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Linked article: This is a mini commentary on R Mellis et al., pp. 52–61 in this issue. To view this article visit https://doi.org/10.1111/1471‐0528.16869 [ABSTRACT FROM AUTHOR]

Gain-of-function variants in the WDR44 gene have recently been associated with an X-linked ciliopathy-related neurodevelopmental phenotype. Here, we report on a WDR44 loss-of-function (LOF) variant identified in the genome sequence from a male fetus enrolled in the Prenatal Genetic Diagnosis by Genomic Sequencing (PrenatalSEQ) multicenter study. The phenotype is consistent with the described X-linked ciliopathy that includes developmental delay, microcephaly, congenital heart defects, kidney abnormalities, cryptorchidism, musculoskeletal abnormalities, craniofacial dysmorphism, and effusions. This is the first report of a WDR44 LOF variant in an affected individual with a prenatal presentation and supports LOF as a mechanism for the X-linked WDR44 ciliopathy-related phenotype., (© 2024 Wiley Periodicals LLC.)

Objective: Intellectual disability is often the outcome of neurodevelopmental disorders and is characterized by significant impairments in intellectual and adaptive functioning. X-linked intellectual disability (XLID) is a subset of these disorders caused by genetic defects on the X chromosome, affecting about 2 out of 1,000 males. In syndromic form, it leads to a broad range of cognitive, behavioral, ocular, and physical disabilities., Methods: Employing exome or genome sequencing, here we identified 4 missense variants (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K, c.953C > T; p.S318L) and a putative truncating variant (c.1413_1414del; p.Y471*) in the SRPK3 gene in 9 XLID patients from 5 unrelated families. To validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish., Results: The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Together, these data indicate a pathological role of SRPK3 in neurodevelopmental disorders. In post-fertilization day 5 larvae (free swimming stage), KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients. In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability., Interpretation: Overall, these results suggest a crucial role of SRPK3 in the pathogenesis of syndromic X-linked intellectual disability and provide new insights into brain development, cognitive and ocular dysfunction in both humans and zebrafish. ANN NEUROL 2024;96:914-931., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: To describe the association between geographic location of residence and use of aneuploidy screening or prenatal genetic counseling and how it is modified by maternal race and ethnicity., Methods: Retrospective cohort of individuals at a tertiary care center between 2017-2019. County of residence was classified as rural or metropolitan based in US Office of Management and Budget 2019 definitions. Maternal race and ethnicity were self-identified. Our composite outcome was defined as use of aneuploidy screening or genetic counseling visit. The composite outcome was compared by geographic location and ethnicity. Logistic regression was used to model the relationship between geographic location and the composite outcome., Results: A total of 8774 pregnancies were included. Of these, 4770 (54%) had genetic screening, and 3781 (43%) had at least 1 genetic counseling visit. Rural patients were significantly less likely to have the composite outcome compared with metropolitan peers (37.1% vs 47.2%, P < .001). In addition, we identified differences in the composite outcome between White rural patients and LatinX rural patients (37.7% vs 35.6%, P < .001) and between Asian rural patients and LatinX and Black rural patients (41.0% vs 35.6%, P < .001; 41.0% vs 36.8%, P < .001). Logistic regression demonstrated that rural patients were significantly less likely to have the composite outcome compared with metropolitan peers, after adjusting for LatinX ethnicity and gestational age at first prenatal visit (OR 0.72, [0.55, 0.95], P = .002)., Conclusion: Rural, minority patients were significantly less likely to receive reproductive genetic services compared with metropolitan peers extending our knowledge of disparities in maternity care., Competing Interests: Conflict of Interest Asha N. Talati receives research support from the National Institutes of Health, Billion to One, and The Greenwall Foundation. Divya P. Mallampati receives salary support from the Department of Health and Human Services. Neeta L. Vora receives research support from National Institutes of Health and received supplies in kind from Illumina unrelated to this research., (Copyright © 2024. Published by Elsevier Inc.)

