range of 5.96 to 11.14 for the noncontributing parent. Detailed examination of 13 duos (involving 16 chromosomes) showed an AB% = 52.0% +/- 4.85% consistent with biparental origin of the chromosome of interest. In 6 duos (6 chromosomes), the AB% = 97.2% +/- 2.6% and a range of 92.9% to 99.4% were consistent with UPD. CONCLUSION: Our results demonstrate utility of a SNP microarray to detect UPD. Distinct MIE ranges were observed that defined UPD or biparental inheritance. In duos, the AB% calculation effectively detected UPD. The diagnostic yield for UPD testing is significantly decreased when large regions of homozygosity are not detected by routine microarray analysis, which has implications for UPD test ordering practices.

Clinical and molecular characteristics of 26 fetuses with lethal multiple congenital contractures.

Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes.

Exploring factors impacting haplotype-based noninvasive prenatal diagnosis for single-gene recessive disorders.

Haplotype-based noninvasive prenatal diagnosis (NIPD) is applicable for various recessive single-gene disorders in proband families. However, a comprehensive exploration of critical factors influencing the assay performance, such as fetal fraction, informative single nucleotide polymorphism (SNP) count, and recombination events, has yet to be performed. It is critical to identify key factors affecting NIPD performance, including its accuracy and success rate, and their impact on clinical diagnostics to guide clinical practice. We conducted a prospective study, recruiting 219 proband families with singleton pregnancies at risk for eight recessive single-gene disorders (Duchenne muscular dystrophy, spinal muscular atrophy, phenylketonuria, methylmalonic acidemia, hemophilia A, hemophilia B, non-syndromic hearing loss, and congenital adrenal hyperplasia) at 7-14 weeks of gestation. Haplotype-based NIPD was performed by evaluating the relative haplotype dosage (RHDO) in maternal circulation, and the results were validated via invasive prenatal diagnosis or newborn follow-ups. Among the 219 families, the median gestational age at first blood draw was 8+5 weeks. Initial testing succeeded for 190 families and failed for 29 due to low fetal fraction (16), insufficient informative SNPs (9), and homologous recombination near pathogenic variation (4). Among low fetal fraction families, successful testing was achieved for 11 cases after a redraw, while 5 remained inconclusive. Test failures linked to insufficient informative SNPs correlated with linkage disequilibrium near the genes, with F8 and MMUT exhibiting the highest associated failure rates (14.3% and 25%, respectively). Homologous recombination was relatively frequent around the DMD and SMN1 genes (8.8% and 4.8%, respectively) but led to detection failure in only 44.4% (4/9) of such cases. All NIPD results from the 201 successful families were consistent with invasive diagnostic findings or newborn follow-up. Fetal fraction, informative SNPs count, and homologous recombination are pivotal to NIPD performance. Redrawing blood effectively improves the success rate for low fetal fraction samples. However, informative SNPs count and homologous recombination rates vary significantly across genes, necessitating careful consideration in clinical practice. We have designed an in silico method based on linkage disequilibrium data to predict the number of informative SNPs. This can identify genomic regions where there might be an insufficient number of SNPs, thereby guiding panel design. With these factors properly accounted for, NIPD is highly accurate and reliable.

Prenatal diagnosis of a 15q24.1 microdeletion in a fetus with cerebral and urogenital abnormalities.

15q24.1 microdeletion syndrome is a recently described condition often resulting from non-allelic homologous recombination (NAHR). Typical clinical features include pre and post-natal growth retardation, facial dysmorphism, developmental delay and intellectual disability. Nonspecific urogenital, skeletal, and digit abnormalities may be present, although other congenital malformations are less frequent. Consequently, only one case was reported prenatally, complicating the genotype-phenotype correlation and the genetic counseling. We identified prenatally a second case, presenting with cerebral abnormalities including hydrocephaly, macrocephaly, cerebellum hypoplasia, vermis hypoplasia, rhombencephalosynapsis, right kidney agenesis with left kidney duplication and micropenis. Genome-wide aCGH assay allowed a diagnosis at 26 weeks of amenorrhea revealing a 1.6 Mb interstitial deletion on the long arm of chromosome 15 at 15q24.1-q24.2 (arr[GRCh37] 15q24.1q24.2(74,399,112_76,019,966)x1). A deep review of the literature was undertaken to further delineate the prenatal clinical features and the candidate genes involved in the phenotype. Cerebral malformations are typically nonspecific, but microcephaly appears to be the most frequent in postnatal cases. Our case is the first reported with a frank cerebellar involvement.

