Post-test Genetic Counseling Research Articles

Expert consensus on the clinical application strategy of NIPT2.0, a new-generation non-invasive prenatal screening technology

The new-generation non-invasive prenatal screening technology (NIPT2.0) is a new method successfully realized in recent years based on high-throughput sequencing to synchronously and accurately detect fetal chromosomal aneuploidies, microdeletion/microduplication syndromes and dominantly inherited monogenic disorders. NIPT2.0 can circumvent the shortcomings of previous non-invasive prenatal screening techniques (NIPT and NIPT Plus) including incapability to detect fetal monogenic disorders, insufficient accuracy of detection and low positive predictive values for certain chromosomal abnormalities (in particular trisomy 13, sex chromosomal abnormalities, and small-segment microdeletions and microduplication syndromes). How to apply NIPT2.0 reasonably and normatively to maximize its clinical value has become an issue which requires clarification. The Reproductive Health Branch of the Chinese Maternal and Child Health Care Association and the Genetic Diagnosis Branch of the Genetics Society of China have organized experts to fully discuss and jointly drafted this consensus, which has put forwards suggestions over the clinical application strategy for NIPT2.0, including the scope of application, target disease, pre-test consultation, clinical application pathway, post-test genetic counseling and intervention, quality control and limitations, for the reference by peers, with a view to standardize its application and provide better clinical service.

Abstract B100: Improving access to hereditary cancer genetic testing in diverse populations: Outcomes in over 33,000 patients tested by genetics and non-genetics providers in Kaiser Permanente Southern California

Abstract Kaiser Permanente Southern California is an integrated health care organization serving over 4.7 million members in 14 medical centers. KPSC members are 42% Hispanic/Latino, 28 % Non-Hispanic White, 11% Asian/Pacific Islander, 8% Black/African American, and 12% Other/Unk. To facilitate detection of hereditary cancer syndromes among patients with personal and/or family histories of breast, colorectal, ovarian, pancreas and other cancers, we offered a 48-gene hereditary cancer multigene-panel test designed to detect all the most common hereditary cancer conditions. Patients seen by genetic counselors or geneticists (Gen providers) receive pre-test genetic counseling and include those with a family history of cancer with or without personal history of cancer. Our mainstreaming program allows non-genetics (non-Gen) providers including medical and surgical oncologists, gastroenterologists, and other specialists to order the test at the point of care (based on NCCN criteria) on their patients with cancer without pre-test genetic counseling. Providers place the order in the EMR system and patients receive an email/text message with information about the test, potential results, links to educational videos and a Genetics phone number for questions. When results are ready patients receive an automatic email/text notifying them and providing a link to their test report. Those with a positive test result receive post-test genetic counseling. Patients with negative or uncertain significance (VUS) results receive a message with a link to their test report, information about their result and the option to schedule a visit with genetics. From April 2021 to May 2024, we completed 33,173 tests: 13,076 (39%) ordered by non-Gen and 20,097 (61%) by Gen providers. The results distribution was similar in both groups: pathogenic/likely pathogenic (PV/LPV): 15% for Gen orders, 12% for non-Gen; VUS: 28% Gen, 30% non-Gen, and negative: 56% Gen, 58% Non-Gen. The patients tested closely reflected the diversity of our population, except for under-representation of Hisp/Latino patients and over-representation of Non-Hisp Whites: 14,400 (42%); Hisp/Latino 9,863 (29%); Asian/PI 4,279 (13%); AA/Black 3,209 (9%); and Oth/Unk 2,415 (7%). Eliminating single MUTYH variants the top 5 genes with the highest number and percentage of PV/LPV results for each of the race/ethnicity categories were as follows: AA/Black: BRCA2=60, BRCA1=38, ATM=36, MUTYH=18; Asian/PI: BRCA2=101, ATM=40, BRCA1=37, PMS2=24; Hisp/Latino: BRCA2=250, BRCA1=171, ATM=127, CHEK2=125; CDKN2A=113; Non Hisp White: CHEK2=346; BRCA2=304; ATM=200, BRCA1=196, FH=100; Oth/Unk: BRCA2=50, BRCA1=41, CHEK2=40, PALB2=30, ATM=20. Our results represent one of the largest and most diverse patient cohorts completing hereditary cancer testing from a single institution. They indicate that mainstreaming hereditary cancer testing can improve access for patients from under-represented groups and suggest differences in the frequency of deleterious variants in different hereditary cancer genes across race/ethnic groups. Citation Format: Monica Alvarado, Trevor Hoffman, Reina Haque, Hilary Kershberg, John Goff. Improving access to hereditary cancer genetic testing in diverse populations: Outcomes in over 33,000 patients tested by genetics and non-genetics providers in Kaiser Permanente Southern California [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B100.

