Prenatal Setting Research Articles

The potential impact of implementation of expanded carrier screening on pediatric patient diagnoses: A retrospective chart review of patients who receive care in an outpatient genetics clinic in the northeast.

The use of expanded carrier screening (ECS) to assess reproductive risk for autosomal recessive (AR) or X-linked recessive (XLR) conditions has been increasingly integrated into obstetrical care. The aim of this study was to determine what proportion of pediatric patients seen by a medical genetics practice could have had their diagnosis predicted if the parent(s) had undergone currently available ECS at the time of data collection in 2021. A retrospective chart review of patients seen for a medical genetic evaluation at a large academic institution was performed from June 1, 2017, through June 1, 2020. At this institution, 8% of patients were diagnosed with an AR or XLR condition. Of these patients, 61% of the diagnoses could have been predicted in advance if the parent(s) had undergone ECS via the panel referenced in this study. The results of this study highlight the broad range of conditions currently seen in a clinical setting that could be identified as a risk prior to or during pregnancy via ECS. In the prenatal setting, ascertainment of reproductive risk via ECS enables prospective parents to undertake interventions such as prenatal and preimplantation genetic diagnosis. For parents who decline reproductive risk-reducing measures, knowledge about neonatal risk allows for prompt confirmatory testing. In the pediatric setting, the option of early and focused testing can benefit affected individuals and their families.

The role of a multidisciplinary team in managing variants of uncertain clinical significance in prenatal genetic diagnosis

BackgroundAlthough in general prenatal exome sequencing only reports (likely) pathogenic variants, in some cases a variant of uncertain significance (VUS) is disclosed. The aims of this retrospective study were to evaluate the types of VUS that have been reported to prospective parents, possible reclassification and to design a standard flow chart to determine which types of VUS could be considered for reporting in prenatal settings. Furthermore, we investigated what the crucial elements are to facilitate rapid management of uncertain results in a prenatal setting. Material and methodsWe reviewed exome results from 451 pregnancies performed in 2019–2021. We analyzed which factors that were taken into account by the multidisciplinary team (MDT) contributed towards decision making on reporting VUS after prenatal exome sequencing. ResultsIn 9/451 (2%) pregnancies tested with exome sequencing using a broad panel analysis a VUS was reported. After birth 3/9 VUS could be reclassified to likely pathogenic variants based on new clinical follow up data. We considered reporting VUS in genes: 1) matching the fetal phenotype, 2) associated with a severe disorder when a functional test is available or 3) possibly associated with a disorder where early post-partum diagnosis and treatment are crucial for a better prognosis. Two flowcharts were designed to guide first the laboratory specialist and then the MDT in decisions on reporting VUS. The crucial elements that enabled timely decisions on VUS disclosure were regular meetings, appropriate expertise, professional connections with other experts and psychological safety within the MDT. ConclusionIn this study three out of nine VUS could be re-classified as likely pathogenic after clinical follow-up. In order to protect pregnant couples from the burden of uncertain results, the genetic professionals have to take the responsibility to limit the reporting of VUS. This can be done not only by automated filtering of data, by following professional guidelines and by building standardized decision flows, but also by discussing individual cases considering personal situations and the involved disease and by sharing professional experience and responsibility in a multidisciplinary prenatal team setting.

Prenatal phenotypes and pregnancy outcomes of fetuses with recurrent 1q21.1 microdeletions and microduplications.

Chromosomal 1q21.1 deletions and duplications are genomic disorders that are usually diagnosed postnatally. However, the genotype-phenotype correlations of 1q21.1 copy number variants (CNVs) during the prenatal period are still not clear. This study aimed to provide a systematic summary of prenatal phenotypes for such genomic disorders. In total, 26 prenatal amniotic fluid samples diagnosed with 1q21.1 microdeletions/microduplications were obtained from pregnant women who opted for invasive prenatal testing. Karyotypic analysis and chromosomal microarray analysis (CMA) were performed for all cases simultaneously. The pregnancy outcomes and health conditions after birth in all cases were followed up. Meanwhile, prenatal cases with 1q21.1 microdeletions or microduplications in the literature were retrospectively collected. In total, 11 pregnancies (11/8,252, 0.13%) with 1q21.1 microdeletions and 15 (15/8,252, 0.18%) with 1q21.1 microduplications were identified. Among these 1q21.1 CNVs, 4 cases covered the thrombocytopenia-absent radius (TAR) region, 16 cases covered the 1q21.1 recurrent microdeletion/microduplication region, and 6 cases covered all regions mentioned above. The prenatal abnormal ultrasound findings were recorded in four participants with 1q21.1 deletions and seven participants with 1q21.1 duplications. Finally, three cases with 1q21.1 deletions and five with 1q21.1 duplications terminated their pregnancies. In the prenatal setting, 1q21.1 microdeletions were associated with increased nuchal translucency (NT), anomalies of the urinary system, and cardiovascular abnormalities, while 1q21.1 microduplications were correlated with cardiovascular malformations, nasal bone dysplasia, and increased NT. In addition, cerebral ventriculomegaly might be correlated with 1q21.1 microduplications. Considering the variable expressivity and incomplete penetrance of 1q21.1 CNVs, long-term follow-up after birth should be carried out in these cases.