The association between parental age differences and perinatal outcomes.

STUDY QUESTION: Are there significant associations existing between parental age differences and adverse perinatal outcomes? SUMMARY ANSWER: Large differences in parental age are associated with adverse perinatal outcomes, particularly with older mothers paired with younger fathers. WHAT IS KNOWN ALREADY: The association between advanced maternal age and perinatal outcomes is well-documented with women over 35 years showing an increased risk of several adverse outcomes. Other studies have identified potential associations between advanced paternal age and adverse perinatal outcomes. STUDY DESIGN, SIZE, DURATION: A historical (retrospective) cohort analysis was performed utilizing a multivariable logistic regression model to evaluate the association between varying differences in parental age and adverse perinatal outcomes while controlling for demographic and health-related covariates. Data were compiled from the National Vital Statistics System for 20 613 704 births between 2012 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Parental age differences, categorized into eleven 4-year intervals, were stratified by seven maternal age categories and evaluated for their associations with adverse perinatal outcomes. Main outcome measures included low birth weight, very low birth weight, preterm birth, very preterm birth, small size for gestational age, low 5-min appearance, pulse, grimace, activity, and respiration score, congenital defects, and chromosomal anomalies. MAIN RESULTS AND THE ROLE OF CHANCE: Increased parental age differences, in either direction, were associated with significant risks for all adverse outcomes, aside from congenital defects, even when controlling for maternal age. Restricting maternal age to the reference range of 25-29 years, infants born to fathers aged 9-12 years younger (n = 3773) had 27% (odds ratio (OR) 1.27, 95% CI, 1.17-1.37) higher odds of having any adverse perinatal outcome. Infants born to fathers aged >16 years older (n = 98 555) had 14% (OR 1.14, 95% CI, 1.12-1.16) higher odds of having any adverse perinatal outcome. LIMITATIONS, REASONS FOR CAUTION: Data extracted from US birth certificates may be compromised by errors in reporting or documentation. Information regarding the mother's socioeconomic status was estimated using proxy variables and may be susceptible to uncontrolled factors. Use of a pre-compiled dataset may potentially exclude additional maternal comorbidities that could impact perinatal outcomes. WIDER IMPLICATIONS OF FINDINGS: Older mothers paired with younger fathers demonstrated the highest risk, even when maternal age was below the threshold of 35 years. For the clinical setting, parental age differences should be considered alongside maternal and paternal age when assessing risks of adverse perinatal outcomes for potential parents. This is particularly relevant for older women with younger male partners as this may exacerbate the impact of advanced maternal age. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the NIH Research Fellowship T35 Training Grant. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

A Deep Learning Pipeline Using Prior Knowledge for Automatic Evaluation of Placenta Accreta Spectrum Disorders With MRI.

BACKGROUND: The diagnosis of prenatal placenta accreta spectrum (PAS) with magnetic resonance imaging (MRI) is highly dependent on radiologists' experience. A deep learning (DL) method using the prior knowledge that PAS-related signs are generally found along the utero-placental borderline (UPB) may help radiologists, especially those with less experience, to mitigate this issue. PURPOSE: To develop a DL tool for antenatal diagnosis of PAS using T2-weighted MR images. STUDY TYPE: Retrospective. SUBJECTS: Five hundred and forty pregnant women with clinically suspected PAS disorders from two institutions, divided into training (409), internal test (103), and external test (28) datasets. FIELD STRENGTH/SEQUENCE: Sagittal T2-weighted fast spin echo sequence at 1.5 T and 3 T. ASSESSMENT: An nnU-Net was trained for placenta segmentation. The UPB straightening approach was used to extract the utero-placental boundary region. The UPB image was then fed into DenseNet-PAS for PAS diagnosis. DenseNet-PP learnt placental position information to improve the PAS diagnosis performance. Three radiologists with 8, 10, and 12 years of experience independently evaluated the images. Two radiologists marked the placenta tissue. Histopathological findings were the reference standard. STATISTICAL TESTS: Area under the curve (AUC) was used to evaluate the classification. Dice coefficient evaluated the segmentation between radiologists and the model performance. The Mann-Whitney U-test or the chi-squared test assessed the significance of differences. Decision curve analysis was used to determine clinical effectiveness. DeLong's test was used to compare AUCs. RESULTS: Of the 540 patients, 170 had PAS disorders confirmed by histopathology. The DL model using UPB images and placental position yielded the highest AUC of 0.860 and 0.897 in internal test and external test cohorts, respectively, significantly exceeding the performance of three radiologists (internal test AUC, 0.737-0.770). DATA CONCLUSION: By extracting the UPB image, this fully automatic DL pipeline achieved high accuracy and may assist radiologists in PAS diagnosis using MRI. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Prenatal Diagnosis of Cerebellar Cortical Dysplasia: Case Report.