A content analysis of parents' reflections on pathogenic and uncertain pediatric oncology germline sequencing results.

Germline genomic sequencing is increasingly integrated into pediatric cancer care, with pathogenic cancer-predisposing variants identified among 5-18% of affected children and variants of uncertain significance (VUS) in up to 70%. Given the potential medical implications for children and their families, parents' psychosocial responses to learning results are important to understand. Parents of children with cancer who learned their children's germline pathogenic or VUS results following paired tumor and germline genomic sequencing described their cognitive and affective responses to results in an open-ended write-in question after disclosure (M = 10 months post-disclosure; range = 1-28). Responses were coded and categorized using content analysis, then compared across results using chi-square and Fisher's exact test. Parents of children with pathogenic (n = 9), VUS (n = 52), and pathogenic plus VUS results (n = 9) described negative emotions, positive reactions, mixed emotions (i.e., positive and negative emotions), and neutral reactions. Negative emotions were described significantly more frequently with pathogenic results than VUS only (χ2 = 5.19; p = .02), with peace of mind and empowerment only described for those with VUS. Parents also described approach(es) to coping (e.g., faith, plan of action) and reactions specific to the uncertainty of VUS (e.g., disappointment at no explanation for cancer etiology). A subset with VUS described decreasing worry/distress with increased understanding of results, whereas others displayed misconceptions regarding VUS. Screening for emotional adjustment is warranted for parents of children with cancer receiving pathogenic germline results, and screening for understanding is warranted with VUS. Findings highlight the importance of pre-and posttest genetic counseling.

Genetics Navigator: protocol for a mixed methods randomized controlled trial evaluating a digital platform to deliver genomic services in Canadian pediatric and adult populations

IntroductionGenetic testing is used across medical disciplines leading to unprecedented demand for genetic services. This has resulted in excessive waitlists and unsustainable pressure on the standard model of genetic healthcare....

P-509 Unveiling reproductive risks: a retrospective analysis of carrier screening in 873 non-consanguineous couples

