Secondary Findings Research Articles

Ethical Approaches in Secondary Findings Report from Exome Sequencing Analysis

In Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) approaches, incidental findings (IFs) or more precisely secondary findings (SFs) have indicated controversial reports. To address SFs issues, well-known guidelines have been released such as the versions of the American College of Medical Genetics and Genomics (ACMG); however, when, to whom, why, and how these SFs should be reported are the key questions that need to be addressed ethically. The current review aimed to investigate the papers with a focus on the ethical approaches regarding IFs/SFs. In this comprehensive review, we searched the PubMed data-base for related publications, and 58 papers were selected as the narrowest reports. There was a positive tendency to disclose the SFs by the professionals and an enthusiasm in patients to be informed about all of their genetic reports. Several studies have addressed that guidelines could not cover all aspects of IFs/SFs ethically and medically. The main focus of these studies was the modernized opt-in informed consent according to some items including prenatal/post-natal or pediatric/adulthood issues. Other foci are genetic variant clinical actionability, cancer status, population-based backgrounds, time- and cost-effectiveness, the education level of sub-jects and clinicians, and the combinations of pharmacogenomics findings to introduce medicinal treatments and personalized prescrip-tions leading to more suitable healthcare. Altogether, concerns remain about the ethical approaches in the SFs; however, the present review introduced remarkable solutions which will be ethically and practically possible to be utilized. This review also found that recent reports are concentrated on the high-volume Exome Sequencing tests of subjects from biobanks and healthcare centers.

Secondary findings in genes related to cancer phenotypes in Turkish exome sequencing data from 2020 individuals.

Big data generated from exome sequencing (ES) and genome sequencing (GS) analyses can be used to detect actionable and high-penetrance variants that are not directly associated with the primary diagnosis of patients but can guide their clinical follow-up and treatment. Variants that are classified as pathogenic/likely pathogenic and are clinically significant but not directly associated with the primary diagnosis of patients are defined as secondary findings (SF). The aim of this study was to examine the frequency and variant spectrum of cancer-related SF in 2020 Turkish ES data and to discuss the importance of the presence of cancer-related SF in at-risk family members in terms of genetic counseling and follow-up. A total of 2020 patients from 2020 different families were evaluated by ES. SF were detected in 28 unrelated cases (1.38%), and variants in BRCA2 (11 patients) and MLH1 (4 patients) genes were observed most frequently. A total of 21 different variants were identified, with 4 of them (c.9919_9932del and c.3653del in the BRCA2 gene, c.2002A>G in the MSH2 gene, c.26_29del in the TMEM127 gene) being novel variations. In three different families, c.1189C>T (p.Gln397*) variation in BRCA2 gene was detected, suggesting that this may be a common variant in the Turkish population. This study represents the largest cohort conducted in the Turkish population, examining the frequency and variant spectrum of cancer-related SF. With the identification of frequent variations and the detection of novel variations, the findings of this study have contributed to the variant spectrum. Genetic testing conducted in family members is presented as real-life data, showcasing the implications in terms of counseling, monitoring, and treatment through case examples.

Expectations, needs and mid-term outcomes in people accessing to secondary findings from ES: 1st French mixed study (FIND Study)

Generation and subsequently accessibility of secondary findings (SF) in diagnostic practice is a subject of debate around the world and particularly in Europe. The French FIND study has been set up to assess patient/parent expectations regarding SF from exome sequencing (ES) and to collect their real-life experience until 1 year after the delivery of results. 340 patients who had ES for undiagnosed developmental disorders were included in this multicenter mixed study (quantitative N = 340; qualitative N = 26). Three groups of actionable SF were rendered: predisposition to late-onset actionable diseases; genetic counseling; pharmacogenomics. Participants expressed strong interest in obtaining SF and a high satisfaction level when a SF is reported. The medical actionability of the SF reinforced parents’ sense of taking action for their child and was seen as an opportunity. While we observed no serious psychological concerns, we showed that these results could have psychological consequences, in particular for late-onset actionable diseases SF, within families already dealing with rare diseases. This study shows that participants remain in favor of accessing SF despite the potential psychological, care, and lifestyle impacts, which are difficult to anticipate. The establishment of a management protocol, including the support of a multidisciplinary team, would be necessary if national policy allows the reporting of these data.