Project Inclusive Genetics: Protecting reproductive autonomy from bias via prenatal patient-centered counseling

Clinician bias negatively impacts the healthcare received by marginalized communities. In this study, we explored factors that influence clinician and trainee bias against individuals with intellectual disabilities and its impact on clinical judgment in prenatal genetic testing settings. Specifically, we examined bias toward a fetus with a higher chance of developing a disability. We compared genetics specialists with their non-expert counterparts. This web-based study included clinical vignettes, implicit association tests (IATs), and an educational module. 595 participants were recruited via their institution or professional society. We conducted statistical analyses, including regression models controlling for key demographic characteristics, to analyze recommendation patterns and degree of change after the module. Genetics expertise strongly correlated with appropriate testing recommendation when the patient would not consider pregnancy termination (r= 1.784 pre-module, r= 1.502 post-module, p<0.01). Factors that influenced pre-module recommendation to test include increased age (r= -0.029, p<0.05), high religiosity (r= 0.525, p<0.05), and participant personal preference against testing (r= 1.112, p<0.01). Responses among participants without genetics expertise improved after the educational module (Z= -4.435, p<0.01). 42% of non-experts who answered inappropriately changed their answer to match guidelines after the module. Individual bias, along with structural and institutional bias, permeates family planning encounters and significantly decreases quality of care. We demonstrate here that anti-bias training is effective, particularly for non-expert providers, and it can improve the care provided to individuals with intellectual disability. Evidence-based training such as this one can help providers make appropriate genetic counseling recommendations.

Prenatal Chromosomal Microarray Analysis: Does Increased Resolution Equal Increased Yield?

Chromosomal microarray analysis (CMA) is considered a first-tier test for patients with developmental disabilities and congenital anomalies and is also routinely applied in prenatal diagnosis. The current consensus size cut-off for reporting copy number variants (CNVs) in the prenatal setting ranges from 200 Kb to 400 Kb, with the intention of minimizing the impact of variants of uncertain significance (VUS). Very limited data are currently available on the application of higher resolution platforms prenatally. The aim of this study is to investigate the feasibility and impact of applying high-resolution CMA in the prenatal setting. To that end, we report on the outcomes of applying CMA with a size cut-off of 20 Kb in 250 prenatal samples and discuss the findings and diagnostic yield and also provide follow-up for cases with variants of uncertain significance. Overall, 19.6% (49) showed one or more chromosomal abnormalities, with the findings classified as Pathogenic (P) or Likely Pathogenic (LP) in 15.6% and as VUS in 4%. When excluding the cases with known familial aberrations, the diagnostic yield was 12%. The smallest aberration detected was a 32 Kb duplication of the 16p11.2 region. In conclusion, this study demonstrates that prenatal diagnosis with a high-resolution aCGH platform can reliably detect smaller CNVs that are often associated with neurodevelopmental phenotypes while providing an increased diagnostic yield, regardless of the indication for testing, with only a marginal increase in the VUS incidence. Thus, it can be an important tool in the prenatal setting.

Housing instability: Exploring socioecological influences on the health of birthing people.