Abstract Study question What is the prevalence of at-risk couples for recessive genetic diseases, and can preconception carrier testing effectively identify these potential couples at risk? Summary answer High-risk couples, comprising mostly carriers of the ABCA4 and HBB genes, accounted for 3.7% of the analyzed cases, while another 3.2% categorized as moderate risk. What is known already It is widely recognized that approximately 2-3% of couples may be at risk of having an affected child with a genetic recessive disease. Expanded carrier screening tests (ECS) are currently employed to identify carrier status in healthy individuals for various severe recessive and X-linked diseases that manifest early in life, and often lack treatment options. ECS facilitates the detection of couples sharing mutated genes, allowing for risk calculation and further interventions to avoid affected pregnancies. Study design, size, duration In this retrospective descriptive study, we evaluated couples in which both partners elected to complete ECS before undergoing medically assisted reproduction across our Spanish and Italian clinics between August 2018 and January 2024. A total of 873 non-consanguineous couples were identified during the study period. Participants/materials, setting, methods All couples received pre-test genetic counseling alongside the informed consent for ECS. Saliva or blood samples were sent to an external genetics lab for the analysis of 309 genes (recessive and X linked), using NGS and complementary molecular techniques to detect pathogenic and likely pathogenic variants. Each couple’s risk was subsequently calculated. Post-test genetic counselling was offered to all of couples. Main results and the role of chance A total of 55 couples were identified as having reproductive risk, carrying pathogenic or likely pathogenic variants in genes exhibiting recessive or recessive digenic inheritance. These couples were categorized into high and moderate-risk groups based on the severity, actionability, and probability of causing classical gene-linked diseases. Ultimately, 3.5% (n = 31/873) of couples were deemed high-risk, with ABCA4 and HBB being the most frequently mutated genes, observed in 6 and 5 couples respectively (0.7% and 0.6%). Additionally, 24 couples (2.74%) were classified as moderate risk, primarily carrying a classical pathogenic variant and a non-classical pathogenic variant in the CFTR gene. This allele combination could result in a child presenting a mild cystic fibrosis phenotype, predominantly observed in males, and characterized by the absence of a vas deferens. Limitations, reasons for caution The main limitation of the study rests in interpreting the variants in healthy patients. The study does not delve into exploring the genetic heterogeneity within the identified risk groups, which may influence the severity and manifestation of diseases. Wider implications of the findings The cumulative risk observed in close to 6% of the cohort underscores the critical importance of carrier testing in guiding preconception interventions and the role and importance of having a well-trained, multidisciplinary genetics team to support these couples in reproductive decision-making with minimal anxiety and maximum knowledge. Trial registration number Not Applicable

Prenatal exome sequencing for morphologically normal fetus: Should we be doing it?

We aimed to investigate the yield of prenatal exome sequencing (pES) in morphologically normal fetuses. This retrospective study analyzed 254 families with morphologically normal fetuses who underwent prenatal trio exome sequencing based on parental request between September 2020 and October 2023. Overall, abnormal findings were detected in 8 families (3.1%, 8/254) by pES. Among these, 6 families (2.3%, 6/254) were found to have fetuses affected with monogenic disorders (2 autosomal recessive conditions and 4 autosomal dominant conditions), while 2 families (0.8%, 2/254) were incidentally found to be couples at risk of having a future pregnancy with a recessive condition. Among the six fetuses detected with monogenic disorders, two fetuses carried a de novo variant in OPA1 and NF1, which are known to cause Optic atrophy 1 and Neurofibromatosis, respectively. One fetus was detected with a maternally inherited variant in PKD2 related to polycystic kidney disease 2 (not known to the mother until then). One fetus was detected with a maternally inherited variant in SDHB associated with Pheochromocytoma. Two fetuses carried compound heterozygous variants in NAGLU and GJB2 associated with Mucopolysaccharidosis type IIIB and Deafness, respectively. In the 2 families where parents were found to be carriers but the fetuses were unaffected, heterozygous variants in the GJB2 and SERPINB7 genes were detected in the parents, respectively, which are associated with deafness and palmoplantar keratoderma. Our research indicated that pES can provide significant critical information for families with morphologically normal fetuses. Prenatal screening with exome sequencing requires careful management and detailed pre-test and post-test genetic counseling.

Expert consensus on clinical genetic counseling of α-thalassemia gene analysis

α-thalassemia is a type of microcytic hypochromic anemia caused by variants of alpha-globin gene, and is one of the most common monogenic disorders in southern China. The population screening model based on hematologic phenotype has achieved great results in areas with high incidence of thalassemia. However, with the continuous decline of the cost of genetic testing and implementation of screening programs for thalassemia gene carriers, more variants in the alpha-globin gene have been discovered, which also brings great challenges to clinical genetic counseling. From the perspective of alpha-globin genetic analysis, this consensus has discussed the contents of pre- and post-test genetic counseling, with an aim to provide standardized guidance for clinicians.