Abstract 1308: Policy guiding secondary findings from genome sequencing pertinent to cancer: Results from a systematic review

Abstract Background: While genomic sequencing has personalized patient care across disciplines like oncology, secondary findings (SFs) unrelated to the primary indication are a common complicating factor. SFs relevant for oncology are categorized as cancer-related potentially leading to a cancer diagnosis (CA-SFs) or non-cancer findings revealing important medical conditions, predispositions, or carrier status in cancer patients (NC-SFs). These SFs can inform disease prevention, early detection, or management decisions, but may cause distress, overdiagnosis, and overuse of resources if actionability is limited. There is a lack of consensus for identifying, analyzing, and interpreting the clinical relevance of SFs. This significantly impacts cancer care, where paired tumor-normal sequencing is standard practice. Widespread practice variation can lead to detrimental impacts on patient outcomes and overall health. We synthesized policy guiding the clinical investigation of SFs for cancer to help providers navigate decisions regarding SFs. Methods: We carried out a systematic review of international guidance directing the identification, analysis, and management of SFs from genomic sequencing, and analyzed the subset of policies specifically relating to oncology. We searched the grey literature (IFHGS members) and academic databases including MEDLINE, Embase and Cochrane. Two reviewers independently assessed policy documents for screening, data extraction and quality assessment (using AGREE-II). Results: We identified 7 policies guiding the investigation of SFs relating to cancer across the general population (n=4), adults (n=1), pediatrics (n=1) and research (n=2) contexts. Most policies included guidelines for SF variant selection (identification; n=5) and management (n=4), with a minority detailing analysis processes (n=2). Recommended CA-SFs included medically actionable cancer predisposition variants, while suggested NC-SFs were variants important for drug therapies (identification). Laboratories were advised to ensure adequate coverage and read depth during SF analysis (analysis), while policies recommended that a medical genetics healthcare provider return results, specifically discussing their clinical utility (management). Conclusions: To our knowledge, our review is the most comprehensive synthesis of policy guiding SFs for cancer. Policies outline the types of SFs to investigate from genome sequencing in cancer and non-cancer patients, and related strategies for disclosure. However, best practices for SF analyses and patient follow-up including SF surveillance, treatment, etc. remain poorly described. This synthesis will help cancer care providers navigate critical decision points based on current evidence and direct policymakers on gaps to fill in the future. Citation Format: Safa Majeed, Christine Johnston, Saumeh Saeedi, Chloe Mighton, Vanessa Rokoszak, Ilham Abbasi, Sonya Grewal, Vernie Aguda, David Malkin, Yvonne Bombard. Policy guiding secondary findings from genome sequencing pertinent to cancer: Results from a systematic review [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 1308.

Feasibility and Clinical Utility of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified in Research Germline Sequencing: A Prospective Interventional Study.

Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant secondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician. This prospective, interventional cohort study enrolled Total Cancer Care participants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic analysis in a Clinical Laboratory Improvement Amendments-certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College of Medical Genomics and Genetics SF v2.0 genes. After a protocol modification in consenting patients, the MTB reported PGVs to treating oncology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing. Of the 781 enrolled participants, 32 (4.1%) harbored cancer predisposition PGVs, 24 (3.1%) were heterozygous carriers of an autosomal recessive cancer predisposition syndrome, and 14 (1.8%) had other hereditary disease PGVs. Guideline-directed testing would have missed 37.5% (12/32) of the inherited cancer predisposition PGVs, which included BRCA1, BRCA2, MSH6, SDHAF2, SDHB, and TP53 variants. Three hundred fifteen participants consented to reporting results; results for all living patients were reported to the clinical team with half referred to a licensed genetic counselor. There was concordance between all research variants identified in patients (n = 9) who underwent clinical confirmatory sequencing. MTB reporting of research-grade germline sequencing to the clinical oncology team is feasible. Over a third of PGVs identified using a universal testing strategy would have been missed by guideline-based approach, suggesting a role for expanding germline testing.