To describe how socioecological influences of housing instability affect pregnancy health among birthing and postpartum people. We used the socioecological framework to guide this exploratory descriptive study using semi-structured, in-depth interviews. We purposively recruited birthing people in the southern mid-Atlantic region. Seventeen one-time, semi-structured interviews were conducted between February 2020 and December 2021 with English-speaking unstably housed participants ≥18 years old, currently pregnant, or recently postpartum. Qualitative and quantitative content approaches were used to analyse transcribed interviews. Dedoose software was used to identify code patterns and refine the codebook until group consensus. The team examined code patterns, explored meaning in text and codified code-generated categories to describe experiences. Majority (82.4%) of participants were African Americans between 22 and 41 years, and most were postpartum (76.5%). Participants described multiple forms of housing instability, reasons for losing housing, challenges with finding housing and strategies for finding housing. Participants did not describe housing instability as a barrier to receiving prenatal care. Building and sustaining individual relationships and social support were prominent factors affecting their housing challenges. Participants also reported a lack of obstetric provider inquiry about housing status during pregnancy. Many reported that challenges with housing triggered mental health issues, especially depression. Nurses and other obstetric providers are key points of contact in the prenatal care setting for assessing housing stability. Additionally, refining social structures and funding support services within communities and prenatal health systems should be a strategy for future programme and policy planning improvement. This study highlights critical areas for consideration when addressing social determinants for birthing people and reinforces the need for more comprehensive assessment in the prenatal setting. Members of the public participated in this study as key informants for study interviews.

#4113 CLINICAL EXOME SEQUENCING AS A TOOL FOR GENETIC DIAGNOSIS OF ALPORT SYNDROME AND THIN BASEMENT MEMBRANE DISEASE

Abstract Background and Aims Alport syndrome (AS) is an inherited nephropathy caused by pathogenic variants in COL4A3 (autosomal dominant -AD- and autosomal recessive -AR- inheritance), COL4A4 (AR) and COL4A5 (X-linked dominant -XLD). It is characterized by glomerular nephropathy with hematuria progressing to end-stage renal disease, frequently associated with sensorineural deafness and ocular anomalies. In thin basement membrane disease (TBMD) most patients are asymptomatic and are incidentally noted to have microhematuria, mild proteinuria, and occasionally gross hematuria, with normal renal function. This condition is caused by pathogenic variants in COL4A3 and COL4A4 (AD). We have systematically applied genetic testing to pediatric and adult patients with clinical features suggestive of AS (Table 1). Method Clinical exome sequencing (CES) was performed on a cohort of 95 patients referred to our center from 2019 to 2022. Analyses were performed on an in-silico designed panel including 523 renal genes. Whenever possible, identified variants were segregated by Sanger sequencing. Results We identified causative (C4/C5) variants in 43 (45.3%) patients. Among them, genetic diagnosis of AS was obtained in 25 patients (58.1%): one (4.0%) with biallelic variants in COL4A4, 13 (52.0%) with COL4A5 variants (6 females and 7 males), 5 (20.0%) with COL4A3 variants (4 heterozygous and 1 homozygous) and 6 (24.0%) cases with coexisting variants in one or more other collagen genes. In 16 (37.2%) patients, we found causative monoallelic variants compatible with TBMD: 12 (75.0%) patients with variants in COL4A4 and 4 (25.0%) in COL4A3. Lastly, in 2 cases, we found variants in COL4A1 (#120130) and MYH9 (#160775), both genes associated with other renal diseases with a clinical presentation partially overlapping with AS. In additional 16 cases (16.8%), we identified C3 variants in collagen genes. In the remaining patients, genetic testing was negative (14 patients, 14.7%) or inconclusive (22, 23.2%). Of note, we identified 6 families with digenic AS. In 4 of them - 3 with COL4A5/COL4A4 variants and one with COL4A3/COL4A4 variants – the co-existence of two variants was associated to earlier renal failure, compared to family members bearing a single variant. In contrast, in the remaining 2 families (33.3%), members with COL4A5/COL4A3 missense variants had a milder phenotype compared to male family members with the single variant COL4A5 variant. In families with digenic AS, at least one variant involved the substitution of a glycine with another amino acid in the triple helix domain, frameshift indel variants in the triple helix domain or inframe indel in the collagen IV domain non-collagenous. To better understand the impact of multiple variants on collagen structure, computational studies are currently ongoing. Conclusion CES is a powerful tool to clearly define the diagnosis when AS or TBMD are suspected, as witnessed by a detection rate of 43.2%. Genetic diagnosis allows to identify the causative gene offering the possibility of extending diagnosis to other family members, also in the prenatal setting. In addition, it offers the possibility to identify multiple variants in collagen genes associated with digenic AS, as well as to find variants in other genes implicated in kidney disease. Notably, the presence of digenic variants is not necessarily predictive of a worse disease outcome. For all these reasons, molecular diagnosis can be useful to improve clinical management, to calculate recurrence risk and to better define the prognosis of the patient.