Background: Amniocentesis for genetic diagnosis is most commonly done between 15 and 22 weeks of gestation but can be performed at later gestational ages. The safety and genetic diagnostic accuracy of amniocentesis have been well-established through numerous large-scale multicenter studies for procedures before 24 weeks, but comprehensive data on late amniocentesis remain sparse., Objective: To evaluate the indications, diagnostic yield, safety, and maternal and fetal outcomes associated with amniocentesis performed at or beyond 24 weeks of gestation., Study Design: We conducted an international multicenter retrospective cohort study examining pregnant individuals who underwent amniocentesis for prenatal diagnostic testing at gestational ages between 24w0d and 36w6d. The study, spanning from 2011 to 2022, involved 9 referral centers. We included singleton or twin pregnancies with documented outcomes, excluding cases where other invasive procedures were performed during pregnancy or if amniocentesis was conducted for obstetric indications. We analyzed indications for late amniocentesis, types of genetic tests performed, their results, and the diagnostic yield, along with pregnancy outcomes and postprocedure complications., Results: Of the 752 pregnant individuals included in our study, late amniocentesis was primarily performed for the prenatal diagnosis of structural anomalies (91.6%), followed by suspected fetal infection (2.3%) and high-risk findings from cell-free DNA screening (1.9%). The median gestational age at the time of the procedure was 28w5d, and 98.3% of pregnant individuals received results of genetic testing before birth or pregnancy termination. The diagnostic yield was 22.9%, and a diagnosis was made 2.4 times more often for fetuses with anomalies in multiple organ systems (36.4%) compared to those with anomalies in a single organ system (15.3%). Additionally, the diagnostic yield varied depending on the specific organ system involved, with the highest yield for musculoskeletal anomalies (36.7%) and hydrops fetalis (36.4%) when a single organ system or entity was affected. The most prevalent genetic diagnoses were aneuploidies (46.8%), followed by copy number variants (26.3%) and monogenic disorders (22.2%). The median gestational age at delivery was 38w3d, with an average of 59 days between the procedure and delivery date. The overall complication rate within 2 weeks postprocedure was 1.2%. We found no significant difference in the rate of preterm delivery between pregnant individuals undergoing amniocentesis between 24 and 28 weeks and those between 28 and 32 weeks, reinforcing the procedure's safety across these gestational periods., Conclusion: Late amniocentesis, at or after 24 weeks of gestation, especially for pregnancies complicated by multiple congenital anomalies, has a high diagnostic yield and a low complication rate, underscoring its clinical utility. It provides pregnant individuals and their providers with a comprehensive diagnostic evaluation and results before delivery, enabling informed counseling and optimized perinatal and neonatal care planning., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: In utero fetal exposures may have sex-specific placental gene responses. Our objective was to measure sex-based differences in placental gene expression from dams fed high-fat diet (HFD) versus control diet (CD)., Study Design: We fed timed pregnant Friend virus B-strain dams either a CD ( n  = 5) or an HFD ( n  = 5). We euthanized dams on embryonic day 17.5 to collect placentas. We extracted placental RNA and hybridized it to a customized 96-gene Nanostring panel focusing on angiogenic, inflammatory, and growth genes. We compared normalized gene expression between CD and HFD, stratified by fetal sex, using analysis of variance. Pathway analysis was used to further interpret the genomic data., Results: Pups from HFD-fed dams were heavier than those from CD-fed dams (0.97 ± 0.06 vs. 0.84 ± 0.08 g, p  < 0.001). Male pups were heavier than females in the HFD (0.99 ± 0.05 vs. 0.94 ± 0.06 g, p  = 0.004) but not CD (0.87 ± 0.08 vs. 0.83 ± 0.07 g, p  = 0.10) group. No sex-based differences in placental gene expression in CD-fed dams were observed. Among HFD-fed dams, placentas from female pups exhibited upregulation of 15 genes ( q  = 0.01). Network analyses identified a cluster of genes involved in carbohydrate metabolism, cellular function and maintenance, and endocrine system development and function ( p  = 1 × 10 -23 ). The observed female-specific increased gene expression following in utero HFD exposure was predicted to be regulated by insulin ( p  = 5.79 × 10 -13 )., Conclusion: In female compared with male pups, in utero exposure to HFD upregulated placental gene expression in 15 genes predicted to be regulated by insulin. Sex-specific differences in placental expression of these genes should be further investigated., Key Points: · Male pups were heavier than female pups at the time of sacrifice when dams were fed an HFD.. · HFD was associated with upregulated gene expression in female placentas.. · Female-specific increased gene was predicted to be regulated by insulin.., Competing Interests: None declared., (Thieme. All rights reserved.)

Noninvasive cfDNA testing for monogenic disorders (sgNIPT) has become integrated into the care of pregnant women at increased risk based on carrier status, known family history, or ultrasound anomalies. The availability of commercial tests for common autosomal recessive and de novo autosomal dominant conditions has led to the use of these tests in low-risk pregnancies. However, is the technology ready for use in this low-risk population? This report is a summary of the debate on this topic at the 27 th International Conference on Prenatal Diagnosis and Therapy. Both expert debaters provided strong arguments in favor and against the use of sgNIPT in low-risk pregnancies. The argument in favor of sgNIPT for autosomal recessive conditions is that it allows the identification of affected pregnancies without the need for involving the partner in testing. Arguments for sgNIPT for autosomal dominant conditions include identification of affected fetuses that would have either presented later in pregnancy with fetal anomalies or not been detected prenatally given normal ultrasounds, respect for patient autonomy and patient desire for information. Strong arguments were made against offering sgNIPT screening. Given that traditional carrier screening for recessive conditions can be carried out in many jurisdictions, the added value of sgNIPT has not been clearly demonstrated. Arguments against sgNIPT for autosomal dominant conditions included the total lack of clinical validation studies and the risk of false reassurance in cases of negative results and unnecessary invasive procedures in cases of false positive results. Although there is a desire to take advantage of new technologies to improve the detection of monogenic disorders in low-risk populations, based on the discussion and the audience vote, it appears premature to offer sgNIPT to all low risk pregnant women. Further clinical validation studies are needed prior to broad implementation., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objective: GREB1L has been linked prenatally to Potter's sequence, as well as less severe anomalies of the kidney, uterus, inner ear, and heart. The full phenotypic spectrum is unknown. The purpose of this study was to characterize known and novel pre- and postnatal phenotypes associated with GREB1L., Methods: We solicited cases from the Fetal Sequencing Consortium, screened a population-based genomic database, and conducted a comprehensive literature search to identify disease cases associated with GREB1L. We present a detailed phenotypic spectrum and molecular changes., Results: One hundred twenty-seven individuals with 51 unique pathogenic or likely pathogenic GREB1L variants were identified. 24 (47%) variants were associated with isolated kidney anomalies, 19 (37%) with anomalies of multiple systems, including one case of hypoplastic left heart syndrome, five (10%) with isolated sensorineural hearing loss, two (4%) with isolated uterine agenesis; and one (2%) with isolated tetralogy of Fallot., Conclusion: GREB1L may cause complex congenital heart disease (CHD) in humans. Clinicians should consider GREB1L testing in the setting of CHD, and cardiac screening in the setting of GREB1L variants., (© 2024 John Wiley & Sons Ltd.)