Systematic review of the uptake and outcomes from returning secondary findings to adult participants in research genomic testing.

The increasing use of genomic sequencing in research means secondary findings (SF) is more frequently detected and becoming a more pressing issue for researchers. This is reflected by the recent publication of multiple guidelines on this issue, calling for researchers to have a plan for managing SF prior to commencing their research. A deeper understanding of participants' experiences and outcomes from receiving SF is needed to ensure that the return of SF is conducted ethically and with adequate support. This review focuses on the uptake and outcomes of receiving actionable SF for research participants. This review included studies from January 2010 to January 2023. Databases searched included Medline, Embase, PsycINFO, and Scopus. Of the 3903 studies identified, 29 were included in the analysis. The uptake of SF ranged between 20% and 97%, and outcomes were categorized into psychological, clinical, lifestyle and behavioral, and family outcomes. The results indicate there is minimal psychological impact from receiving SF. Almost all participants greatly valued receiving SF. These findings highlight considerations for researchers when returning results, including the importance of involving genetic health professionals in consenting, results return process, and ensuring continuity of care by engaging healthcare providers.

Returning Secondary Genomic Findings to a Sickle Cell Disease Cohort

Introduction: As gene therapy for sickle cell disease (SCD) continues to advance, there is growing potential for genomic screening to be utilized in determining eligibility for this therapy. With this comes the ethical obligation to look for secondary findings (SF) in clinical exome and whole genome sequencing. The American College of Medical Genetics (ACMG) has issued recommendations for returning SF in clinical care and annually updates a list of pathogenic variants. This abstract reports on our experience with returning SF to a SCD study population in research. Methods: The INSIGHTS Study (NCT02156102) is a cross-sectional perspective research study examining phenotypic variation in adults living with SCD. All study participants consented to whole genome sequencing (WGS) and agreed to have secondary genomic findings returned. Participants completed the study between 2014-2020. To date, 264 samples have undergone WGS, performed at the National Institutes of Health Intramural Sequencing Center. Results: In accordance with the guidelines issued by ACMG, 12 participants (4.5%) were found to have genetic variants on the current list (ACMG SF v3.2) that were eligible for return (Table 1). Additionally, one participant was found to have a sex chromosome aneuploidy, and after a full ethics board review, it was determined this result should also be returned based on its clinical actionability and the risk/benefit analysis. Of these 12 participants, three were deceased. One participant was already aware of the secondary finding. We contacted the remaining eight participants and as of July 2023 five participants provided a new sample for CLIA confirmation. Results were returned in consultation with the Secondary Findings Consult Service at the National Human Genome Research Institute, which provided a genetic counselor. Participants met with a clinical member of the study team and the genetic counselor either by telephone or in person. The consultation consisted of sharing the result and associated risk of disease, obtaining pertinent medical history and detailed family history, and providing recommendations and referrals. Discussion: With the expansion of genomics into hematological and sickle cell disease research, it is paramount that the implications of its integration continue to be examined. The responsibility of the research team to facilitate and/or provide ancillary care to their study participants to best support them in receiving SF results should be clearly defined. In addition, each patient will have unique needs that should be considered and may require specialized assistance. Questions on how the SF affects the patient's primary diagnosis will need to be addressed, which will require a multidisciplinary approach to care. These consultations will require a high level of patient coordination and clinical support. It is important that these patient encounters 1) involve a known and trusted medical professional; 2) provide accurate and understandable information on the genomic finding, usually by a genetic counselor; and 3) refer the patient to an appropriate clinical provider who is an expert in that disease.

Frequency of actionable secondary findings in 7472 Korean genomes derived from the National Project of Bio Big Data pilot study.