Implementation of video assisted point-of-care germline genetic education and testing for patients with peri-diagnostic pancreatic cancer.

e22530 Background: Germline genetic testing is universally recommended for patients with exocrine pancreatic cancer (PC). Pretest consultation with a genetics professional is recommended to ensure patients are informed about risks, benefits, and limitations of testing. This is a resource intensive process and is associated with a suboptimal testing rate (~30%). Prior work demonstrates that video-assisted pre-test education does not increase patient anxiety compared to traditional pre-test genetic counseling in peridiagnostic ovarian cancer patients. In this report, we assess the feasibility of using a similar video assisted, streamlined genetic education and testing approach in peridiagnostic PC patients. Methods: As part of a pilot quality improvement initiative, patients with a diagnosis of exocrine PC seen in a single academic practice were offered streamlined, video-assisted genetic education followed by germline testing. Patient eligibility for this pilot included: new diagnosis or radiographic suspicion of PC; English language proficiency; and no prior germline testing. After this approach was presented by the medical oncology team, eligible patients viewed a 9-minute educational video describing the goals, pros, and cons of germline genetic testing. After watching the video, patients were given the option to proceed with testing that day. Patients with pathogenic mutations were referred for formal post-test genetic counseling, and patients with variants of uncertain significance (VUSs) were referred on a case-by-case basis. Following IRB approval, we conducted a retrospective review of the experience of all patients presenting to this pilot site from April-Dec 2023. Results: During the study period, 56 new patients with exocrine PC presented to the pilot site. 50 patients were eligible for participating in the pilot program. All patients, except one who declined on the basis of transferring care, consented to testing (49/50; 98%). Median patient age was 71, 49% were female. Race distribution was: White (30), Asian (6), Black (4), Other (2), Declined (7). Median time from patient diagnosis to testing was 11 days. One patient had a germline ATM mutation, and this patient was seen for formal posttest counseling 18 days after testing was initiated. Seven patients had VUSs. Six new patients presenting during the study period were not eligible for this pilot, all due to limited English proficiency. All 6 of these patients underwent genetic testing after translation service assisted counseling by either the primary oncology or cancer genetics team. Conclusions: Video assisted point-of-care genetics education and testing led to nearly universal uptake of genetic testing in peridiagnostic PC patients. This workflow was feasible, timely, and optimized use of genetic counseling resources.

The Role of Genetic Testing in Adult CKD.

Mounting evidence indicates that monogenic disorders are the underlying cause in a significant proportion of patients with CKD. In recent years, the diagnostic yield of genetic testing in these patients has increased significantly as a result of revolutionary developments in genetic sequencing techniques and sequencing data analysis. Identification of disease-causing genetic variant(s) in patients with CKD may facilitate prognostication and personalized management, including nephroprotection and decisions around kidney transplantation, and is crucial for genetic counseling and reproductive family planning. A genetic diagnosis in a patient with CKD allows for screening of at-risk family members, which is also important for determining their eligibility as kidney transplant donors. Despite evidence for clinical utility, increased availability, and data supporting the cost-effectiveness of genetic testing in CKD, especially when applied early in the diagnostic process, many nephrologists do not use genetic testing to its full potential because of multiple perceived barriers. Our aim in this article was to empower nephrologists to (further) implement genetic testing as a diagnostic means in their clinical practice, on the basis of the most recent insights and exemplified by patient vignettes. We stress why genetic testing is of significant clinical benefit to many patients with CKD, provide recommendations for which patients to test and which test(s) to order, give guidance about interpretation of genetic testing results, and highlight the necessity for and essential components of pretest and post-test genetic counseling.

Abstract 6133: Genetic profiling landscape among gynecological and breast cancer patients in the borde city of Tijuana, Mexico: A comprehensive study