Impact of Variation in Practice in the Prenatal Reporting of Variants of Uncertain Significance by Commercial Laboratories: Need for Greater Adherence to Published Guidelines

ABSTRACT Ultrasound will identify fetal structural anomalies in up to 2% to 3% of pregnancies; these can vary from minor isolated defects to severe multisystem abnormalities. As genetic investigations into the causes can assist with prenatal and perinatal decision-making, various tests exist to assist in this endeavor. Rapid aneuploidy detection and chromosomal microarray analysis are both used for detecting chromosomal aneuploidy and microdeletions or duplications (termed copy number variations) for pregnancies with fetal abnormalities. Approximately 6% of fetuses with identifiable structural abnormalities have pathogenic copy number variations, and 32% have an abnormal karyotype. In the last 8 years, whole exome sequencing (WES) has been used for making a genetic diagnosis in the remaining undiagnosed pregnancies, and a recent meta-analysis determined an exome sequencing diagnostic yield of 31% following nondiagnostic chromosomal microarray analysis or karyotype. Use of exome sequencing is complicated, however, by its association with possibly detecting variants of uncertain significance (VUSs) and pathogenic/likely pathogenic (P/LP) variants in genes possibly noncausal for the prenatal phenotypes. Thus, the value of reporting VUSs is under debate, with various policies worldwide. This study's purpose was to evaluate the clinical impact of WES and targeted panel implementation at the clinical level when fetal structural anomalies suggest a single underlying gene disorder or syndrome. The study focus was the frequency of reporting VUSs, the diagnostic yield, and the contribution of reported VUSs toward a final diagnosis. This retrospective chart review at the Provincial Medical Genetics Program at BC Women's Hospital in Vancouver included patients undergoing WES between January 2016 and December 2020. Amniocentesis was used for obtaining fetal samples, except for 4 cases of sample acquisition at the time of pregnancy termination. A total of 124 patients underwent prenatal WES or panel testing at different commercial laboratories following the identification of fetal structural anomalies by ultrasound. Patients had either WES (n = 90) or panel testing (n = 31), with 3 patients undergoing both, as decided by the ordering clinical geneticist. Genetic diagnoses of variants classified by the laboratory as P or LP were obtained in 20 of 93 patients (21.5%) via prenatal WES and in 9 of 34 patients (26%) who underwent panel testing. The 2 tests' overall diagnostic yield was 23%. Of these, 20 patients (69%) were diagnosed with autosomal dominant disorders. Overall, 32% of patients with panel testing and 42% of patients who had WES had at least 1 VUS, and 23% of WES and 15% of panels reported more than 1 VUS. There was great variation in the reporting of VUSs between laboratories. The study uncovered a lack of strict adherence to guidelines for reporting of prenatal VUSs among various laboratories. One weakness (and strength) of the study is its use of multiple commercial laboratories for the WES, panel testing, and VUS reporting. Although this is beneficial to gain various perspectives (such as the lack of adherence to guidelines), it also diminishes the consistency of the results across the entire study because of varied procedures for diagnoses. In conclusion, this study reports on 124 pregnancies with fetal anomalies at a large tertiary care center experiencing the provision of prenatal WES (or targeted gene panels) with variant interpretation and sequencing outsourced to various laboratories. A result of 23% diagnostic yield for WES and panel testing occurred based on the laboratory-reported LP and P variants. The large number of VUSs reported by laboratories implies significant resource implications due to the time to review evidence and further examine or investigate the fetus and/or parent. This is essential, and the authors emphasize the complex nature of the required posttest genetic counseling. Based on these results, the authors strongly encourage strict adherence to recommendations on VUS reporting in the prenatal setting, with the importance of a multidisciplinary approach bringing laboratory and clinical expertise of prenatal genomics and genetics together.