Exome and genome sequencing (ES/GS) in genetic medicine and research leads to discovering genomic secondary findings (SFs) unrelated to the purpose of the primary test. There is a lack of agreement to return the SF results for individuals undergoing the test. The aim of this study is to investigate the frequency of actionable secondary findings using GS data obtained from the rare disease study and the Korean Genome and Epidemiology Study (KoGES) in the National Project of Bio Big Data pilot study. Pathogenic (P) or likely pathogenic (LP) variants of 78 SF genes recommended by the American College of Medical Genetics and Genomics (ACMG) were screened in the rare disease study and KoGES. The pathogenicity of SF gene variants was determined according to the ACMG interpretation. The overall SF rate was 3.75% for 280 individuals with 298 P/LP variants of 41 ACMG SF genes which were identified among 7472 study participants. The frequencies of genes associated with cardiovascular, cancer, and miscellaneous phenotypes were 2.17%, 1.22%, and 0.58%, respectively. The most frequent SF gene was TTN followed by BRCA2. The frequency of actionable SFs among participants with rare disease and general population participants in the Korean population presented here will assist in reporting results of medically actionable SFs in genomic medicine.

The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings

Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.

Clinically actionable secondary findings in 130 triads from sub-Saharan African families with non-syndromic orofacial clefts.

The frequency and implications of secondary findings (SFs) from genomic testing data have been extensively researched. However, little is known about the frequency or reporting of SFs in Africans, who are underrepresented in large-scale population genomic studies. The availability of data from the first whole-genome sequencing for orofacial clefts in an African population motivated this investigation. In total, 130 case-parent trios were analyzed for SFs within the ACMG SFv.3.0 list genes. Additionally, we filtered for four more genes (HBB, HSD32B, G6PD and ACADM). We identified 246 unique variants in 55 genes; five variants in four genes were classified as pathogenic or likely pathogenic (P/LP). The P/LP variants were seen in 2.3% (9/390) of the subjects, a frequency higher than ~1% reported for diverse ethnicities. On the ACMG list, pathogenic variants were observed in PRKAG (p. Glu183Lys). Variants in the PALB2 (p. Glu159Ter), RYR1 (p. Arg2163Leu) and LDLR (p. Asn564Ser) genes were predicted to be LP. This study provides information on the frequency and pathogenicity of SFs in an African cohort. Early risk detection will help reduce disease burden and contribute to efforts to increase knowledge of the distribution and impact of actionable genomic variants in diverse populations.

Clinical utility of reporting research genetic predisposition testing results to Total Cancer Care participants.

10602 Background: The American College of Medical Genomics and Genetics (ACMG) has identified genes with highly penetrant phenotypes with treatment, prevention, or early disease identification strategies called secondary findings (SF) genes. ACMG recommends clinical laboratories report pathogenic/likely pathogenic (P/LP) SF variants identified during genomic testing. Cancer patients may undergo germline sequencing as part of research studies that can identify valuable SF variants. The objective of this institutional sub-study is to evaluate the feasibility of using ACMG SF genes to assess hereditary disease risk in a cancer population undergoing research sequencing. Methods: Between June 2017 and January 2021, patients unselected for family history, disease site, or stage enrolled in the prospective, observational Total Cancer Care study. Patients underwent research-grade germline whole exome sequencing, with bioinformatic analysis in a CLIA certified laboratory to identify P/LP variants in any ACMG SF v2.0 genes. P/LP variants were reported to treating oncologists with recommendations for genetic counseling referral. We assessed if patients with P/LP variants met NCCN guideline-directed germline testing criteria to quantify benefit from reporting research results. Results: We enrolled 786 patients, which included those with gynecologic (182, 23%), colorectal (124, 16%), lung/bronchus (83, 11%), and head/neck (82, 10%) cancers. The median age was 61 (IQR 52-68) years, 57% were female, 96% were non-Hispanic White, 51% had stage III/IV disease, and 64% resided in an Appalachian community. We identified 57 patients (7%) with cancer predisposition and 14 (2%) with other hereditary disease variants. 2021 NCCN guideline-directed testing would have missed 59% (42/71) of these patients. Incremental high penetrance cancer gene variants included: BRCA1 – endometrial cancer (n = 1); BRCA2– cholangiocarcinoma (n = 1), colon neuroendocrine tumor (n = 1), and lung (n = 2), endometrial (n = 1), and non-epithelial ovarian (n = 1) cancers; MSH6 – duodenal cancer (n = 1); SDHAF2 – non-melanoma skin cancer (n = 1); SDHB – head/neck cancer (n = 1); and TP53 – CNS tumor (n = 1) and head/neck cancer (n = 1). We identified patients at risk for other hereditary diseases including hypertrophic/dilated cardiomyopathy (n = 1), malignant hyperthermia (n = 3), arrhythmogenic right ventricular cardiomyopathy (n = 1), Romano-Ward long QT / Brugada syndromes (n = 4), familial hypercholesterolemia (n = 4), and ornithine transcarbamylase deficiency (n = 1). Conclusions: Reporting germline variants identified during research sequencing is feasible and can benefit cancer patients and their relatives. Though not traditionally assessed, non-cancer predisposition genetic variants may have important intervention opportunities and unexpected patterns may have oncologic implications that require further study.