This was a study of 12 cerebellar cortical dysplasias (CCDs) fetuses, these cases were characterized by a disorder of cerebellar fissures. Historically, CCD diagnosis was primarily performed using postnatal imaging. Unique to this study was the case series of CCD for prenatal diagnosis using prenatal ultrasound, as well as we found that AXIN1 and FOXC1 mutations may be related to CCD.

45,X/46,XY mosaicism: Clinical manifestations and long term follow-up.

45,X/46,XY chromosomal mosaicism presents a range of clinical manifestations, including phenotypes from Turner syndrome through genital abnormalities to apparently unaffected phenotypic males; however, the full clinical spectrum has not yet been fully delineated since prior studies on the clinical phenotype and associated risk of gonadal tumors included small cohorts and limited follow-up. To better describe the clinical manifestations and long-term outcome of patients with 45,X/46,XY mosaicism. We conducted a retrospective chart review of patients with 45,X/46,XY from three health centers (Hospital for Sick Children and Mount Sinai Hospital in Canada, and University of Pittsburgh Medical Center in United States). Of 100 patients with 45,X/46,XY karyotype, 47 were raised as females and 53 as males. Females were significantly shorter than males (p = 0.04) and height Z-score was significantly decreased with age for both genders (p = 0.02). Growth hormone (GH) treatment did not result in a significant height increase compared to the untreated group (p = 0.5). All females required puberty induction in contrast to majority of males. Five females were diagnosed with gonadal tumors, while no males were affected. Around 58% of patients exhibited at least one Turner syndrome stigmata. This study expands the clinical spectrum, long-term outcomes, and associated tumor risk in a large cohort of patients with 45,X/46,XY mosaicism. Additionally, it highlights our experience with GH therapy and prophylactic gonadectomy.

Severe Phenotype With RECQL4 Syndrome: A Report of Two Cases.

Baller-Gerold syndrome (BGS, OMIM: 218600), RAPADILINO syndrome (OMIM 266280), and Rothmund-Thomson syndrome (RTS, OMIM 266280), which are caused in some cases by RECQL4 pathogenic variants, show autosomal recessive inheritance. Some refer to them collectively as RECQL4 syndromes. Most cases have been reported during infancy and childhood periods. However, there have been no reports of phenotypes resulting in a lethal course in the perinatal period. We identified two fetuses with biallelic RECQL4 pathogenic variants during the perinatal period. The two fetuses with RECQL4 syndrome showed structural abnormalities, including severely hypoplastic forearms and lower legs. One fetus also had severe pulmonary hypoplasia. One case resulted in neonatal death because of respiratory failure, and the other was artificially terminated during pregnancy. The RECQL4 pathogenic variants were identified by exome sequencing followed by Sanger sequencing. The biallelic RECQL4 pathogenic variants can induce a lethal skeletal disorder.

Dandy-Walker malformation in an individual with ABL1 variant.

Dandy-Walker malformation (DWM) is often sporadic, but there are a growing number of genetic disorders that have been associated with this condition. We present a female individual with a de novo variant in ABL1, c.734A>G (p.Y245), who was diagnosed prenatally with DWM. ABL1-related neurodevelopmental disorder was recently identified but brain malformations have not been well characterized to date. We reviewed the published literature and identified one additional individual with DWM and ABL1-related disorder, which suggests a possible association with this malformation.

