Pan-ethnic Screening Research Articles

P-497 Increasing use of pan-ethnic carrier screening for donor gametes creates new challenges for clinics and recipient counselling

Abstract Study question How can clinics support recipients to understand a positive or negative carrier status following pan-ethnic carrier screening. Summary answer A combination of recipient testing and genetic counselling enables the use of donor sperm irrespective of pan-ethnic screening results. What is known already Data reported by the HFEA, UK reveals that in 2020, more than half of new donor registrations were from donor imports - 48% were American or Danish in origin, where the level of genetic screening for recessive conditions can vary from 3 to 502 genes. Donor banks generally state that donors are screened to professional guidelines for the countries they supply. Variations in the practice for carrier screening of gamete donors and how this information is shared and charged can be opaque to clinics and complex for recipients to navigate without specialist support to understand relevance and reproductive risk. Study design, size, duration This study reports on the number of genetic counselling requests from several IVF clinic referrals in the UK for the period Jan 2020 - Dec 2023. A total of 412 recipients interested in purchasing samples from donors identified as a positive carrier of one or more recessive condition(s) after undergoing extended carrier screening. Referrals for ECS negative donors were not received. Participants/materials, setting, methods Recipients were provided with the opportunity of genetic counselling to include the meaning of the carrier status, risk estimates, and options. Recipients were then given the opportunity to review the consultation report and were supported through their subsequent decision-making. The recipient’s choice to accept the risk for using the donor or proceed to counter-screening was evaluated to give insight into the recipient decision-making for accepting risk or wishing to undertake carrier screening. Main results and the role of chance UK screening recommendations cumulatively account for only 9.3% of identified mutations within a sperm donor applicant population at a single commercial US sperm bank screened using ECS, highlighting international inconsistencies in donor recruitment and acceptance criteria. 15.3 % (n = 63) of recipients elected to be screened for the conditions their donor was a carrier for, with most opting to be screened on a matched gene panel to provide information for a child and allow future matching with an alternative donor. 84.7% (n = 359) proceeded with treatment without counter screening appreciating their relatively low reproductive risk. Patients who undertake consultation with a genetic professional can understand their reproductive risk for autonomous decision-making, indicating ECS positive results are not a barrier to donor gamete selection for treatment. Limitations, reasons for caution ECS panels are variable by commercial provider, donor banks may vary their carrier screening policy or commercial ECS options over time, limiting the findings to the time frame in which the abstract was written Wider implications of the findings Review and implementation of carrier screening guidelines are required to ensure consistency and transparency with access to suitably qualified genetics professionals to provide information counselling and genetic testing options. This allows recipients to maintain a level of autonomy for donor selection and may ultimately widen the available donor pool. Trial registration number not applicable

Populational pan-ethnic screening panel enabled by deep whole genome sequencing

Birth defect is a global threat to the public health systems. Mitigating neonatal anomalies is hampered by elusive molecular mechanisms of pathogenic mutations and poor subsequent translation into preventative measures. Applying appropriate strategies in China to promote reproductive health is particularly challenging, as the Chinese population compromises complex genomic diversity due to the inclusion of many ethnic groups with distinct genetic backgrounds. To investigate and evaluate the feasibility of implementing a pan-ethnic screening strategy, and guide future reproductive counselling, high-quality variants associated with autosome recessive (AR) diseases derived from the largest publicly available cohort of the Chinese population were re-analysed using a bottom-up approach. The analyses of gene carrier rates (GCRs) across distinct ethnic groups revealed that substantial heterogeneity existed potentially due to diverse evolutionary selection. The sampling population, sequencing coverage and underlying population structure contributed to the differential variants observed between ChinaMAP and the East Asian group in gnomAD. Beyond characteristics of GCR, potential druggable targets were additionally explored according to genomic features and functional roles of investigated genes, demonstrating that phase separation could be a therapeutic target for autosomal recessive diseases. A further examination of estimated GCR across ethnic groups indicated that most genes shared by at least two populations could be utilised to direct the design of a pan-ethnic screening application once sequencing and interpreting costs become negligible. To this end, a list of autosomal recessive disease genes is proposed based on the prioritised rank of GCR to formulate a tiered screening strategy.