Background: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis., Objective: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome., Study Design: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site., Results: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019)., Conclusion: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To evaluate whether deep prenatal phenotyping of fetal brain abnormalities (FBAs) increases diagnostic yield of trio-exome sequencing (ES) compared with standard phenotyping., Methods: Retrospective exploratory analysis of a multicenter prenatal ES study. Participants were eligible if an FBA was diagnosed and subsequently found to have a normal microarray. Deep phenotyping was defined as phenotype based on targeted ultrasound plus prenatal/postnatal magnetic resonance imaging, autopsy, and/or known phenotypes of other affected family members. Standard phenotyping was based on targeted ultrasound alone. FBAs were categorized by major brain findings on prenatal ultrasound. Cases with positive ES results were compared with those that have negative results by available phenotyping, as well as diagnosed FBAs., Results: A total of 76 trios with FBAs were identified, of which 25 (33%) cases had positive ES results and 51 (67%) had negative results. Individual modalities of deep phenotyping were not associated with diagnostic ES results. The most common FBAs identified were posterior fossa anomalies and midline defects. Neural tube defects were significantly associated with receipt of a negative ES result (0% vs 22%, P = .01)., Conclusion: Deep phenotyping was not associated with increased diagnostic yield of ES for FBA in this small cohort. Neural tube defects were associated with negative ES results., Competing Interests: Conflict of Interest Neeta Vora receives supplies in kind from Illumina for an NIH grant on whole genome sequencing unrelated to the data in this paper. All other authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families. Our GS analytic framework identified a diagnostic variant in 7.8% of ASD probands, almost 2-fold more than CMA (4.3%) and 3-fold more than ES (2.7%). However, when we systematically captured copy-number variants (CNVs) from the exome data, the diagnostic yield of ES (7.4%) was brought much closer to, but did not surpass, GS. Similarly, we estimated that GS could achieve an overall diagnostic yield of 46.1% in unselected FSAs, representing a 17.2% increased yield over karyotype, 14.1% over CMA, and 4.1% over ES with CNV calling or 36.1% increase without CNV discovery. Overall, GS provided an added diagnostic yield of 0.4% and 0.8% beyond the combination of all three standard-of-care tests in ASD and FSAs, respectively. This corresponded to nine GS unique diagnostic variants, including sequence variants in exons not captured by ES, structural variants (SVs) inaccessible to existing standard-of-care tests, and SVs where the resolution of GS changed variant classification. Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs., Competing Interests: Declaration of interests M.E.T. and H.R. receive research funding from Microsoft Inc and/or research reagents from Illumina Inc. M.E.T. also received research funding from Levo Therapeutics and research reagents from Ionis Therapeutics for unrelated research projects., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Neural tube defects (NTDs), including anencephaly and spina bifida, are common major malformations of fetal development resulting from incomplete closure of the neural tube. These conditions lead to either universal death (anencephaly) or severe lifelong complications (spina bifida). Despite hundreds of genetic mouse models of neural tube defect phenotypes, the genetics of human NTDs are poorly understood. Furthermore, pharmaceuticals, such as antiseizure medications, have been found clinically to increase the risk of NTDs when administered during pregnancy. Therefore, a model that recapitulates human neurodevelopment would be of immense benefit to understand the genetics underlying NTDs and identify teratogenic mechanisms. Using our self-organizing single rosette cortical organoid (SOSR-COs) system, we have developed a high-throughput image analysis pipeline for evaluating the SOSR-CO structure for NTD-like phenotypes. Similar to small molecule inhibition of apical constriction, the antiseizure medication valproic acid (VPA), a known cause of NTDs, increases the apical lumen size and apical cell surface area in a dose-responsive manner. GSK3β and HDAC inhibitors caused similar lumen expansion; however, RNA sequencing suggests VPA does not inhibit GSK3β at these concentrations. The knockout of SHROOM3 , a well-known NTD-related gene, also caused expansion of the lumen, as well as reduced f-actin polarization. The increased lumen sizes were caused by reduced cell apical constriction, suggesting that impingement of this process is a shared mechanism for VPA treatment and SHROOM3 -KO, two well-known causes of NTDs. Our system allows the rapid identification of NTD-like phenotypes for both compounds and genetic variants and should prove useful for understanding specific NTD mechanisms and predicting drug teratogenicity.

Purpose: To describe psychological outcomes among people with recurrent anomalous pregnancies pursuing trio-exome sequencing (exome sequencing (ES)) compared to those with one affected., Methods: We analyzed data from a prospective ES cohort, enrolling patients with major fetal anomaly and normal microarray. Participants completed validated scales before and after ES. We (1) compared responses of those with multiple anomalous pregnancies to those with one affected and (2) conducted linear regression to examine associations between multiple affected pregnancies and post-ES constructs., Results: Of 166 trios, 61 (37%) received results from ES. Forty (24%) had more than one affected pregnancy and 45% of those received a result explaining the fetal phenotype. All participants had clinically significant presequencing generalized psychological distress. For the 93 who completed the post-ES surveys, those with multiple affected pregnancies had higher psychological adaptation scores but worse test related distress scores (9.3 (6.2) versus 7.1(5.6), p = 0.12) and (14.3 (1.5) versus 15.4 (1.4), p = 0.01). In linear regression models, there were no significant differences in post-ES constructs after adjusting for clinically relevant covariates., Conclusions: All individuals experienced significant generalized psychological distress in the pre-ES period, extending our knowledge of how pregnancy history contributes to parental sequencing outcomes., (© 2023 John Wiley & Sons Ltd.)

Exome sequencing is a powerful tool in prenatal and postnatal genetics and can help identify novel candidate genes critical to human development. We describe seven unpublished probands with rare likely pathogenic variants or variants of uncertain significance that segregate with recessive disease in TBC1D32, including four fetal probands in three unrelated pedigrees and three pediatric probands in unrelated pedigrees. We also report clinical comparisons with seven previously published patients. Index probands were identified through an ongoing prenatal exome sequencing study and through an online data sharing platform (Gene Matcher™). A literature review was also completed. TBC1D32 is involved in the development and function of cilia and is expressed in the developing hypothalamus and pituitary gland. We provide additional data to expand the phenotype correlated with TBC1D32 variants, including a severe prenatal phenotype associated with life-limiting congenital anomalies., (© 2023 Wiley Periodicals LLC.)