Abstract Background: Individuals in Tijuana have been identified as having multicultural and racial diversity. In Baja, California, Mexico, the prevalence and composition of cancer-predisposing germline variants in gynecologic cancers in Tijuana patients have not been evaluated. Aim and Methods: We aimed to evaluate the prevalence of pathogenic variants (PV) using a panel of 84 cancer-predisposing genes in breast, endometrial, and ovarian cancer from the General Hospital of Tijuana during the period of October 2021-October 2023, who were contacted and invited to participate in the evaluation. Pre- and post-test genetic counseling was given, and a questionnaire on personal, gyneco-obstetric, demographic, and lifestyle variables was conducted. Peripheral blood samples were obtained from all patients, and Next-generation sequencing (NGS) was performed on the Illumina commercial platform (Illumina, SD, USA). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG). Data was collected and descriptive statistics was applied to describe the characteristics of the population. Results: A total of 51 patients were included in our cohort; 98.0% (50/51) were females and 2% (1/51) were males. Among study participants (mean age ±standard deviation: 46.1 ± 10.9), 49% reported a personal history of cancer (25/51). Diagnosis of breast cancer was present in 80.3% of the patients (41/51), 9% (5/51) with ovarian cancer, and 3.9% (2/51) with endometrial cancer. Twenty-five percent of participants (13/51) harbor a PV or likely pathogenic (LP) variant distributed among four cancer-risk genes (BRCA1, BRCA2, ATM, and TP53). The distribution by gene in the patients with a PV was: BRCA1 in 61% (8/13), BRCA2 in 23% (3/13), TP53 in 8% (1/13), and ATM in 8% (1/13). Whereas 39.2% (20/51) had variants of uncertain clinical significance in genes with ambiguous or non-well-established risk association for cancer (BARD1, AXIN2, GPC3, NF2, CEBPA, MSH3, ALK, DIS3L2, CDC73, BAP1, RAD51D, NF1, MSH2, BLM, NBN, BRCA2, BARD1, RUNX1, RECQL4, EGFR, PALB2, CASR, and POLD1), and 35.2% (18/51) had negative results for both; PV and VUS. Conclusion: Our findings show a diverse pathogenic variant composition among the recruited individuals of the gynecological cancer population in Tijuana, Mexico, consistent with being a high-risk population for genetic diseases, which warrants further investigation to adequately assess the burden of hereditary cancer and implement appropriate preventative programs. Disparities in access to testing have a significant impact on affected populations, due in part to underrepresentation in surveys of regional cancer etiology and in genomic variant databases. Citation Format: Jorge Alberto Guadarrama-Orozco, Paula Leal-Anaya, Eva Guerrero-Santillan. Genetic profiling landscape among gynecological and breast cancer patients in the borde city of Tijuana, Mexico: A comprehensive study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6133.

Human Genetics Society of Australasia Position Statement: Predictive and Presymptomatic Genetic Testing in Adults and Children.

This Position Statement provides guidelines for health professionals who work with individuals and families seeking predictive genetic testing and laboratory staff conducting the tests. It presents the major practical, psychosocial and ethical considerations associated with presymptomatic and predictive genetic testing in adults who have the capacity to make a decision, children and young people who lack capacity, and adults living with reduced or fluctuating cognitive capacity.Predictive Testing Recommendations: (1) Predictive testing in adults, young people and children should only be offered with pretest genetic counseling, and the option of post-test genetic counseling. (2) An individual considering whether to have a predictive test should be supported to make an autonomous and informed decision. Regarding Children and Young People: (1) Predictive testing should only be offered to children and young people for conditions where there is likely to be a direct medical benefit to them through surveillance, use of prevention strategies, or other medical interventions in the immediate future. (2) Where symptoms are likely to develop in childhood, in the absence of direct medical benefit from this knowledge, genetic health professionals and parents/guardians should discuss whether undertaking predictive testing is the best course of action for the child and the family as a whole. (3) Where symptoms are likely to develop in adulthood, the default position should be to postpone predictive testing until the young person achieves the capacity to make an autonomous and informed decision. This is applicable regardless of whether there is some action that can be taken in adulthood.

Hereditary Aortic Aneurysms and Dissections: Clinical Diagnosis and Genetic Testing.

