Uptake rate of carrier screening among consanguineous couples.

OBJECTIVE: To quantify the uptake rates of Carrier Screening (CS) in consanguineous couples and compare this rate to that of non-consanguineous couples. METHODS: We performed a matched case control study of 82 consanguineous couples seen at Rutgers-Robert Wood Johnson Medical school who were offered carrier screening between January 1, 2012 and October 10, 2022. We then matched each consanguineous female patient to a non-consanguineous female control patient who was also offered CS at the time of their genetic counseling appointment. A 2 × 2 contingency table analysis was used to compare rates of acceptance and declination between the consanguineous and non-consanguineous groups. RESULTS: The overall acceptance rate among consanguineous couples was 82.9%, whereas the overall acceptance rate among non-consanguineous couples was 56.1%. After statistical analysis, consanguineous couples were significantly more likely to accept CS as compared to non-consanguineous couples (OR = 3.801, 95% CI; p < 0.0001). We also report the carrier couple rates and individual carrier statistics between these two groups. CONCLUSION: This study supports the idea that consanguineous couples are more likely to pursue CS and have a higher carrier couple yield.

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.

Rate of manifesting carriers and other unexpected findings on carrier screening.

OBJECTIVES: To ascertain the rate of unexpected findings on carrier screening (CS) and assess whether implications are disclosed to patients. METHODS: We performed a retrospective observational study of subjects who had CS after pre-test counseling from a licensed genetic counselor at a large tertiary care center. We quantified the rate of unexpected finding on CS, defined as manifesting carriers (MCs), genotypes predicting phenotype, and chromosome abnormalities. We determined how often patients were informed of implications. We performed subgroup analyses by type of unexpected finding and calculated odds ratios (OR) and 95% confidence intervals (CI) for carrier testing methodology (genotype) and number of genes tested. RESULTS: A total of 4685 patients had CS over the selected time frame. Of those patients, 412 patients (8.8%) had one unexpected finding and 29 patients (0.6%) had two or more findings. In total, 466 unexpected findings were identified, including 437 MC conditions, 23 genotypes predicting phenotype, and 6 chromosome abnormalities. Patients were informed of the implications for MCs, genotypes predicting phenotype, and chromosome abnormalities in 27.6%, 91.3%, and 100% of cases, respectively. More unexpected findings were detected with sequencing compared to genotyping (OR 2.21 and 95% CI 1.76-2.76) and with ≥200 gene panels compared to <200 gene panels (OR 1.79 and 95% CI 1.47-2.17). CONCLUSION: This study highlights that nondisclosure of unexpected findings on CS is common and underscores the need for further research to improve post-test counseling and follow-up.

Trends in coverage and reimbursement for reproductive genetic counseling in New Jersey by multiple payers from 2010 to 2018.

Lack of consistent insurance coverage for genetic counseling services billed under Current Procedural Terminology (CPT) code 96040 creates a barrier for access to this service. This retrospective study examined coverage and reimbursement for reproductive genetic counseling encounters billed under CPT code 96040 as a professional fee over an eight-year period at Rutgers Robert Wood Johnson Medical School, a regional perinatal center in New Jersey, a state requiring licensure. Descriptive statistics were tabulated to assess the disparity between Medicare/Medicaid, Managed Care Medicaid, and commercial insurance payers, including how often encounters were covered and if reimbursed, at what percentage of the amount billed. A comparison of individual plan types (Health Maintenance Organization, Point of Service, and Preferred Provider Organization) was carried out. Overall trends in reimbursement were assessed across payers. The study found 61% of 60-min encounters billed to Medicare/Medicaid, Managed Care Medicaid, and commercial insurance payers received coverage. Of all covered 60-min encounters billed to Managed Care Medicaid and commercial insurance payers, an average of 36% of the amount billed was reimbursed. Medicare/Medicaid encounters were never reimbursed. Commercial insurance covered 65% of encounters billed but this varied between payers. Across all payers, an overall downward trend of reimbursement was demonstrated over the eight-year period. Lack of consistent service coverage creates a barrier and patients cannot universally access genetic counseling services. Steps to improve coverage need to include passing of legislation, notably the next bill to replace the former H.R. 3235, 'Access to Genetic Counselor Services Act of 2019' and provisions within third-party payers that allow for credentialing of genetic counseling providers.

Reproductive male partner testing when the female is identified to be a genetic disease carrier.