Lessons learned from the first national population-based genetic carrier-screening program for Duchenne muscular dystrophy

PurposeTo summarize the results of first year implementation of pan-ethnic screening testing for Duchenne muscular dystrophy (DMD) and present the ensuing challenges. MethodsData acquisition for this study was performed by retrospective search of Ministry of Health registry for reports of all laboratories performing genetic screening tests. DMD testing was performed by multiplex ligation-dependent probe amplification technology. In case of single-exon deletion, sequencing of the specific exon was performed to rule out underlying single-nucleotide variant. ResultsOf overall 85,737 DMD tests, 82 clinically significant findings were noted (0.095%, or 1:1,046 women). In addition, 80 findings with uncertain clinical significance were detected (0.093%, or 1:1072), as well as 373 cases (0.4%, or 1:230) of single-exon deletions subsequently identified as false positives because of underlying single-nucleotide variant, mostly variants in exon 8 in North African Jewish population, and in exon 48 in Arab Muslim population. ConclusionInterpretation of population-based DMD carrier screening is complex, occasionally requiring additional genetic testing methods and ethical considerations. Multicenter data registry, including ethnic origin and familial segregation in selected cases, is crucial for optimal definition of the results during genetic counseling and informed decisions regarding prenatal testing.

International experience in the primary prevention of cystic fibrosis (part one)

Preconceptional genetic screening (genetic testing of individuals at the stages of family planning and birth of a healthy child) has an important place in the prevention of hereditary diseases. This review focuses on the preconceptional prevention of cystic fibrosis (CF), one of the most common hereditary diseases of the Caucasian race. The first part highlights the general principles of screening for hereditary diseases, including CF, the advantages and disadvantages of pan-ethnic screening for CF, and the economic rationale for the programme, using international studies and guidelines, as illustrated by international sources.

Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG)

Carrier screening began 50 years ago with screening for conditions that have a high prevalence in defined racial/ethnic groups (e.g., Tay–Sachs disease in the Ashkenazi Jewish population; sickle cell disease in Black individuals). Cystic fibrosis was the first medical condition for which panethnic screening was recommended, followed by spinal muscular atrophy. Next-generation sequencing allows low cost and high throughput identification of sequence variants across many genes simultaneously. Since the phrase “expanded carrier screening” is nonspecific, there is a need to define carrier screening processes in a way that will allow equitable opportunity for patients to learn their reproductive risks using next-generation sequencing technology. An improved understanding of this risk allows patients to make informed reproductive decisions. Reproductive decision making is the established metric for clinical utility of population-based carrier screening. Furthermore, standardization of the screening approach will facilitate testing consistency. This practice resource reviews the current status of carrier screening, provides answers to some of the emerging questions, and recommends a consistent and equitable approach for offering carrier screening to all individuals during pregnancy or preconception.

Impact of Pan-Ethnic Expanded Carrier Screening in Improving Population Health Outcomes: Proceedings from a Multi-Stakeholder Virtual Roundtable Summit, June 25, 2020.

Impact of Pan-Ethnic Expanded Carrier Screening in Improving Population Health Outcomes: Proceedings from a Multi-Stakeholder Virtual Roundtable Summit, June 25, 2020.

Expanded carrier screening: counseling and considerations.

The primary goal of carrier screening is to identify asymptomatic individuals who carry variants associated with genetic diseases, to inform about the risk of having a child with a genetic disease. Carrier screening can be accomplished through different approaches including ethnicity-based screening, pan-ethnic screening, and expanded carrier screening (ECS), and the decision to pursue carrier screening is voluntary. ECS takes a broad approach by screening for a large number of genetic diseases irrespective of ethnic background, and ideally is performed prior to conception. ECS has many benefits, including that it does not depend on accuracy of reported ancestry, as well as its greater yield of information that can be used for reproductive decision-making. However, there are also many important limitations of ECS to consider, ranging from the yield of unexpected information, uncertainty about the phenotype of a particular disease for which an individual is a carrier, and greater downstream costs associated with further testing and genetic counseling. Detailed genetic counseling both prior to and after ECS is essential in order for patients to understand the breadth of this approach, potential and actual results, and limitations.