Hereditary aortic aneurysms and dissections, such as Marfan syndrome, differ in that they occur in younger patients without generally recognized risk factors, have a predilection for the thoracic rather than the abdominal aorta, and are at risk for dissection even at smaller aortic diameters. Early diagnosis, careful follow-up, and early intervention, such as medication to reduce aortic root growth and prophylactic aortic replacement to prevent fatal aortic dissection, are essential for a better prognosis. Molecular genetic testing is extremely useful for early diagnosis. However, in actual clinical practice, the question often arises as to when and to which patient genetic testing should be offered since the outcome of the tests can have important implications for the patient and the relatives. Pre- and post-test genetic counseling is essential for early intervention to be effective. (This article is a secondary translation of Jpn J Vasc Surg 2023; 32: 261-267.).

Impact of genetic counseling strategy on diagnostic yield and workload for genome-sequencing-based tumor diagnostics

PurposeGenome sequencing (GS) enables comprehensive molecular analysis of tumors and identification of hereditary cancer predisposition. According to guidelines, directly determining pathogenic germline variants (PGVs) requires pretest genetic counseling, which is cost-ineffective. Referral for genetic counseling based on tumor variants alone could miss relevant PGVs and/or result in unnecessary referrals. MethodsWe validated GS for detection of germline variants and simulated 3 strategies using paired tumor-normal GS data of 937 metastatic patients. In strategy-1, genetic counseling before tumor testing allowed direct PGV analysis. In strategy-2 and -3, germline testing and referral for post-test genetic counseling is based on tumor variants using Dutch (strategy-2) or Europen Society for Medical Oncology (ESMO) Precision Medicine Working Group (strategy-3) guidelines. ResultsIn strategy-1, PGVs would be detected in 50 patients (number-needed-to counsel; NTC = 18.7). In strategy-2, 86 patients would have been referred for genetic counseling and 43 would have PGVs (NTC = 2). In strategy-3, 94 patients would have been referred for genetic counseling and 32 would have PGVs (NTC = 2.9). Hence, 43 and 62 patients, respectively, were unnecessarily referred based on a somatic variant. ConclusionBoth post-tumor test counseling strategies (2 and 3) had significantly lower NTC, and strategy-2 had the highest PGV yield. Combining pre-tumor test mainstreaming and post-tumor test counseling may maximize the clinically relevant PGV yield and minimize unnecessary referrals.

Remotely Delivered Cancer Genetic Testing in the Making Genetic Testing Accessible (MAGENTA) Trial

Requiring personalized genetic counseling may introduce barriers to cancer risk assessment, but it is unknown whether omitting counseling could increase distress. To assess whether omitting pretest and/or posttest genetic counseling would increase distress during remote testing. Making Genetic Testing Accessible (MAGENTA) was a 4-arm, randomized noninferiority trial testing the effects of individualized pretest and/or posttest genetic counseling on participant distress 3 and 12 months posttest. Participants were recruited via social and traditional media, and enrollment occurred between April 27, 2017, and September 29, 2020. Participants were women aged 30 years or older, English-speaking, US residents, and had access to the internet and a health care professional. Previous cancer genetic testing or counseling was exclusionary. In the family history cohort, participants had a personal or family history of breast or ovarian cancer. In the familial pathogenic variant (PV) cohort, participants reported 1 biological relative with a PV in an actionable cancer susceptibility gene. Data analysis was performed between December 13, 2020, and May 31, 2023. Participants completed baseline questionnaires, watched an educational video, and were randomized to 1 of 4 arms: the control arm with pretest and/or posttest genetic counseling, or 1 of 3 study arms without pretest and posttest counseling. Genetic counseling was provided by phone appointments and testing was done using home-delivered saliva kits. The primary outcome was participant distress measured by the Impact of Event Scale 3 months after receiving the results. Secondary outcomes included completion of testing, anxiety, depression, and decisional regret. A total of 3839 women (median age, 44 years [range 22-91 years]), most of whom were non-Hispanic White and college educated, were randomized, 3125 in the family history and 714 in the familial PV cohorts. In the primary analysis in the family history cohort, all experimental arms were noninferior for distress at 3 months. There were no statistically significant differences in anxiety, depression, or decisional regret at 3 months. The highest completion rates were seen in the 2 arms without pretest counseling. In the MAGENTA clinical trial, omitting individualized pretest counseling for all participants and posttest counseling for those without PV during remote genetic testing was not inferior with regard to posttest distress, providing an alternative care model for genetic risk assessment. ClinicalTrials.gov Identifier: NCT02993068.