OBJECTIVE: To quantify carrier testing uptake rates for male partners of women found to be a carrier(s) for autosomal recessive conditions and to understand reasons for declining testing (uptake rate). METHODS: A retrospective chart review of 513 female patients seen at Rutgers-Robert Wood Johnson Medical School found to be carriers through expanded carrier screening (ECS) panels. The aims of this study were to determine how often their male partner chose testing, reasons for declining and the type of methodology chosen for their screening. RESULTS: Male partner uptake rate was 77%. We identified that the most significant barrier to male partner testing is female patients not following up on their own carrier screening results, thus missing the opportunity for partner testing. When male partners were provided options for testing, the most reported reason for declining is the belief it would have no impact on pregnancy management (20%). A carrier couple rate of 8.3% was identified of partners tested. CONCLUSION: Despite a relatively high male testing uptake rate, a quarter of carrier females did not proceed with testing their partner. To ascertain fetal risk, results for both parents is necessary. Pretest counseling should stress need for potential male partner follow-up testing.

Smith-Lemli-Opitz's Syndrome as a Possible Cause of Recurrent Pregnancy Loss: A Case Report.

Based on the known carrier frequency of Smith-Lemli-Opitz's syndrome (SLOS), the prevalence of this disease should be significantly higher than what is observed in the population. This may be due to a higher rate of pregnancy loss in affected embryos. Here, we present the case of a couple who underwent expanded carrier screening (ECS) after experiencing three first trimester pregnancy losses. Both parents were found to be carriers of SLOS mutations, and DNA analysis of the fetal remains of the third loss revealed the aborted fetus had inherited both the maternal and paternal mutations. This suggests SLOS as a reason for this patient's recurrent pregnancy loss (RPL), and therefore, ECS should be considered as part of the RPL work-up.

Beyond the "Jewish panel": the importance of offering expanded carrier screening to the Ashkenazi Jewish population.

OBJECTIVE: To assess whether or not the current American College of Obstetricians and Gynecologists (ACOG) recommendations regarding carrier screening are sufficiently robust in detecting mutations in the Ashkenazi Jewish (AJ) population. DESIGN: Cross-sectional study. SETTING: Outreach program at university community center. PATIENTS: Self-identified Jewish students, 18-24 years of age, interested in genetic carrier testing. INTERVENTIONS: Expanded carrier screening (ECS) with the use of a commercially available targeted genotyping panel including >700 mutations in 180 genes. MAIN OUTCOME MEASURES: Gene mutations found in this population were grouped into three categories based on ACOG's 2017 committee opinion regarding carrier screening: category 1: the four commonly recommended genetic conditions known to be a risk for this population; category 2: 14 genetic disorders that should be considered for more comprehensive screening, including those of category 1; and category 3: the ECS panel, which includes category 2. RESULTS: A total of 81 students underwent screening and 36 (44.4%) were ascertained to be carriers of at least one mutation. A total of 45 mutations were identified, as 8 students were carriers for more than one condition. If testing were limited to category 1, 84% of the mutations would not have been identified, and if limited to category 2, 55% of mutations would have gone undetected. CONCLUSIONS: Individuals of Ashkenazi Jewish descent are at significant risk for carrying a variety of single-gene mutations and therefore they should be offered panethnic ECS to increase the likelihood of detecting preventable disorders.

Whole exome sequencing for prenatal diagnosis in cases with fetal anomalies: Criteria to improve diagnostic yield.

Whole exome sequencing (WES) for prenatal diagnosis has a reported diagnostic yield of 6.2%-57%. Our aim was to identify patients with a high likelihood of genetic diagnosis using WES in cases with fetal ultrasound anomalies. This is a series of five selected cases for prenatal WES at our institution. Pregnant couples were initially identified due to fetal ultrasound anomalies. Candidates for WES for fetal diagnosis had a normal fetal karyotype and negative microarray with at least one of the following: parental consanguinity, large regions of homozygosity on fetal microarray, or high likelihood of single gene disorder based on ultrasound findings. All trios underwent sequencing of parental and fetal samples. WES was diagnostic in four of the five cases (80%). We identified two recessive conditions and two de novo mutations. Four couples consented to secondary findings and in one case, the father was found to have an MSH2 mutation associated with Lynch syndrome. The use of specific selection criteria for WES increased diagnostic yield to 80%. This is higher than previously reported. Wide application of our criteria can help identify those who may benefit most from this testing in prenatal diagnosis.