First-trimester noninvasive prenatal diagnosis of seven facioscapulohumeral muscular dystrophy type 1 families using SNP-based amplicon sequencing: An earlier, rapid and safer way.

The study is to explore the feasibility and value of SNP-based noninvasive prenatal diagnosis (NIPD) for facioscapulohumeral muscular dystrophy type 1 (FSHD1) in early pregnancy weeks. We prospectively collected seven FSHD1 families, with an average gestational age of 8+6. Among these seven couples, there were three affected FSHD1 mothers and four affected fathers. A multiplex-PCR panel comprising 402 amplicons was designed to selective enrich for highly heterozygous SNPs upstream of the DUX4 gene. Risk haplotype was constructed based on familial linkage analysis. Fetal genotypes were accurately inferred through relative haplotype dosage analysis using Bayes Factor. All tests were successfully completed in a single attempt, and no recombination events were detected. NIPD results were provided within a week, which is 4 weeks earlier than karyomapping and 7 weeks earlier than Bionano single-molecule optical mapping (BOM). Ultimately, five FSHD1 fetuses and two normal fetuses were successfully identified, with a 100% concordance rate with karyomapping and BOM. Therefore, SNP-based NIPD for FSHD1 was demonstrated to be feasible and accurate in early weeks of gestation, although the risk of recombination events cannot be completely eliminated. In the future, testing of more cases is still necessary to fully determine the clinical utility.

Clinical and molecular characteristics of hemophilia A affected individuals and carriers: A 24 years experience from three centers.

Hemophilia A is a rare bleeding disorder with variable expressivity and allelic heterogeneity. Despite the advancement of prenatal diagnostics and molecular studies, the number of studies reviewing the reproductive choices of hemophilia A carriers and affected individuals remains limited. Through this retrospective review, we hope to gain a deeper understanding of hemophilia A-affected individuals' clinical and molecular characteristics, as well as the reproductive choices of the at-risk couples. A total of 122 individuals harboring likely causative F8 gene alterations from 64 apparently unrelated families attending three centers between 3/2000 and 3/2023 were included in this study. Their clinical and molecular findings as well as reproductive choices were gathered in a clinical setting and verified through the electronic medical record database of the public health system. Forty-seven affected males and 75 female heterozygous carriers were included in the analysis. Among 64 apparently unrelated families, 36 distinct pathogenic/likely pathogenic variants were identified, of which 30.6% (11/36) of variants were novel. While the majority of clinical findings and genotype-phenotype correlations appear to be in accordance with existing literature, female carriers who had no fertility intention were significantly more likely to have affected sons than those who had fertility intention (5/19 vs. 4/5; p = 0.047). Through this retrospective review, we summarized the clinical and molecular characteristics of 122 individuals harboring pathogenic/likely pathogenic F8 variants, as well as their fertility intentions and reproductive outcomes. Further studies are required to look into the considerations involved in reproductive decision-making.

Prenatal screening after preimplantation genetic testing for aneuploidy: time to evaluate old strategies.

RESEARCH QUESTION: How does first-trimester aneuploidy screening perform in pregnancies achieved through IVF with preimplantation genetic testing for aneuploidy (PGT-A) in a medical setting? DESIGN: This retrospective cohort study was undertaken in a single tertiary care centre between January 2013 and June 2022. In total, 20,237 women had prenatal follow-up at the study centre and were included in the study. The women were divided into three groups: singleton pregnancies conceived through the transfer of a PGT-A-screened euploid embryo (n = 510); singleton pregnancies conceived through IVF without PGT-A (n = 3291); and singleton pregnancies conceived naturally (n = 16,436). RESULTS: The conventional combined screening test for pregnancies conceived through IVF with PGT-A had specificity of 91%; sensitivity could not be calculated as there were no cases of fetal aneuploidy in this group. In 89.1% of pregnancies conceived through IVF with PGT-A with high risk for trisomy 21, 18 or 13, the result was related to advanced maternal age (>35 years at time of screening). CONCLUSIONS: The current screening strategy for trisomies 21, 18 and 13 can generate unnecessary tests in pregnancies achieved through IVF with PGT-A. A new protocol is needed for these patients, with greater weight given to ultrasound markers.