Genetic counseling and testing for females at elevated risk for breast cancer: Protocol for the randomized controlled trial of the Know Your Risk intervention

BackgroundGenetic counseling and testing have an important role in the care of patients at elevated risk for breast cancer. However, conventional pre- and post-test genetic counseling is labor and time intensive, less accessible for patients living outside major urban centers, and impractical on a large scale. A patient-driven approach to genetic counseling and testing may increase access, improve patients' experiences, affect efficiency of clinical practice, and help meet workforce demand. The objective of this 2-arm randomized controlled trial is to determine the efficacy of Know Your Risk (KYR), a genetic counseling patient preference intervention. MethodsFemales (n = 1000) at elevated risk (>20% lifetime) for breast cancer will be randomized to the KYR intervention or conventional genetic counseling. The study will provide comprehensive assessment of breast cancer risk by multigene panel testing and validated polygenic risk score. Primary outcome is adherence to National Comprehensive Cancer Network guidelines for a clinical encounter every 6–12 months and an annual mammogram (breast MRI if recommended) determined by medical record review. Secondary outcomes include adherence to other recommended cancer screening tests determined by medical record review and changes in breast cancer knowledge, perception of risk, post-test/counseling distress, and satisfaction with counseling by completion of three surveys during the study. Study aims will be evaluated for non-inferiority of the KYR intervention compared to conventional genetic counseling. ConclusionIf efficacious, the KYR intervention has the potential to improve patients' experience and may change how genetic counseling is delivered, inform best practices, and reduce workforce burden.Trial Registration: ClinicalTrials.govNCT05325151

The growing needs of genetic counselling-Feasibility in utilization of tele-genetic counselling in Asia and Hong Kong.

The need for the expansion of genomic services has been at a record time high in the past decade. As technological advancement continues to strengthen the entire genetic and genomic pipeline and clinical operational workflow, the major challenge remains to be the speed of workforce development to meet service growth. In particular, the international expansion of genetic counselling (GC) services has been a topic of interest for the past few years. GC is an emerging profession in most of Asia, and in many countries the profession of GC often refers to physicians or front-line health workers with expertise in genetics to provide GC services rather than being a specific independent profession. As genetic and genomic services, especially pre-test and post-test GC, expand globally, the need to tackle the longstanding obstacles of GC personnel shortage and funding issues must not be overlooked. There is an urgent need internationally, and especially in Asia, where GC profession is comparatively less well-established, to seek alternative approaches to meet service demand. The present review examines the global development and feasibility of tele-genetics and tele-genetic counselling (TGC), and serves as the foundation to explore a possible roadmap in Hong Kong via the Hong Kong Genome Project.

The Evolution of Genetic Testing from Focused Testing to Panel Testing and from Patient Focused to Population Testing: Are We There Yet?

The field of cancer genetics has evolved significantly over the past 30 years. Genetic testing has become less expensive and more comprehensive which has changed practice patterns. It is no longer necessary to restrict testing to those with the highest likelihood of testing positive. In addition, we have learned that the criteria developed to determine who has the highest likelihood of testing positive are neither sensitive nor specific. As a result, the field is moving from testing only the highest risk patients identified based on testing criteria to testing all cancer patients. This requires new service delivery models where testing can be mainstreamed into oncology clinics and posttest genetic counseling can be provided to individuals who test positive and those with concerning personal or family histories who test negative. The use of videos, testing kiosks, chatbots, and genetic counseling assistants have been employed to help facilitate testing at a larger scale and have good patient uptake and satisfaction. While testing is important for cancer patients as it may impact their treatment, future cancer risks, and family member's cancer risks, it is unfortunate that their cancer could not be prevented in the first place. Population testing for all adults would be a strategy to identify individuals with adult-onset diseases before they develop cancer in an attempt to prevent it entirely. A few research studies (Healthy Nevada and MyCode) have offered population testing for the three Centers for Disease Control and Prevention Tier 1 conditions: hereditary breast and ovarian cancer syndrome, Lynch syndrome, and familial hypercholesterolemia finding a prevalence of 1 in 70 individuals in the general population. We anticipate that testing for all cancer patients and the general population will continue to increase over the next 20 years and the genetics community needs to help lead the way to ensure this happens in a responsible manner.