Advanced paternal age, infertility, and reproductive risks: A review of the literature.

Advanced paternal age (APA) is associated with infertility and other reproductive risks. Studies looking at APA and outcomes have used different paternal age cut-offs, which has complicated systematic evaluations of reproductive risk associated with paternal aging. This review of the literature suggests that the impact of paternal aging on adverse reproductive outcomes is small, but significant. Studies suggest the incidence of paternal age effect disorders attributed to de novo autosomal dominant mutations is less than 0.5%. Other risks associated with APA include infertility, miscarriage, birth defects, poor neurodevelopmental outcomes, and childhood cancer. Although the increasing prevalence of APA has mirrored the rise in maternal age, this topic has not received similar attention. In this review, we summarize the available literature on the reproductive risks associated with APA to provide a framework for comprehensive genetic counseling and evidence-based management of APA pregnancies.

Trends in invasive prenatal diagnostic testing at a single institution.

OBJECTIVE: As diagnostic methodologies evolve, we sought to determine whether invasive testing rates would decline, whether there would be a shift in indications for invasive testing, and whether the diagnostic yield would increase. METHODS: We conducted a retrospective, observational study from 2006 through 2015. We quantified the number of invasive procedures per year and examined what percentage of these procedures yielded abnormal results. We also examined the indications for testing and determined the trend of these indications during the study period. RESULTS: The number of amniocenteses showed a steady decline (P < .05). The number of CVS procedures has increased and was recently equivalent to amniocentesis. The percentage of abnormal results steadily increased from 11.4% to 27.0% (P < .001). The abnormal aneuploidy screening indication remained constant over time. Advanced maternal age (AMA) as the sole indication substantially declined from 42.3% to 15.52% (P < .001). Testing for a known single gene disorder steadily increased from 3.0% to 9.20% (P = .018). CONCLUSION: Our study showed a significant decline in the number of amniocenteses, a steady increase in the percentage of abnormal results from invasive testing, and a decline in AMA as the sole indication for invasive testing.

Genetic Counselors' Perspectives and Practices Regarding Expanded Carrier Screening after Initial Clinical Availability.

Expanded carrier screening (ECS), introduced in 2009, identifies carriers for dozens or hundreds of recessive diseases. At the time of its introduction into clinical use, perspectives of the genetic counseling community regarding ECS were unknown. We conducted a survey in early 2012 of GCs and report the results here. They represent a snapshot of opinions and usage at that time, providing a baseline for comparison as the technology continues to evolve and as usage increases. The survey assessed personal perspectives, opinions on clinical implementation and clinical utilization of ECS. The sample included 337 GCs of varying clinical fields, of whom 150 reported practicing in reproductive settings. Our findings demonstrate that, at the time, GCs indicated general agreement with ECS as a concept - for example, most GCs agreed that carrier screening should address diseases outside of current guidelines and also indicated personal interest in electing ECS. There were also disagreements or concerns expressed regarding appropriate pre- and post-test counseling (e.g., the content and delivery mode of adequate informed consent) and practical implementation (e.g., the amount of time available for follow-up care). This was the first quantitative study of a large number of GCs and it revealed initial overall support for ECS among the GC profession. The authors plan to re-administer a similar survey, which may reveal changes in opinions and/or utilization over time. A follow up survey would also allow further exploration of questions uncovered by these data.

Exome sequencing positively identified relevant alterations in more than half of cases with an indication of prenatal ultrasound anomalies.

OBJECTIVE: Exome sequencing is a successful option for diagnosing individuals with previously uncharacterized genetic conditions, however little has been reported regarding its utility in a prenatal setting. The goal of this study is to describe the results from a cohort of fetuses for which exome sequencing was performed. METHODS: We performed a retrospective analysis of the first seven cases referred to our laboratory for exome sequencing following fetal demise or termination of pregnancy. All seven pregnancies had multiple congenital anomalies identified by level II ultrasound. Exome sequencing was performed on trios using cultured amniocytes or products of conception from the affected fetuses. RESULTS: Relevant alterations were identified in more than half of the cases (4/7). Three of the four were categorized as 'positive' results, and one of the four was categorized as a 'likely positive' result. The provided diagnoses included osteogenesis imperfecta II (COL1A2), glycogen storage disease IV (GBE1), oral-facial-digital syndrome 1 (OFD1), and RAPSN-associated fetal akinesia deformation sequence. CONCLUSION: This data suggests that exome sequencing is likely to be a valuable diagnostic testing option for pregnancies with multiple congenital anomalies detected by prenatal ultrasound; however, additional studies with larger cohorts of affected pregnancies are necessary to confirm these findings.