Great expectations: patients' preferences for clinically significant results from genomic sequencing.

We aimed to describe patient preferences for a broad range of secondary findings (SF) from genomic sequencing (GS) and factors driving preferences. We assessed preference data within a trial of the Genomics ADvISER, (SF decision aid) among adult cancer patients. Participants could choose from five categories of SF: (1) medically actionable; (2) polygenic risks; (3) rare diseases; (4) early-onset neurological diseases; and (5) carrier status. We analyzed preferences using descriptive statistics and drivers of preferences using multivariable logistic regression models. The 133 participants were predominantly European (74%) or East Asian or mixed ancestry (13%), female (90%), and aged > 50years old (60%). The majority chose to receive SF. 97% (129/133) chose actionable findings with 36% (48/133) choosing all 5 categories. Despite the lack of medical actionability, participants were interested in receiving SF of polygenic risks (74%), carrier status (75%), rare diseases (59%), and early-onset neurologic diseases (53%). Older participants were more likely to be interested in receiving results for early-onset neurological diseases, while those exhibiting lower decisional conflict were more likely to select all categories. Our results highlight a disconnect between cancer patient preferences and professional guidelines on SF, such as ACMG's recommendations to only return medically actionable secondary findings. In addition to clinical evidence, future guidelines should incorporate patient preferences.

Management of patients with presumed germline pathogenic variant from tumor-only genomic sequencing: A retrospective analysis at a single facility.

Cancer treatment is increasingly evolving toward personalized medicine, which sequences numerous cancer-related genes and identifies therapeutic targets. On the other hand, patients with germline pathogenic variants (GPV) have been identified as secondary findings (SF) and oncologists have been urged to handle them. All SF disclosure considerations for patients are addressed and decided at the molecular tumor boards (MTB) in the facility. In this study, we retrospectively summarized the results of all cases in which comprehensive genomic profiling (CGP) test was conducted at our hospital, and discussed the possibility of presumed germline pathogenic variants (PGPV) at MTB. MTB recommended confirmatory testing for 64 patients. Informed consent was obtained from attending physicians for 53 of them, 30 patients requested testing, and 17 patients tested positive for a confirmatory test. Together with already known variants, 4.5 % of the total confirmed in this cohort. Variants verified in this study were BRCA1 (n = 12), BRCA2 (n = 6), MSH2 (n = 2), MSH6 (n = 2), WT1 (n = 2), TP53, MEN1, CHEK2, MLH1, TSC2, PTEN, RB1, and SMARCB1. There was no difference in the tumor's VAF between confirmed positive and negative cases for variants determined as PGPV by MTB. Current results demonstrate the actual number of cases until confirmatory germline test for patients with PGPV from tumor-only CGP test through the discussion at the MTB. The practical results at this single facility will serve as a guide for the management of the selection and distribution of SF in the genome analysis.