Introduction: Rapid advances in prenatal genetic screening technology make it difficult for providers to deliver adequate prenatal counseling. The aim of this study was to understand how prenatal screening educational approaches can meet the needs of patients., Methods: Qualitative content analysis was conducted on a diverse population who were interviewed to explore their perceived experiences and preferences for prenatal screening educational delivery., Results: Twenty-two women from three US sites were interviewed. Participants were racially/ethnically diverse with 22.7% identifying as Black or African American (n = 5), 40.9% as Hispanic (n = 9), and 4.5% as Pacific Islander (n = 1). Four themes were identified: prenatal screening education, prenatal screening decision-making, return of results, and suggestions for creating a decision aid. Most results were consistent with previous research not targeting a diverse population., Discussion/conclusion: Our results indicate that learning style preferences vary between patients and that current methods are not consistently satisfying patient's desire for understanding, particularly with 'high-risk' results, suggesting that a standardized tool could improve knowledge and decrease decisional conflict. This diverse cohort suggested a list and description of each of the testing options offered, information about each condition being screened for, a timeline for the testing and return of results, costs associated, and non-technical language., (© 2023 John Wiley & Sons Ltd.)

We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 ( MAP4K4 ). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.

Objective: To evaluate the incidence and clinical outcomes of cell-free DNA results suspicious for maternal malignancy on prenatal cell-free DNA screening with single-nucleotide polymorphism (SNP)-based technology., Methods: This retrospective cohort study included data from SNP-based, noninvasive prenatal screening samples from a commercial laboratory from January 2015 to October 2021. Maternal plasma was screened for trisomy 21, 18, and 13; monosomy X; and triploidy. Cases were considered suspicious for maternal malignancy if retrospective bioinformatics and visual inspection of the SNP plot were suggestive of multiple maternal copy number variants across at least two of the tested chromosomes. Clinical follow-up on patients was obtained by contacting individual referring clinician offices by telephone, facsimile, or email., Results: A total of 2,004,428 noninvasive prenatal screening samples during the study period met criteria for inclusion in the analysis. Of these, 38 samples (0.002% or 1 in 52,748, 95% CI 1:74,539-1:38,430) had SNP-plot results that were suspicious for maternal malignancy. Maternal health outcomes were obtained in 30 of these patients (78.9%); eight were lost to follow-up. Maternal malignancy or suspected malignancy was identified in 66.7% (20/30) of the 30 patients with clinical follow-up provided by the clinic. The most common maternal malignancies were lymphoma (n=10), breast cancer (n=5), and colon cancer (n=3)., Conclusion: Results suspicious for maternal malignancy are rare with SNP-based noninvasive prenatal screening (1:53,000), but two thirds of patients who had a noninvasive prenatal screening result concerning for malignancy in this study had a cancer diagnosis. Investigation for malignancy should be recommended for all pregnant patients with this type of result., Funding Source: This study was funded by Natera, Inc., Competing Interests: Financial Disclosure Georgina Goldring, Cindy Trotter, Jeffrey T. Meltzer, Vivienne Souter, Wendy DiNonnno, Wenbo Xu, and Jeffrey N. Wetizel are employees of Natera, Inc with stocks or options to own stocks in the company. Neeta L. Vora receives supplies in kind from Illumina for an NIH funded grant on whole genome sequencing in fetal anomalies. Wendy DiNonno disclosed that Natera has applied for a patent directly related to this study. Natera also covers travel expenses to educational meetings. Neeta L. Vora disclosed that they receive supplies in kind from Illumina for an NIH funded grant that is unrelated to the work described in this article. Lynn Pais did not disclose any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To measure maternal/fetal SARS-CoV-2 antibody levels., Methods: A prospective observational study of eligible parturients admitted to the hospital for infant delivery was conducted between April and September 2020. SARS-CoV-2 antibody levels were measured in maternal and umbilical cord specimens using an in-house ELISA based on the receptor-binding domain (RBD) of the spike protein. Among SARS-CoV-2 seropositive patients, spike RBD antibody isotypes (IgG, IgM, and IgA) and ACE2 inhibiting antibodies were measured., Results: In total, 402 mothers were enrolled and spike RBD antibodies in 388 pregnancies were measured (336 maternal and 52 cord specimens). Of them, 19 were positive (15 maternal, 4 cord) resulting in a seroprevalence estimate of 4.8% (95% confidence interval 2.9-7.4). Of the 15 positive maternal specimens, all had cord blood tested. Of the 15 paired specimens, 14 (93.3%) were concordant. Four of the 15 pairs were from symptomatic mothers, and all four showed high spike-ACE2 blocking antibody levels, compared to only 3 of 11 (27.3%) from asymptomatic mothers., Conclusion: A variable antibody response to SARS-CoV-2 in pregnancy among asymptomatic infections compared to symptomatic infections was found, the significance of which is unknown. Although transfer of transplacental neutralizing antibodies occurred, additional research is needed to determine how long maternal antibodies can protect the infant against SARS-CoV-2 infection., (© 2022 International Federation of Gynecology and Obstetrics.)

Objective: To determine the cost-effectiveness of first-trimester ultrasound before fetal aneuploidy screening with cell-free DNA (cfDNA) compared with screening by cfDNA alone., Methods: A decision analytic model was constructed for 400 000 pregnant individuals with advanced maternal age who desired first-trimester aneuploidy screening with cfDNA in the USA, to compare two screening strategies: (1) cfDNA only and (2) ultrasound performed within 4 weeks before cfDNA. Input parameters included probability of fetal aneuploidy, cfDNA performance, desire for diagnostic testing, pregnancy outcomes, and pregnancy and lifetime costs and utilities. The primary outcome measure was the incremental cost-effectiveness ratio (ICER), in terms of cost in 2020 US dollars (USD) per quality-adjusted life year (QALY) gained. Secondary outcomes included procedure-related loss, pregnancy termination, live birth with aneuploidy, live birth with structural anomaly and stillbirth. Discounting was performed at 3% per year with an estimated maternal lifespan of 81 years starting at the age of 35 years. One-way, multiway and Monte Carlo probabilistic sensitivity analyses were performed. All base-case estimates and ranges of uncertainty were derived from the literature. The willingness-to-pay threshold was set at 100 000 USD per QALY., Results: In the base-case analysis, ultrasound before cfDNA screening was more cost-effective than cfDNA screening without pretest ultrasound, with an ICER of 12 588 USD and higher net monetary benefit (24 241 vs 20 466). The strategy involving ultrasound before cfDNA was more costly by 544 USD but also more effective (by 0.04 QALY) compared with cfDNA alone. Base-case results were robust in sensitivity analyses with the strategy involving ultrasound before cfDNA always remaining the most cost-effective approach with the highest net monetary benefit., Conclusion: First-trimester ultrasound before cfDNA is a more cost-effective strategy for non-invasive prenatal aneuploidy screening compared with cfDNA alone. © 2022 International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 International Society of Ultrasound in Obstetrics and Gynecology.)