Discordant embryonic aneuploidy testing and prenatal ultrasonography prompting androgen insensitivity syndrome diagnosis.

BACKGROUND: Multimodal prenatal screening for developmental pathology is increasingly common. In this case, definitive prenatal diagnosis of androgen insensitivity syndrome was diagnosed after discordant results from karyotypes determined by embryonic preimplantation genetic screening and antenatal ultrasound results. CASE: A 38-year-old woman, gravida 2 para 0010, undergoing in vitro fertilization with preimplantation genetic screening transferred one male and one female embryo. An anatomic ultrasonogram revealed two fetuses with female genitalia. Cell-free fetal DNA analyzed using noninvasive prenatal screening demonstrated Y chromosome material, and amniocentesis confirmed one 46,XX and one 46,XY fetus. Sequencing of the androgen receptor for the 46,XY fetus identified a mutation. CONCLUSION: With increased use, discordance among prenatal testing modalities such as preimplantation genetic screening, noninvasive prenatal screening, and ultrasonography will become more common requiring expert navigation to identify true pathology.

Differential utilization of expanded genetic screening tests in patients of reproductive ages from private and academic practices.

OBJECTIVE: We sought to evaluate the types of genetic screening tests that are performed in women of childbearing ages in New Jersey. METHOD: Data from patients who had a reproductive genetics consultation between January 1, 2012, and July 31, 2012, were stratified according to the referring providers, i.e., those from academic or private practices, and descriptive analyses performed. Unconventional genetic screening was defined as any test ordered by the referring health care provider outside the recommendations from the American Congress of Obstetricians and Gynecologists or the American College of Medical Genetics and Genomics. RESULTS: Overall, 30% of 371 patients referred for a genetic consultation underwent unconventional screening. As compared to patients from academic practices, the relative rate of unconventional screening was 10-fold higher among patients from private practices, resulting in a relative 34-fold increase in the estimated cost in genetic screening (P<0.01). CONCLUSION: This set of preliminary observations highlight the need for further state, nationwide, and international studies to understand the financial, personal, and societal impact that this discrepancy health care system in the use of genetic carrier screening portends.

The significance of a positive second trimester serum screen for trisomy 18.

OBJECTIVES: We designed this study to estimate the proportion of fetuses in pregnancies with positive second trimester serum screens for trisomy 18 who actually have trisomy 18, to estimate the proportion of women with trisomy 18 who have a negative serum screen, and to assess the role of ultrasound in the diagnosis of trisomy 18. METHODS: Retrospective study of two cohorts of pregnant women in 2004 and 2005: (1) those with a second trimester serum screen positive for trisomy 18 and (2) those with fetuses having trisomy 18. RESULTS: There were 93 women with positive serum screens for trisomy 18. Of these, only three had a fetus with trisomy 18. There were five other cases of trisomy 18, three of which had a negative second trimester serum screen for trisomy 18. All fetuses with trisomy 18 had multiple major structural abnormalities detected on targeted genetic sonography. CONCLUSIONS: A positive second trimester serum screen has a poor sensitivity and poor prediction for trisomy 18. Trisomy 18 is highly unlikely if a woman with a positive screen for trisomy 18 has no fetal abnormalities detected on targeted genetic sonography. Women with a positive second trimester serum screen for trisomy 18 should be offered genetic sonography, and the practice of routine amniocentesis for all women with a positive screen should be discouraged when targeted genetic sonography is available.

Successful conservative management of hereditary hemorrhagic telangiectasia in pregnancy. A case report.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a condition characterized by multiple telangiectases and arteriovenous malformations. Women with HHT may develop life-threatening complications in pregnancy. In particular, death from pulmonary hemorrhage has been reported. Consequently, these women are often advised not to conceive or to terminate their pregnancies. CASE: We report a case of conservative management of HHT in pregnancy with a good outcome. CONCLUSION: This case demonstrates that in carefully selected cases, women with HHT who are managed conservatively may have good pregnancy outcomes. A diagnosis of HHT alone is not reason to advise women against pregnancy, nor should these women routinely be advised to undergo pregnancy termination.