Experiences of Discrimination and Treatment Outcomes Among Pregnant and Postpartum People With Opioid Use Disorder [ID: 1376917

INTRODUCTION: Experiences of discrimination among pregnant and postpartum people with opioid use disorder (OUD) are common and likely affect utilization of medication for OUD (MOUD), which is associated with reduced risk of overdose and death. We aimed to examine experiences of discrimination by prenatal care (PNC) and substance use disorder (SUD) treatment settings and estimate its effect on the risk of various MOUD utilization outcomes. METHODS: Patient-stakeholders co-designed survey questions to measure self-reported outcomes related to MOUD treatment utilization, return to substance use, and overdose. First, we examined the proportion of participants who endorsed items on a modified Healthcare Discrimination Scale and summed the total scores. Next, we quantified the effect of discrimination experienced by health care setting on postpartum MOUD utilization, return to use, and overdose using log-binomial models to calculate relative risk (RR) and 95% CIs. RESULTS: Among the 100 participants enrolled in the study, 57 reported experiencing discrimination, 56 within PNC and 33 within SUD treatment settings. Discrimination within PNC (RR 2.6, CI 1.06–6.40) and SUD treatment (RR 3.26, CI 1.59–6.70) were associated with increased risk of not using MOUD as prescribed. Discrimination within SUD treatment settings correlated with an increased risk of MOUD discontinuation (RR 2.56, CI 1.19–5.54) and return to use (RR 2.36, CI 1.18–4.73). CONCLUSION: Experiences of discrimination were common, especially within prenatal care settings, and discrimination was associated with poor MOUD treatment outcomes and risk of return to use. Interventions to address discrimination within health care settings can improve outcomes for pregnant and postpartum people with OUD.

Identification of bi-allelic LFNG variants in three patients and further clinical and molecular refinement of spondylocostal dysostosis 3.

Spondylocostal dysostosis (SCD), a condition characterized by multiple segmentation defects of the vertebrae and rib malformations, is caused by bi-allelic variants in one of the genes involved in the Notch signaling pathway that tunes the "segmentation clock" of somitogenesis: DLL3, HES7, LFNG, MESP2, RIPPLY2, and TBX6. To date, seven individuals with LFNG variants have been reported in the literature. In this study we describe two newborns and one fetus with SCD, who were found by trio-based exome sequencing (trio-ES) to carry homozygous (c.822-5C>T) or compound heterozygous (c.[863dup];[1063G>A]) and (c.[521G>T];[890T>G]) variants in LFNG. Notably, the c.822-5C>T change, affecting the polypyrimidine tract of intron 5, is the first non-coding variant reported in LFNG. This study further refines the clinical and molecular features of spondylocostal dysostosis 3 and adds to the numerous investigations supporting the usefulness of trio-ES approach in prenatal and neonatal settings.

Acceptability, feasibility, and preliminary efficacy of a prenatal walking program for depressed pregnant women

Depression is common during pregnancy, yet pregnant women often do not engage in standard mental health treatments, which is concerning due to negative consequences associated with untreated maternal depression. Given that exercise can help to decrease depressive symptoms, and most pregnant women are able to safely engage in mild to moderate physical activity, physical activity interventions may be helpful in improving mood among pregnant women, even those with clinical levels of depression. In an open trial, we piloted a 10-week prenatal walking intervention in 18 depressed pregnant women (mean age=28.7 years). Participants wore a pedometer daily to track activity and attended 6 brief counseling sessions over the 10-week period. Indicators of acceptability and feasibility were assessed, as were changes in depression, physical activity, and other clinical outcomes. Results suggest that the prenatal walking intervention is feasible and acceptable. No adverse events were observed, and most women (83%) completed the intervention, attending on average 5.5 of 6 intervention sessions. Findings also support preliminary efficacy of the intervention: depression scores were reduced by endpoint, and physical activity levels increased based on self-report and objective measurement. Women also reported lower anxiety, and positive changes in affect at endpoint. Participants reported high satisfaction on a questionnaire. Though preliminary, findings suggest that a lifestyle physical activity intervention could be a valuable strategy to improve mood during pregnancy. Further research is needed to evaluate the intervention in a more rigorous randomized trial. If proven efficacious, this simple, low-cost intervention could be implemented in prenatal care settings.

Pregnant Latinas' perspectives on pursuing expanded carrier screening: "It is better to know than not".