Secondary findings in a large Pakistani cohort tested with whole genome sequencing.

Studies on genomic secondary findings (SFs) are diverse in participants' characteristics, sequencing methods, and versions of the ACMG SF list. Based on whole genome sequencing and the version 3.1 of the ACMG SF list, we studied SFs in 863 individuals from five different regions in Pakistan. We identified 24 ACMG SFs in 23 (2.7%) of 863 individuals: 18 of 24 were related to cardiovascular disease and four to cancer syndromes. In addition to ACMG SFs, we identified 16 (1.9%) participants with pathogenic and likely pathogenic variants in genes that were not related to the participants' clinical conditions but with clear medical actionability (non-ACMG SFs): 4 of 16 were related to eye diseases, two to metabolic disorders, and two to urinary system disorders. By testing a large Pakistani cohort with whole genome sequencing, we concluded that in countries such as Pakistan, the ACMG SF list could be expanded, and our non-ACMG SF list is one example.

Offering and Returning Secondary Findings in the Context of Exome Sequencing for Hearing Loss: Clinicians’ Views and Experiences

Background There is ongoing debate regarding whether and under which circumstances secondary findings (SF) should be offered in the pediatric context. Although studies have examined patient perspectives on receiving SF, little research has been conducted examining the experiences of clinicians offering SF to parents of newborns receiving genomic sequencing for a recently diagnosed medical condition. Methods To address this, we conducted qualitative interviews exploring the views and experiences of 12 clinicians who offered SF to parents of infants who had diagnostic exome sequencing (ES) to identify the cause of their hearing loss. Interviews explored clinicians’ accounts of parents’ choices and decision-making about receiving SF, their views on whether and when to offer SF, their experiences returning SF, and any ethical challenges they encountered. Interviews were audio-recorded, transcribed and analyzed using inductive content analysis. Results Clinicians reported parents who declined all SF often felt finding out about future conditions unrelated to their child’s hearing loss may be unhelpful, or even harmful, or were overwhelmed by their child’s diagnosis. Clinicians also reported that some parents chose SF because they felt obliged to, even if they did not want to receive them. They explained that while some parents experienced decision-making regarding SF as positive, for others, this process was challenging or distressing. While clinicians generally agreed SF should be offered, mainly to promote parental choice, most felt SF should be offered after disclosing diagnostic results, primarily to avoid overwhelming parents. Clinicians encountered several ethical challenges, including balancing parental autonomy with non-maleficence, wanting to report or not report certain SF, and questioning whether parents can make an autonomous choice regarding SF. Conclusions Our findings, which are novel as they relate to parents of young infants with a recent diagnosis of hearing loss, add new insights into clinicians’ and parents’ decision-making regarding SF in pediatrics.

Challenges of secondary finding disclosure in genomic medicine in rare diseases: A nation-wide survey of Japanese facilities outsourcing comprehensive genetic testing.

Comprehensive genome analysis may reveal secondary findings (SFs) including pathogenic variants of genes other than those originally targeted. Comprehensive genetic analysis of rare diseases is generally performed as research in Japan. Therefore, the status and difficulties in SF disclosure remain unclear. To obtain information for the appropriate disclosure of SFs in rare diseases, we conducted a survey on how SFs are handled in clinical practice by facilities that outsource comprehensive genetic testing to other facilities. The response rate was 66.7% (40/60). Among the responding facilities, 55% had a policy of disclosing SFs with clinical utility and considered targeting actionable SFs with high penetrance. These facilities had difficulties in determining the disclosure targets (51%) and in genetic counseling (38%). Improving genetic literacy, establishment of surveillance systems, and providing insurance coverage for medical care to unaffected carriers were commonly cited as solutions to these difficulties. A comparison of the willingness to disclose SFs between overseas and in Japan showed more reluctance in Japan (86% vs. 65% for actionable SFs and 62% vs. 16% for non-actionable SFs). The group with difficulty in determining disclosure targets was significantly more likely to discuss this at conferences with other facilities and to refer guidelines. This suggests that the group with difficulties was unable to make decisions solely at their own facility and sought collaboration with other facilities. These findings suggest the necessity for a system that allows consultation with experts across facilities and guidelines that set forth policies for determining SFs.