Advantages of expanded universal carrier screening: what is at stake?

Expanded universal carrier screening (EUCS) entails a twofold expansion of long-standing (preconception) carrier screening programmes: it not only allows the simultaneous screening of a large list of diseases ('expanded'), but also refers to a pan-ethnic screening offer ('universal'). Advocates mention three main moral advantages of EUCS as compared with traditional (targeted and/or ancestry-based) forms of carrier screening: EUCS will (1) maximise opportunities for autonomous reproductive choice by informing prospective parents about a much wider array of reproductive risks; (2) provide equity of access to carrier testing services; (3) reduce the risk of stigmatisation. This empirical ethics study aims to widen this account and provide a balanced picture of the potential pros and cons of EUCS. Semi-structured interviews were conducted with 17 health (policy) professionals and representatives of patient organisations about their views on carrier screening including a possible EUCS scenario. Stakeholders acknowledged the potential benefits of EUCS, but also expressed five main moral concerns: (1) Does EUCS respond to an urgent problem or population need? (2) Is it possible to offer couples both understandable and sufficient information about EUCS? (3) How will societal views on 'reproductive responsibility' change as a result of EUCS? (4) Will EUCS lead to a lower level of care for high-risk populations? (5) Will EUCS reinforce disability-based stigmatisation? While having the potential to overcome some moral limits inherent in traditional carrier screening, EUCS comes with moral challenges of its own. More research is needed to (further) anticipate the ethical and practical consequences of EUCS.

Do people from the Jewish community prefer ancestry-based or pan-ethnic expanded carrier screening?

Ancestry-based carrier screening in the Ashkenazi Jewish population entails screening for specific autosomal recessive founder mutations, which are rarer among the general population. As it is now technically feasible to screen for many more diseases, the question arises whether this population prefers a limited ancestry-based offer or a pan-ethnic expanded carrier screening panel that goes beyond the diseases that are frequent in their own population, and is offered regardless of ancestry. An online questionnaire was completed by 145 individuals from the Dutch Jewish community (≥18 years) between April and July 2014. In total, 64.8% were aware of the existence of ancestry-based carrier screening, and respondents were generally positive about screening. About half (53.8%) preferred pan-ethnic expanded carrier screening, whereas 42.8% preferred ancestry-based screening. Reasons for preferring pan-ethnic screening included ‘everyone has a right to be tested', ‘fear of stigmatization when offering ancestry-based panels', and ‘difficulties with identifying risk owing to mixed backgrounds'. ‘Preventing high healthcare costs' was the most important reason against pan-ethnic carrier screening among those in favor of an ancestry-based panel. In conclusion, these findings show that people from the Dutch Jewish community have a positive attitude regarding carrier screening in their community for a wide range of diseases. As costs of expanded carrier screening panels are most likely to drop in the near future, it is expected that these panels will receive more support in the future.

Development and Performance of a Comprehensive Targeted Sequencing Assay for Pan-Ethnic Screening of Carrier Status

Identifying individuals as carriers of severe disease traits enables informed decision making about reproductive options. Although carrier screening has traditionally been based on ethnicity, the increasing ethnic admixture in the general population argues for the need for pan-ethnic carrier screening assays. Highly multiplexed mutation panels allow for rapid and efficient testing of hundreds of mutations concurrently. We report the development of the Pan-Ethnic Carrier Screening assay, a targeted sequencing assay for routine screening that simultaneously detects 461 common mutations in 91 different genes underlying severe, early-onset monogenic disorders. Mutation selection was aided by the use of an extensive mutation database from a clinical laboratory with expertise in newborn screening and lysosomal storage disease testing. The assay is based on the Affymetrix GeneChip microarray platform but generates genomic DNA sequence as the output. Analytical sensitivity and specificity, using genomic DNA from archived control cultures and from clinical specimens, was found to be >99% for all mutation types. This targeted sequencing assay has advantages over multiplex PCR and next-generation sequencing assays, including accuracy of mutation detection over a range of mutation types and ease of analysis and reporting of results.