With the advance of genetic technologies, the use of expanded carrier screening (ECS) in the prenatal setting is growing. ECS tests for a wide range of inherited genetic disorders regardless of racial/ethnic background and family history. Latinxs are an important ECS stakeholder group as they are the largest minority group with the highest fertility rate in the United States. Yet, the Latinx population has, to date, been underrepresented and understudied in genetics/genomics research. We conducted a study to explore the knowledge and perspectives of pregnant Latinas regarding ECS in which descriptive statistics and content analysis were used to analyze the data. Thirty-two pregnant Latinas - mostly of low educational levels (no education beyond high school) and with less than $20,000 annual household income living in rural areas were surveyed, provided with education about ECS, and interviewed. Participants were found to possess limited knowledge about ECS prior to being interviewed. Most (68.8%), however, expressed interest in pursuing ECS following the educational component that explained ECS. Their interest was mainly driven by the desire to know their baby's chance of developing a genetic disorder, the low risk of ECS procedures for both pregnant Latinas and their fetus, and the opportunity to better prepare for raising a child with a genetic condition. Our findings contribute to the limited research in the genetics/genomics field by providing in-depth insights into the perspectives of pregnant Latinas regarding ECS. Obstetric providers and genetic counselors should provide culturally appropriate education and counseling to empower pregnant Latinas to make informed decisions about the use of ECS.

Prenatal patient perceptions of receiving difficult news over the telephone.

Difficult news has been described as any news that adversely and seriously affects an individual's view of their future. Research in oncology genetic counseling demonstrated that individuals do not prefer in-person or telephone delivery of their genetic test results. However, in the prenatal setting, there is limited research examining how patients prefer news related to their pregnancies be disclosed. This study aimed to assess the experiences and preferences of prenatal patients who received difficult news by telephone. A semi-structured interview guide was developed to assess patients' personal definitions of difficult news and their experiences receiving the news by telephone. Fifteen patients seen prenatally by a genetic counselor were interviewed. Interviews were transcribed and consensus-coded, using inductive content analysis to identify several themes. The most common definition of difficult news included unexpected, life-changing, or devastating information. Participants described aspects of their experience and strategies employed by their genetic counselor that was helpful when receiving the news, which was found to align with the SPIKES protocol, a six-step process of delivering difficult news to patients. Additional techniques that participants identified as beneficial and satisfactory included the genetic counselor's use of empathy, non-directiveness, and continuity and coordination of care. Participants also provided recommendations for improvement, including a discussion of the mode of result disclosure during pretest counseling, an option to follow up with their genetic counselor, personalized resources, and a summary of the results call. The findings of this study demonstrate that a patient-centered approach is preferred by patients who receive difficult news by telephone in the prenatal setting. Patients' identification of beneficial communication techniques and suggestions for improvement can be implemented by any healthcare provider responsible for delivering difficult news to prenatal patients.

Implementation of Exome Sequencing in Prenatal Diagnostics: Chances and Challenges

Whole exome sequencing (WES) has become part of the postnatal diagnostic work-up of both pediatric and adult patients with a range of disorders. In the last years, WES is slowly being implemented in the prenatal setting as well, although some hurdles remain, such as quantity and quality of input material, minimizing turn-around times, and ensuring consistent interpretation and reporting of variants. We present the results of 1 year of prenatal WES in a single genetic center. Twenty-eight fetus-parent trios were analyzed, of which seven (25%) showed a pathogenic or likely pathogenic variant that explained the fetal phenotype. Autosomal recessive (4), de novo (2) and dominantly inherited (1) mutations were detected. Prenatal rapid WES allows for a timely decision-making in the current pregnancy, adequate counseling with the possibility of preimplantation or prenatal genetic testing in future pregnancies and screening of the extended family. With a diagnostic yield in selected cases of 25% and a turn-around time under 4 weeks, rapid WES shows promise for becoming part of pregnancy care in fetuses with ultrasound anomalies in whom chromosomal microarray did not uncover the cause.

Piloting a multidisciplinary approach to improve outcomes of fetal whole exome sequencing: An overview of workflow and case example.