Landscape of Secondary Findings in Chinese Population: A Practice of ACMG SF v3.0 List.

Clinical exome sequencing (CES) has shown great utility in the diagnosis of Mendelian disorders. CES can unravel secondary findings (SFs) unrelated to the primary diagnosis but with potential health implications. The American College of Medical Genetics and Genomics (ACMG) has published a guideline for reporting secondary findings and recently updated an ACMG SF v3.0 list comprising 73 genes. Several studies have been performed to explore the prevalence of SFs. However, the data were limited in the Chinese population. In this study, we evaluated the genetic data of 2987 individuals from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study group in accordance with the ACMG SF v3.0 list. The detected variants were evaluated using the ACMG classification guidelines, HGMD, and ClinVar database. Totally, 157 (157/2987, 5.3%) individuals had reportable variants within genes associated with cancer, cardiovascular, metabolic, and miscellaneous phenotypes. We identified 63 known pathogenic (KP) variants in 72 individuals (72/2987, 2.4%) and 96 expected pathogenic (EP) variants in 105 individuals (3.5%). Forty-five individuals carried SFs in v3.0 newly added genes, which accounted for 1.5% of our cohort. Our findings could contribute to existing knowledge of secondary findings in different ethnicities and indicate the necessity for clinicians to update the SFs gene list.

A Scoping Review of Global Guidelines for the Disclosure of Secondary Genomic Findings to Inform the Establishment of Guidelines in China.

The detection and disclosure of secondary findings (SFs) is a preventive strategy for medically-actionable hereditary health conditions. Some countries have guidelines on management and disclosure of SFs, while others avoid detection and disclosure of SFs. This study is a review of clinical guidelines from six countries and the European Union to identify similarities and differences among SF guidelines. Evidence from this review supports harmonization of guidelines across countries to promote broad international collaborations on genomics and to benefit precision medicine. This study can serve as a reference for development of SF management guidelines in China by contributing evidence from other countries to the ethical and methodological challenges under debate.

Frequency of actionable Exomic secondary findings in 160 Colombian patients: Impact in the healthcare system

IntroductionBy 2021, the American College of Medical Genetics and Genomics (ACMG) published the last version of their secondary findings (SF) reporting recommendations for cases in which a person receives a genetic test. ObjectiveTo determine in a sample of the Colombian population the prevalence of SF for the 59 genes on the ACMG SF v2.0 list associated with 27 genetic diseases. Materials and methodsAn analytical cross-sectional study was developed by examining the sequences of 160 exomes. Based on the ACMG guidelines, a variant classification algorithm was designed to filter and select reportable SF. ResultsEleven pathogenic variants were identified in 13/160 (8.13%) patients in genes APOB, BRCA2, CACNA1S, COL3A1, LDLR, MYBPC3, PCSK9, PKP2, PMS2 and RYR2. No association was found between the sociodemographic variables and the SF to report (P > 0,05). ConclusionWe reported the first approach of actionable pathogenic variants spectrum in the Colombian population. Given the frequency found in this study and the clinical impact of genomic variants on health, it is essential to actively search for SF having the opportunity to receive genetic counselling, prevention and clinical management.

MO15-5 A proposal of efficient operation of expert panel for genomic medicine by pre-review meeting (pre-EP)

Under the National Health Insurance system in Japan, the cancer genome core hospitals must hold expert panels (EP) which consist of multidisciplinary specialists to evaluate the indication of treatments and possibilities of secondary findings (SFs). After August 2021, serum-based cancer comprehensive genomic profiling test was also reimbursed by National Health Insurance system. This situation will increase the number of cases which must be evaluated by EP. However, some cases have obvious druggable genomic alterations or some cases have neither recommended treatment nor SFs.