Incidence and causes of perinatal death in prenatally diagnosed vasa previa: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to estimate the perinatal mortality associated with prenatally diagnosed vasa previa and to determine what proportion of those perinatal deaths are directly attributable to vasa previa. DATA SOURCES: The following databases have been searched from January 1, 1987, to January 1, 2023: PubMed, Scopus, Web of Science, and Embase. STUDY ELIGIBILITY CRITERIA: Our study included all studies (cohort studies and case series or reports) that had patients in which a prenatal diagnosis of vasa previa was made. Case series or reports were excluded from the meta-analysis. All cases in which prenatal diagnosis was not made were excluded from the study. METHODS: The programming language software R (version 4.2.2) was used to conduct the meta-analysis. The data were logit transformed and pooled using the fixed effects model. The between-study heterogeneity was reported by I2. The publication bias was evaluated using a funnel plot and the Peters regression test. The Newcastle-Ottawa scale was used to assess the risk of bias. RESULTS: Overall, 113 studies with a cumulative sample size of 1297 pregnant individuals were included. This study included 25 cohort studies with 1167 pregnancies and 88 case series or reports with 130 pregnancies. Moreover, 13 perinatal deaths occurred among these pregnancies, consisting of 2 stillbirths and 11 neonatal deaths. Among the cohort studies, the overall perinatal mortality was 0.94% (95% confidence interval, 0.52-1.70; I2=0.0%). The pooled perinatal mortality attributed to vasa previa was 0.51% (95% confidence interval, 0.23-1.14; I2=0.0%). Stillbirth and neonatal death were reported in 0.20% (95% confidence interval, 0.05-0.80; I2=0.0%) and 0.77% (95% confidence interval, 0.40-1.48; I2=0.0%) of pregnancies, respectively. CONCLUSION: Perinatal death is uncommon after a prenatal diagnosis of vasa previa. Approximately half of the cases of perinatal mortality are not directly attributable to vasa previa. This information will help in guiding physicians in counseling and will provide reassurance to pregnant individuals with a prenatal diagnosis of vasa previa.

The Hard Palate Sweep: a multiplanar 2-dimensional sonographic method for the prenatal detection of cleft palate.

BACKGROUND: Prenatal diagnosis of cleft palate is challenging. Numerous 2-dimensional and 3-dimensional methods have been proposed to assess the integrity of the fetal palate, yet detection rates remain relatively low. We propose the "Hard Palate Sweep," a novel 2-dimensional method that enables clear demonstration of the entire fetal palate throughout pregnancy, in a single sweep, avoiding acoustic shadows cast by surrounding bones. OBJECTIVE: This study aimed to assess the feasibility and performance of the Hard Palate Sweep, performed throughout pregnancy. STUDY DESIGN: This was a prospective cross-sectional study performed between 2018 and 2022 in pregnant patients referred for a routine or targeted anomaly scan between 13 and 40 weeks of gestation. The presence or absence of a cleft palate was determined using the "Hard Palate Sweep." This was compared with the postnatal palate integrity assessment. Test feasibility and performance indices, including sensitivity, specificity, and positive and negative predictive values were calculated. Offline clips were reviewed by 2 investigators for the assessment of inter- and intraoperator agreement, using Cohen's kappa formula. The study protocol was approved by the institutional ethics committee. All participating patients were informed and provided consent. RESULTS: A total of 676 fetuses were included in the study. The Hard Palate Sweep was successfully performed in all cases, and 19 cases were determined to have a cleft palate. Of these, 13 cases were excluded because postmortem confirmation was not performed, leaving 663 cases available for analysis. Six cases determined to have a cleft palate were confirmed postnatally. In 655 of 657 cases prenatally determined to have an intact palate, this was confirmed postnatally. In the 2 remaining cases, rare forms of cleft palate were diagnosed postnatally, rendering 75% sensitivity, 100% specificity, 100% positive predictive value, and 99.7% negative predictive value for the Hard Palate Sweep (P<.001). There was complete intra- and interoperator agreement (kappa=1; P<.0001). CONCLUSION: The Hard Palate Sweep is a feasible and accurate method for prenatally detecting a cleft palate. It was successfully performed in all attempted cases between 13 and 40 weeks of gestation. This method is reproducible, offering high sensitivity and specificity. Implemented routinely, the Hard Palate Sweep is expected to increase the prenatal detection of cleft palate.