Whole exome sequencing (WES) has increasingly become integrated into prenatal care and genetic testing pathways. Current studies of prenatal WES have focused on diagnostic yield. The possibility of obtaining a variant of uncertain significance and lack of provider expertise are frequently described as common barriers to clinical integration of prenatal WES. We describe the implementation and workflow for a multidisciplinary approach to effectively integrate prenatal WES into maternal-fetal care to overcome these barriers. A multidisciplinary team reviews and approves potential cases for WES. This team reviews WES results, reclassifying variants as appropriate and provides recommendations for postnatal care. A detailed description of this workflow is provided, and a case example is included to demonstrate effectiveness of this approach. Our team has approved 62 cases for WES with 45 patients ultimately pursuing WES. We have achieved a diagnostic yield of 40% and the multidisciplinary team has played a role in variant interpretation in 50% of the reported variants of uncertain significance. This approach facilitates communication between prenatal and postnatal care teams and provides accurate interpretation and recommendations for identified fetal variants. This model can be replicated to ensure appropriate patient care and effective integration of novel genomic technologies into prenatal settings.

Whole-exome sequencing in deceased fetuses with ultrasound anomalies: a retrospective analysis

BackgroundWhole-exome sequencing (WES) is an effective method in the prenatal setting for identification of the underlying genetic etiology of fetal ultrasound abnormalities. To investigate the diagnostic value of WES in fetuses with ultrasound abnormalities that resulted in fetal demise or pregnancy termination.Methods61 deceased fetuses with ultrasound abnormalities and normal copy number variation Sequencing were retrospectively collected. Proband-only or trio-WES were performed on the products of conception.ResultCollectively, 28 cases were positive with 39 variants (10 pathogenic, 22 likely pathogenic and 7 variants of uncertain significance) of 18 genes, and the overall diagnostic rate was 45.9% (28/61), of which 39.2% (11/28) were de novo variants. In addition, 21 variants in 11 genes among the positive cases had not been previously reported. The diagnostic yield for definitive findings for trio analysis was 55.9% (19/34) compared to 33.3% (9/27) for singletons. The most common ultrasound abnormalities were skeletal system abnormalities 39.2% (11/28), followed by multiple system abnormalities (17.9%, 5/28) and genitourinary abnormalities (17.9%, 5/28).ConclusionOur results support the use of WES to identify genetic etiologies of ultrasound abnormalities and improve understanding of pathogenic variants. The identification of disease-related variants provided information for subsequent genetic counseling of recurrence risk and management of subsequent pregnancies.

Clinical Validation and Diagnostic Utility of Optical Genome Mapping in Prenatal Diagnostic Testing

The standard-of-care (SOC) diagnostic prenatal testing includes a combination of cytogenetic methods such as karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray (CMA) using either direct or cultured amniocytes or chorionic villi sampling (CVS). However, each technology has its limitations: karyotyping has a low resolution (>5Mb), FISH is targeted, and CMA does not detect balanced structural variants (SVs). These limitations necessitate the use of multiple tests, either simultaneously or sequentially to reach a genetic diagnosis. Optical genome mapping (OGM) is an emerging technology that can detect several classes of SVs in a single assay, but has not been evaluated in the prenatal setting. This validation study analyzed 114 samples that were received in our laboratory for traditional cytogenetic analysis with karyotyping, FISH, and/or CMA. OGM was 100% concordant in identifying the 101 aberrations that included 29 interstitial/terminal deletions, 28 duplications, 26 aneuploidies, 6 absence of heterozygosity (AOH), 3 triploid genomes, 4 Isochromosomes, 1 translocation, and revealed the identity of 3 marker chromosomes, and 1 chromosome with additional material not determined by karyotyping. Additionally, OGM detected 64 additional clinically reportable SVs in 43 samples. OGM has a standardized laboratory workflow and reporting solution that can be adopted in routine clinical laboratories and demonstrates the potential to replace the current SOC methods for prenatal diagnostic testing.

Pregnancy-Associated Breast Cancer: A Diagnostic and Therapeutic Challenge.

Pregnancy-associated breast cancer (PABC) is commonly defined as a breast cancer occurring during pregnancy, throughout 1 year postpartum, or during lactation. Despite being a rare circumstance, PABC is one of the most common types of malignancies occurring during pregnancy and lactation, with growing incidence in developed countries, due both to decreasing age at onset of breast cancer and to increasing maternal age. Diagnosis and management of malignancy in the prenatal and postnatal settings are challenging for practitioners, as the structural and functional changes that the breast undergoes may be misleading for both the radiologist and the clinician. Furthermore, safety concerns for the mother and child, as well as psychological aspects in this unique and delicate condition, need to be constantly considered. In this comprehensive review, clinical, diagnostic, and therapeutic aspects of PABC (including surgery, chemotherapy and other systemic treatments, and radiotherapy) are presented and fully discussed, based on medical literature, current international clinical guidelines, and systematic practice.