ACMG position statement on prenatal/preconception expanded carrier screening

For years, clinicians have offered gene-by-gene carrier screening to patients and couples considering future pregnancy or those with an ongoing pregnancy early in gestation. Examples include ethnic-specific screening offered to Ashkenazi Jewish patients and panethnic screening for cystic fibrosis and spinal muscular atrophy. Next-generation sequencing methods now available permit screening for many more disorders with high fidelity, quick turnaround time, and lower costs. However, instituting these technologies carries with it perils that must be addressed. The basis for the selection of disorders on expanded carrier screening panels should be disclosed. The information provided about disorders with mild phenotypes, variable expression, low penetrance, and/or characterized by an adult onset should be complete and transparent, allowing patients to opt out of receiving these test results. Patients also must be made aware of the concept of residual risk following negative test results. Laboratories have a duty to participate in and facilitate this information transfer.

Response to Stoll and Resta

To the Editor: We thank Stoll and Resta1 for their feedback on our data in their letter titled “Considering the Cost of Expanded Carrier Screening Panels,” and welcome discussion on the merits of expanded carrier screening. We understand this is the beginning, not the end, of genomic applications in reproductive care and fully expect that enhancements will continually increase the test's efficacy. As we consider the correct path to a test's maximal clinical utility, an analogy to prenatal screening for Down syndrome seems applicable.

An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals

Purpose:Recent developments in genomics have led to expanded carrier screening panels capable of assessing hundreds of causal mutations for genetic disease. This new technology enables simultaneous measurement of carrier frequencies for many diseases. As the resultant rank-ordering of carrier frequencies impacts the design and prioritization of screening programs, the accuracy of this ranking is a public health concern.Methods:A total of 23,453 individuals from many obstetric, genetics, and infertility clinics were referred for routine recessive disease carrier screening. Multiplex carrier screening was performed and results were aggregated for this study.Results:Twenty-four percent of individuals were identified as carriers for at least one of 108 disorders, and 5.2% were carriers for multiple disorders. We report tabulations of carrier frequency by self-identified ethnicity and disease.Conclusion:To our knowledge, this study of a large, ethnically diverse clinical sample provides the most accurate measurements to date of carrier frequencies for hundreds of recessive alleles. The study also yields information on the clinical considerations associated with routine use of expanded panels and provides support for a pan-ethnic screening paradigm that minimizes the use of “racial” categories by the physician, as recommended by recent guidelines.

Comparison of two PCR-based molecular methods in the diagnosis of CMT 1A and HNPP diseases in Chinese

Objectives Current molecular diagnostic methods in detecting Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP) diseases are either not sensitive or time-consuming and costing. The aims of this study are improving the accuracy and speeding up the diagnosis. Patients and methods We developed real-time quantitative PCR (QPCR) and three polymorphic short tandem repeats (STRs) methods to test 53 unrelated CMT1A patients, 12 unrelated HNPP patients and 100 normal control subjects. Results QPCR in detection of pmp22 gene duplication (CMT1A) and deletion (HNPP) showed a sensitivity of 100.00% (53/53) and 100.00% (12/12), respectively. And this method also showed a specificity of 100% (100/100) in CMT1A and 100% (100/100) in HNPP, respectively. In contrast, using three polymorphic STRs method showed a sensitivity of 50/53 (94%) in CMT1A and 12/12 (100.00%) of HNPP patients, respectively. And this method showed a specificity of 97% (100/103) in CMT1A and 100% (100/100) in HNPP, respectively. Conclusion QPCR and three STRs methods both demonstrate a rapid and robust diagnosis with almost complete informativeness. The high sensitivity and heterozygosity of these three polymorphic markers in detecting CMT1A/HNPP subjects of Caucasian and Chinese showed the potential to become pan-ethnic screening markers in the future.