Scalable new model of genomic care delivery: Assessing psychological outcomes.

10600 Background: Germline testing (GT) use is on the rise given testing implications for identifying cancer susceptibility and therapeutically actionable alterations. Scalable models of care that emphasize post-test, as opposed to pre-test, genetic counseling are needed to meet demand. However, little is known about the psychological impact (PI) of test result disclosure in such models. Methods: The enterprise-wide City of Hope INSPIRE study offers all consented patients GT for cancer susceptibility (155 genes) and actionable disorders (59 genes). In 2022, we surveyed a sub-set of English-speaking participants ~1 month following test result disclosure. We evaluated PI using the Feelings about Genomic Testing Results (FACToR) measure (distress/ uncertainty subscales 0-12; positive subscale 0-16) and explored associations between patient characteristics, GT results and PI. Results: Of 1000 patients surveyed, 615 completed at least one of the FACToR questions. Participants were mostly white (n=463, 75%) or Asian (n=12.52, 13%) and female (n=419, 68%) with a mean age of 62 yrs. 357 (61%) had a cancer diagnosis and most opted for both GT panels (97%). Eighteen percent had a pathogenic/likely pathogenic variant (PV/LPV) in an autosomal dominant condition, 8% were carriers for an autosomal recessive condition, 53% had at least one variant of unknown significance (VUS) and 21% had negative results. Most patients (n=583, 95%) had low levels of distress with a mean score of 1.67 (SD 2.31). Out of the 30 (5%) patients with higher levels of distress (score >7), results were similar for patients with and without cancer (5% and 4% respectively). Of the 30 patients with higher distress, 67% had a P/LPV variant (13 with and 7 without cancer). Patients also had low levels of uncertainty with a mean score of 2.22 (SD 2.61) and 93% (n=569) scored <7. For those who scored higher on uncertainty (n=44, 7%), most people had cancer and a VUS (n=16, 36%), followed by cancer and LPV/PV (n=10, 23%) followed by patient without cancer with a VUS (n=6, 14%). Finally, 56% (n=44) had high positivity scores (9-16); mean 9.18 (SD 4.31). Fifty-six percent of patients felt a “good/great deal” happy about their GT and 54% were a good/great deal relieved about their results. Conclusions: After implementing an enterprise-wide germline testing program with an emphasis on robust post-test genetic counseling, we found very little evidence of post-disclosure distress or uncertainty. Similar to prior studies, we found that a small proportion of patients may be more vulnerable to negative PI. More work is needed to prospectively identify at risk patients to provide support to this population as we continue to develop safe, effective, and scalable models of care.

Challenges and Pragmatic Solutions in Pre-Test and Post-Test Genetic Counseling for Prenatal Exome Sequencing.

The yield of genetic prenatal diagnosis has been notably improved by introducing whole genome chromosomal microarray (CMA) and prenatal exome sequencing (pES). However, together with increased numbers of diagnoses made, the need to manage challenging findings such as variants of unknown significance (VUS) and incidental findings (IF) also increased. We have summarized the current guidelines and recommendations and we have shown current solutions used in our tertiary center in the Netherlands. We discuss four of the most common clinical situations: fetus with normal pES results, fetus with a pathogenic finding explaining the fetal phenotype, fetus with a variant of uncertain clinical significance fitting the phenotype and fetus with a variant leading to an incidental diagnosis. Additionally, we reflect on solutions in order to facilitate genetic counseling in an NGS-era.

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.