Pregnancy- and Birth-Related Experiences among Postpartum Women during the Third Wave of the COVID-19 Pandemic—A Multinational European Study

The objective of this study was to describe pregnancy- and birth-related experiences of postpartum women during the third wave of the COVID-19 pandemic and their association with mental health outcomes. An online questionnaire was distributed in five European countries (Belgium, The Netherlands, Norway, Switzerland, UK) between June and August 2021. Participants were recruited though social media platforms including pregnancy- and motherhood-related websites, pregnancy fora, and apps. Postpartum women were asked eleven specific questions about pregnancy- and birth-related changes and the presence of support during delivery. The Edinburgh Depression Scale was used to assess depressive and anxiety symptoms. Covariates included sociodemographics, health and reproductive characteristics, and COVID-19 status. Associations were estimated with logistic regression. The study included 1730 postpartum women. Frequent changes included the exclusion of the partner from pregnancy care appointments (83.2%), changed prenatal care settings (64.4%), and cancellation of hospital information visits (42.7%). Few women, however, were without support apart from medical staff during delivery (1.4%). The number of pregnancy- and birth-related changes was associated with each woman’s mental health status, as well as the type of change. Experiencing changes related to delivery and cancellation or reduction of prenatal examination was associated with a doubling in the odds of symptoms of major depression and anxiety postpartum. These findings highlight the importance of ensuring adequate maternity care for women’s mental health postpartum, as well as during a pandemic.

The uncertainty of copy number variants: pregnancy decisions and clinical follow-up

Next-generation sequencing for copy number variants is often used as a follow-up investigation of unusual fetal ultrasound results and is capable of detecting copy number variations with a resolution of ∼0.1 Mb. In a prenatal setting, observation and subsequent management of pregnancies with a fetal variant of uncertain significance remains problematic for counseling. This study aimed to follow the decision-making processes in pregnancies with a fetal variant of uncertain significance and prospectively assess copy number variation interpretations and implications under the newer 2020 American College of Medical Genetics and Genomics guidelines. In a single prenatal unit, prospective chromosome testing using copy number variation sequencing for 8030 fetuses with unexpected noninvasive findings identified 139 pregnancies with a copy number variation classified as a variant of uncertain significance according to the 2015 American College of Medical Genetics and Genomics guidelines current at the time. Parent-of-origin testing was subsequently performed to determine if the copy number variation was inherited or de novo. All couples were offered specialized genetic counseling to assist in pregnancy management decisions. For the continued pregnancies that reached term, newborns were clinically assessed for evidence of any disease at 0 to 10 months and/or at 2 to 4 years of age. Of the 139 variants of uncertain significance found, most (78%) were inherited with no evidence of disease in the carrier parent. On the basis of primary ultrasound findings combined with results from noninvasive prenatal screening tests, most inherited variant of uncertain significance pregnancies were continued, whereas most pregnancies involving de novo variants of uncertain significance were terminated. From clinical follow-up of the 113 live births, only 5 showed any evidence of a phenotype that was not apparently related to the original variant of uncertain significance. Prospective reanalysis of the 139 variants of uncertain significance using recent 2020 American College of Medical Genetics and Genomics guidelines changed the status of 24 variants of uncertain significance, with 15 reclassified as benign and 9 as pathogenic. However, the 5 children born with an inherited variant of uncertain significance reclassified as pathogenic showed no evidence of a disease phenotype on clinical follow-up. The severity of fetal ultrasound findings combined with results from parent-of-origin testing were the key drivers in pregnancy management decisions for patients. According to birth outcomes from continued pregnancies, most variants of uncertain significance proved to be apparently benign in nature and potentially of low risk of adverse disease outcome. There was a discordance rate of 17% for variant of uncertain significance scoring between the 2015 and 2020 American College of Medical Genetics and Genomics guidelines for defining a variant of uncertain significance, suggesting that difficulties remain for predicting true pathogenicity. Nonetheless, with increasing knowledge of population copy number variation polymorphisms, and a more complete assessment for alternative genetic causes, patients having prenatal assessments should feel less anxious when a fetal variant of uncertain significance is identified.