As prenatal exome sequencing becomes integrated into clinical care, it is critical that providers caring for women with fetal anomalies recognize not only the benefits, but also the challenges and considerations related to this technology. This overview of prenatal sequencing includes information about indications for sequencing, methods, diagnostic yield, clinical utility, variant interpretation, ethical considerations and dilemmas, practical considerations (ie, turnaround time and cost), pre- and posttest counseling points, and psychological impact of testing on families., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: There is a paucity of knowledge regarding the prenatal presentation of Klinefelter syndrome, or 47, XXY. Accurate prenatal counseling is critical and in utero diagnosis is currently limited by a poor understanding of the prenatal phenotype of this condition., Methods: This is a case series of fetuses with cytogenetically confirmed 47, XXY in the prenatal period or up to age 5 years, with prenatal records available for review from four academic institutions between 2006 and 2019. Ultrasound reports were reviewed in detail to assess for increased nuchal translucency and structural abnormalities. Additionally, we reviewed results of cell-free DNA and serum analyte testing when performed to inform our understanding of the detection of fetal 47, XXY through standard genetic screening tests., Results: Forty-one cases with confirmed cytogenetic diagnosis of 47, XXY and prenatal records available for review were identified: 37 had a prenatal diagnosis and 4 had a postnatal diagnosis. Nuchal translucency was increased ≥3.0 mm in 23.1% (6/26) of cases with a documented measurement. In 29.2% (7/24) of cases with a second trimester anatomical ultrasound available for review, a fetal abnormality was identified (3 brain anomalies, 1 cardiac abnormality, 1 echogenic bowel, and 2 limb abnormalities). Among those who had cell-free DNA and serum analytes performed, 92.6% (25/27) and 36.3% (4/11) had an abnormal result respectively., Conclusion: This case series expands our knowledge of the prenatal presentation of 47, XXY by identifying first and second trimester fetal sonographic abnormalities. Prenatal identification of this condition enables accurate counseling, focused prenatal management, and early postnatal interventions to ameliorate some of the known complications., (© 2021 John Wiley & Sons Ltd.)

Purpose: The purpose of this study was to evaluate the clinical performance of carrier screening for cystic fibrosis, hemoglobinopathies, and spinal muscular atrophy with reflex single-gene noninvasive prenatal screening (sgNIPS), which does not require paternal carrier screening., Methods: An unselected sample of 9151 pregnant individuals from the general US pregnant population was screened for carrier status, of which 1669 (18.2%) were identified as heterozygous for one or more pathogenic variants and reflexed to sgNIPS. sgNIPS results were compared with newborn outcomes obtained from parent survey responses or provider reports for a cohort of 201 pregnancies., Results: Overall, 98.7% of pregnant individuals received an informative result (no-call rate = 1.3%), either a negative carrier report or, if identified as heterozygous for a pathogenic variant, a reflex sgNIPS report. In the outcomes cohort, the negative predictive value of sgNIPS was 99.4% (95% CI = 96.0%-99.9%) and average positive predictive value (PPV) of sgNIPS was 48.3% (95% CI = 36.1%-60.1%). Importantly, personalized PPVs accurately reflected the percentage of affected pregnancies in each PPV range, and all pregnancies with a sgNIPS fetal risk of >9 in 10 (90% PPV) were affected., Conclusion: Although traditional carrier screening is most effective when used to assess reproductive risk before pregnancy, more than 95% of the time it is pursued during a pregnancy and is complicated by incomplete uptake of paternal carrier screening (<50%) and misattributed paternity (∼10%). Even in an idealized setting, when both partners have carrier screening, the maximum risk for having an affected pregnancy is 1 in 4 (equivalent of a 25% PPV). Carrier screening with sgNIPS during pregnancy is an alternative that does not require a paternal sample and provides accurate fetal risk in a timely manner that can be used for prenatal counseling and pregnancy management., Competing Interests: Conflict of Interest J.H., J.W., S.R., and J.R.t.B. are employees of BillionToOne and hold stock or options to hold stock in the company. J.A.C. is financially compensated by BillionToOne. E.E.H. received an educational grant from BillionToOne. A.N.T. and N.L.V. declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Obesity is a risk factor for preeclampsia. We investigated how obesity influences preeclampsia in mice lacking ankyrin-repeat-and-SOCS-box-containing-protein 4 (ASB4), which promotes trophoblast differentiation via degrading the inhibitor of DNA-binding protein 2 (ID2). Asb4 -/- mice on normal chow (NC) develop mild preeclampsia-like phenotypes during pregnancy, including hypertension, proteinuria, and reduced litter size. Wild-type (WT) and Asb4 -/- females were placed on a high-fat diet (HFD) starting at weaning. At the age of 8-9 weeks, they were mated with WT or Asb4 -/- males, and preeclamptic phenotypes were assessed. HFD-WT dams had no obvious adverse outcomes of pregnancy. In contrast, HFD- Asb4 -/- dams had significantly more severe preeclampsia-like phenotypes compared to NC- Asb4 -/- dams. The HFD increased white fat weights and plasma leptin and insulin levels in Asb4 -/- females. In the HFD- Asb4 -/- placenta, ID2 amounts doubled without changing the transcript levels, indicating that insulin likely increases ID2 at a level of post-transcription. In human first-trimester trophoblast HTR8/SVneo cells, exposure to insulin, but not to leptin, led to a significant increase in ID2. HFD-induced obesity markedly worsens the preeclampsia-like phenotypes in the absence of ASB4. Our data indicate that hyperinsulinemia perturbs the timely removal of ID2 and interferes with proper trophoblast differentiation, contributing to enhanced preeclampsia.

Background: Use of semi-active and active robotic system for performing Total Knee Arthroplasty (TKA) is increasing. The novel fully automated active robotic system performs milling of the bone surfaces with a high speed burr. The aim of the current study was to assess the safety and efficacy of the system in robotic assisted TKA (RA-TKA)., Materials and Methods: A single center clinical trial was conducted following 30 knees undergoing active RA-TKA for 6 months. Inclusion criteria were patients undergoing RA-TKA for end stage arthritis. Patients undergoing conventional TKA and revision TKA were excluded from the study. Sample size was estimated to be 28 patients with α error of 0.05 and β error of 0.2 with power of study being 80. A pre-defined list of RA-TKA adverse events was employed to study the safety of the system. Efficacy was judged by comparing the planned versus achieved Implant size, alignment and limb alignment on post-operative radiographs. The post-operative clinical evaluation was done by an independent observer who was not part of the operating team. The primary safety and efficacy hypothesis was tested using a one sided Exact binomial test. The p value < 0.05 was considered significant., Results: Pre-defined adverse events did not occur in any of the 30 RA-TKA (statistically significant p value < 0.001). The implant size accuracy was 100% (30 out of 30 knees) for femoral component and 96.67% (29 out of 30 knees) for tibial component (statistically significant, Chi-squared test, p value 0.0105 and 0.0461 respectively). The implant position and limb alignment was accurate in 100% of patients (p value < 0.001)., Conclusion: Early experience of the use of fully automated active robotic system in TKA shows that it is safe and also is effective in achieving accurate implant size and implant/limb alignment., Competing Interests: The authors declare no financial conflicts of interest to disclose., (© 2023 Delhi Orthopedic Association. All rights reserved.)

Objective: Tubulinopathies refer to conditions caused by genetic variants in isotypes of tubulin resulting in defective neuronal migration. Historically, diagnosis was primarily via postnatal imaging. Our objective was to establish the prenatal phenotype/genotype correlations of tubulinopathies identified by fetal imaging., Methods: A large, multicenter retrospective case series was performed across nine institutions in the Fetal Sequencing Consortium. Demographics, fetal imaging reports, genetic screening and diagnostic testing results, delivery reports, and neonatal imaging reports were extracted for pregnancies with a confirmed molecular diagnosis of a tubulinopathy., Results: Nineteen pregnancies with a fetal tubulinopathy were identified. The most common prenatal imaging findings were cerebral ventriculomegaly (15/19), cerebellar hypoplasia (13/19), absence of the cavum septum pellucidum (6/19), abnormalities of the corpus callosum (6/19), and microcephaly (3/19). Fetal MRI identified additional central nervous system features that were not appreciated on neurosonogram in eight cases. Single gene variants were reported in TUBA1A (13), TUBB (1), TUBB2A (1), TUBB2B (2), and TUBB3 (2)., Conclusion: The presence of ventriculomegaly with cerebellar abnormalities in conjunction with additional prenatal neurosonographic findings warrants additional evaluation for a tubulinopathy. Conclusive diagnosis can be achieved by molecular sequencing, which may assist in coordination, prognostication, and reproductive planning., (© 2022 John Wiley & Sons Ltd.)

Background: Congenital cytomegalovirus infection is the most common perinatal infection and a significant cause of sensorineural hearing loss, cerebral palsy, and neurodevelopmental disability. There is a paucity of human gene expression studies examining the pathophysiology of cytomegalovirus infection., Objective: This study aimed to perform a whole transcriptomic assessment of amniotic fluid from pregnancies with live fetuses to identify differentially expressed genes and enriched Gene Ontology categories associated with congenital cytomegalovirus infection., Study Design: Amniotic fluid supernatant was prospectively collected from pregnant women undergoing amniocentesis for suspected congenital cytomegalovirus infection because of first-trimester maternal primary infection or ultrasound features suggestive of fetal infection. Women who had received therapy to prevent fetal infection were excluded. Congenital cytomegalovirus infection was diagnosed via viral polymerase chain reaction of amniotic fluid; cytomegalovirus-infected fetuses were paired with noninfected controls, matched for gestational age and fetal sex. Paired-end RNA sequencing was performed on amniotic fluid cell-free RNA with the Novaseq 6000 at a depth of 30 million reads per sample. Following quality control and filtering, reads were mapped to the human genome and counts summarized across genes. Differentially expressed genes were identified using 2 approaches: voomWithQualityWeights in conjunction with limma and RUVSeq with edgeR. Genes with a false discovery rate <0.05 were considered statistically significant. Differential exon use was analyzed using DEXSeq. Functional analysis was performed using gene set enrichment analysis and Ingenuity Pathway Analysis. Manual curation of differentially regulated genes was also performed., Results: Amniotic fluid samples were collected from 50 women; 16 (32%) had congenital cytomegalovirus infection confirmed by polymerase chain reaction. After excluding 3 samples without matched controls, 13 cytomegalovirus-infected samples collected at 18 to 23 weeks and 13 cytomegalovirus-negative gestation-matched controls were submitted for RNA sequencing and analysis (N=26). Ten of the 13 pregnancies with cytomegalovirus-infected fetuses had amniocentesis because of serologic evidence of maternal primary infection with normal fetal ultrasound, and 3 had amniocentesis because of ultrasound abnormality suggestive of cytomegalovirus infection. Four cytomegalovirus-infected pregnancies ended in termination (n=3) or fetal death (n=1), and 9 resulted in live births. Pregnancy outcomes were available for 11 of the 13 cytomegalovirus-negative controls; all resulted in live births of clinically-well infants. Differential gene expression analysis revealed 309 up-regulated and 32 down-regulated genes in the cytomegalovirus-infected group compared with the cytomegalovirus-negative group. Gene set enrichment analysis showed significant enrichment of multiple Gene Ontology categories involving the innate immune response to viral infection and interferon signaling. Of the 32 significantly down-regulated genes, 8 were known to be involved in neurodevelopment and preferentially expressed by the brain. Six specific cellular restriction factors involved in host defense to cytomegalovirus infection were up-regulated in the cytomegalovirus-infected group. Ingenuity Pathway Analysis predicted the activation of pathways involved in progressive neurologic disease and inflammatory neurologic disease., Conclusion: In this next-generation sequencing study, we revealed new insights into the pathophysiology of congenital cytomegalovirus infection. These data on the up-regulation of the intraamniotic innate immune response to cytomegalovirus infection and the dysregulation of neurodevelopmental genes may inform future approaches to developing prognostic markers and assessing fetal responses to in utero therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Nearly 20% of Total knee Arthroplasty patients remain dissatisfied. This is a major concern in twenty-first century arthroplasty practice. Accurate implant sizing is shown to improve the implant survival, knee balance and patient reported outcome. Aim of the current study is to assess the efficacy of pre-operative three-dimensional (3D) CT scan templating in a robot-assisted TKA in predicting the correct implant sizes and alignment., Materials and Methods: Prospectively collected data in a single center from 30 RA-TKAs was assessed. Inclusion criterion was patients with end stage arthritis (both osteoarthritis and rheumatoid arthritis) undergoing primary TKA. Patients undergoing revision TKA and patients not willing to participate in the study were excluded. Preliminary study of ten patients had indicated almost 100% accuracy in determining the implant size and position. Sample size was estimated to be 28 for 90% reduction in implant size and position error with α error of 0.05 and beta error of 0.20 with power of study being 80. Post-operative radiographs were assessed by an independent observer with respect to implant size and position. The accuracy of femoral and tibial component sizing in the study was compared with the historic control with Chi-squared test. The p value < 0.05 was considered significant., Results: The pre-operative CT scan 3D templating accuracy was 100% (30 out of 30 knees) for femoral component and 96.67% (29 out of 30 knees) for tibial component. The implant position and limb alignment was accurate in 100% of patients. The accuracy of femoral component and tibial component sizing is statistically significant (Chi-squared test, p value 0.0105 and 0.0461, respectively)., Conclusion: The study results show the effectiveness of pre-operative 3 D CT scan planning in predicting the implant sizes and implant positioning. This may have a potential to improve the implant longevity, clinical outcomes and patient satisfaction., Competing Interests: Conflict of interestThe authors declare no financial conflicts of interest to disclose., (© Indian Orthopaedics Association 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Purpose: Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes., Methods: Clinical data was collected through an extensive web-based survey., Results: We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%)., Conclusion: Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes., Competing Interests: Conflict of Interest All authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Objective: This study sought to evaluate the experiences of individuals who chose to participate in a study and receive prenatal genomic sequencing (pGS) for fetuses with congenital structural anomalies., Method: Individuals who received research results of prenatal sequencing were invited to participate in semi-structured interviews about their experiences. A constructivist grounded theory approach was used to code and analyze interviews., Results: Thirty-three participants from 27 pregnancies were interviewed. Participants were motivated to enroll in the study to find out more about their fetus' condition and prepare for the future. The waiting period was a time of significant anxiety for participants. Most participants felt relief and closure upon receiving results, regardless of the category of result, and had a clear understanding of the implications of the results., Conclusion: Participants' experiences with pGS were often intertwined with the experience of having a fetus with an abnormality. Participants were satisfied with the decision to participate in research and the support they received from the healthcare team, although waiting for results was associated with anxiety. The healthcare team plays an integral role in setting expectations and validating feelings of anxiety, fear and uncertainty., (© 2022 John Wiley & Sons Ltd.)

Objective: Sequencing cell-free DNA now allows detection of large chromosomal abnormalities and dominant Mendelian disorders in the prenatal period. Improving upon these methods would allow newborn screening programs to begin with prenatal genetics, ultimately improving the management of rare genetic disorders., Methods: As a pilot study, we performed exome sequencing on the cell-free DNA from three mothers with singleton pregnancies to assess the viability of broad sequencing modalities in a noninvasive prenatal setting., Results: We found poor resolution of maternal and fetal genotypes due to both sampling and technical issues., Conclusion: We find broad sequencing modalities inefficient for noninvasive prenatal applications. Alternatively, we suggest a more targeted path forward for noninvasive prenatal genotyping., (© 2021 John Wiley & Sons Ltd.)

Purpose: To understand motivations for and parental interpretation of results from trio-exome sequencing (ES) for fetal anomalies with a negative standard genetic diagnosis., Methods: Analysis of an ongoing, prospective prenatal trio-ES study of pregnancies with ultrasound-identified congenital anomalies and lack of a standard genetic diagnosis. After determination of pregnancy disposition, participants completed questionnaires and a semi-structured interview pre- and post-sequencing. Interviews were analyzed using a constructivist grounded theory methodology to identify themes. Associations between themes and ES result were also examined., Results: One hundred twenty-six trios have been sequenced. Of those, 45 (36%) resulted in fetal diagnosis. One hundred twenty-five women completed pre-sequencing surveys, and 91 women completed post-sequencing surveys. The main themes identified include (1) variable reasons to pursue ES, (2) limited expectations but high hopes from ES, (3) parental adaptation to uncertain results, (4) impact on personal health and reproduction, and (5) gratitude for the process., Conclusion: Participants pursued ES for various reasons, most often to identify a diagnosis and guide reproduction. Post-sequencing, most participants described the process, their interpretation of results, and the impact of receiving the results. Less frequently, but of most concern, participants expressed anxiety about testing and implications for themselves, relationships, and other family members, thus identifying an area of high need for additional support among patients undergoing prenatal ES., (© 2022 John Wiley & Sons Ltd.)

Background: Preterm birth is the leading cause of neonatal morbidity and mortality, but research efforts in neonatology are complicated due to the unavailability of large volume blood samples. Whole blood assays can be used to overcome this problem by performing both functional and gene expression studies using small amounts of blood. Gene expression studies using RT-qPCR estimate mRNA-levels of target genes normalized to reference genes. The goal of this study was to identify and validate stable reference genes applicable to cord blood samples obtained from developing neonates of different gestational age groups as well as to adult peripheral blood samples. Eight reference gene candidates (ACTB, B2M, GAPDH, GUSB, HPRT, PPIB, RPLP0, RPL13) were analyzed using the three published software algorithms Bestkeeper, GeNorm and NormFinder., Results: A normalization factor consisting of ACTB and PPIB allows for comparative expression analyses of neonatal samples from different gestational age groups. Normalization factors consisting of GAPDH and PPIB or ACTB and GAPDH are suitable when samples from preterm and full-term neonates and adults are compared. However, all candidate reference genes except RPLP0 exhibited significant intergroup gene expression variance and a higher gene expression towards an older age which resulted in a small but statistically significant systematic bias. Systematic analysis of RNA-seq data revealed new reference gene candidates with potentially superior stability., Conclusions: The current study identified suitable normalization factors and proposed the use of the additional single gene RPLP0 to avoid systematic bias. This combination will enable comparative analyses not only between neonates of different gestational ages, but also between neonates and adults, as it facilitates more detailed investigations of developmental gene expression changes. The use of software algorithms did not prevent unintended systematic bias. This generally highlights the need for careful validation of such results to prevent false interpretation of potential age-dependent changes in gene expression. To identify the most stable reference genes in the future, RNA-seq based global approaches are recommended.

Background: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids is a clinically and radiographically distinct inflammatory syndrome affecting multiple structures of the brain, including the cerebellum, brainstem, and spinal cord. The clinical presentation can be variable, including ataxia, nystagmus, dysarthria, dysphagia, and other subacute brainstem, cranial nerve, or cerebellar symptoms. These symptoms can be subacute to chronic, episodic, and progressive, making the diagnosis challenging. The hallmark radiographic magnetic resonance imaging findings are gadolinium-enhancing punctate lesions predominantly "peppering" the pons in a perivascular pattern., Case Presentation: Here, we describe a case and literature review of a 74-year-old Caucasian male who presented with subacute symptoms of ataxia, diplopia, and generalized fatigue. Physical examination was notable for horizontal nystagmus and wide-based gait. Magnetic resonance imaging revealed angiocentric enhancement predominantly in the brainstem and cerebellum, with involvement of the basal ganglia, thalami, and supratentorial white matter. Meanwhile, a screening computed tomography scan demonstrated a right upper lobe mass with biopsy proving primary lung cancer. Biopsy of one of the brain lesions showed perivascular infiltrate primarily composed of CD3+ T cells, scattered CD20+ B cells, and no signs of malignancy. The patient was started on high-dose glucocorticoids followed by a maintenance regimen with rapid improvement clinically and radiographically. Given extensive work-up was negative, these clinical and radiographic findings were consistent with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids., Conclusions: This case illustrates the difficulty of diagnosing chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, given its variable presentation, lack of specific laboratory findings, and poorly understood pathogenesis. We demonstrate a case that responded well to oral corticosteroid burst followed by a taper to the lowest corticosteroid dose clinically possible. Failure to recognize this syndrome could result in permanent central nervous system morbidity. Therefore, earlier recognition is crucial for this treatable condition.

Purpose: To evaluate associations between prenatal trio exome sequencing (trio-ES) and psychological outcomes among women with an anomalous pregnancy., Methods: Trio-ES study enrolling patients with major fetal anomaly and normal microarray. Women completed self-reported measures and free response interviews at two timepoints: pre- (1) and post- (2) sequencing. Pre-sequencing responses were compared with post-sequencing responses; post-sequencing responses were stratified by women who received trio-ES results that may explain fetal findings, secondary findings (medically actionable or couples with heterozygous variants for the same recessive disorder), or negative results., Results: One hundred fifteen trios were enrolled. Of those, 41/115 (35.7%) received results from trio-ES, including 36 (31.3%) who received results that may explain the fetal phenotype. These women had greater post-sequencing distress compared with women who received negative results, including generalized distress (p = 0.03) and test-related distress (p = 0.2); they also had worse psychological adaptation to results (p = 0.001). Genomic knowledge did not change from pre- to post-sequencing (p = 0.51)., Conclusion: Women show more distress after receiving trio-ES results compared with those who do not, suggesting that women receiving results may need additional support or counseling to inform current and future reproductive decisions.

Background: To optimize breast cancer care, the American College of Surgeons Commission on Cancer developed quality measures regarding receipt and timing of adjuvant radiotherapy (RT). Nationwide compliance with these measures and its impact on overall survival (OS) are evaluated herein., Patients and Methods: Patients (n = 285,291) diagnosed with invasive breast cancer from 2004 to 2012 were identified from the National Cancer Database. Compliance with RT administration within 365 days from diagnosis was determined for patients with stage III disease with ≥ 4 positive lymph nodes post mastectomy and stage I-III disease post breast-conserving surgery (BCS). Univariate and multivariate logistic regression and Cox proportional hazard models were used to assess factors associated with compliance and OS, respectively., Results: In the mastectomy cohort, 66.9% received timely RT, showing improved OS versus no RT patients (HR 0.70, 95% CI 0.67-0.73). Delayed RT patients (≥ 365 days) achieved equivalent OS to those receiving timely RT (HR 1.07, 95% CI 0.93-1.23) and superior OS to no RT patients (HR 0.74, 95% CI 0.65-0.85). In the BCS cohort, 89.4% received timely RT, showing improved OS versus no RT patients (HR 0.47, 95% CI 0.45-0.49). Delayed RT was associated with improved OS versus no RT (HR 0.64, 95% CI 0.56-0.74) and decreased OS versus timely RT (HR 1.37, 95% CI 1.19-1.58). Factors associated with noncompliance included insurance type and distance to hospital., Conclusions: Quality measure compliance with adjuvant RT improves OS, regardless of timing after mastectomy. However, timeliness does impact OS after BCS. Focus on modifiable factors to improve compliance such as access to care may lead to improved compliance and OS.