International policies guiding the selection, analysis, and clinical management of secondary findings from genomic sequencing: A systematic review.

Secondary findings (SFs) from genomic sequencing can have significant impacts on patient health, yet existing practices guiding their clinical investigation are inconsistent. We systematically reviewed existing SFs policies to identify variations and gaps in guidance. We cataloged and appraised international policies from academic databases (n = 5, inception-02/2022) and international human genetic societies (n = 64; inception-05/2022), across the continuum of SFs selection, analysis, and clinical management. We assessed quality using AGREE-II and interpreted results using qualitative description. Of the 63 SFs policies identified, most pertained to clinical management of SFs (98%; n = 62; primarily consent and disclosure), some guided SFs analysis (60%; n = 38), while fewer mentioned SFs selection (48%; n = 30). Overall, policies recommend (1) identifying clinically actionable, pathogenic variants with high positive predictive values for disease (selection), (2) bioinformatically filtering variants using evidence-informed gene lists (analysis), and (3) discussing with affected individuals the SFs identified, their penetrance, expressivity, medical implications, and management (clinical management). Best practices for SFs variant analysis, clinical validation, and follow-up (i.e., surveillance, treatment, etc.) were minimally described. Upon quality assessment, policies were highly rated for scope and clarity (median score, 69) but were limited by their rigor and applicability (median scores, 27 and 25). Our review represents a comprehensive international synthesis of policy guiding SFs across the continuum of selection, analysis, and clinical management. Our synthesis will help providers navigate critical decision points in SFs investigation, although significant work is needed to address gaps in SFs analysis, clinical validation, and follow-up processes and to support evidence-based practice.

Return of Results in Genomic Research Using Large-Scale or Whole Genome Sequencing: Toward a New Normal.

Genome sequencing is increasingly used in research and integrated into clinical care. In the research domain, large-scale analyses, including whole genome sequencing with variant interpretation and curation, virtually guarantee identification of variants that are pathogenic or likely pathogenic and actionable. Multiple guidelines recommend that findings associated with actionable conditions be offered to research participants in order to demonstrate respect for autonomy, reciprocity, and participant interests in health and privacy. Some recommendations go further and support offering a wider range of findings, including those that are not immediately actionable. In addition, entities covered by the US Health Insurance Portability and Accountability Act (HIPAA) may be required to provide a participant's raw genomic data on request. Despite these widely endorsed guidelines and requirements, the implementation of return of genomic results and data by researchers remains uneven. This article analyzes the ethical and legal foundations for researcher duties to offer adult participants their interpreted results and raw data as the new normal in genomic research.

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.

Should secondary pharmacogenomic variants be actively screened and reported when diagnostic genome-wide sequencing is performed in a child?

This white paper was prepared by the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream's Pediatric Task Team to review and provide perspective with respect to ethical, legal, and social issues regarding the return of secondary pharmacogenomic variants in children who have a serious disease or developmental disorder and are undergoing exome or genome sequencing to identify a genetic cause of their condition. We discuss actively searching for and reporting pharmacogenetic/genomic variants in pediatric patients, different methods of returning secondary pharmacogenomic findings to the patient/parents and/or treating clinicians, maintaining these data in the patient's health record over time, decision supports to assist using pharmacogenetic results in future treatment decisions, and sharing information in public databases to improve the clinical interpretation of pharmacogenetic variants identified in other children. We conclude by presenting a series of points to consider for clinicians and policymakers regarding whether, and under what circumstances, routine screening and return of pharmacogenomic variants unrelated to the indications for testing is appropriate in children who are undergoing genome-wide sequencing to assist in the diagnosis of a suspected genetic disease.

Preparing for the unexpected: Recommendations for returning secondary findings in late-stage cancer care.

PURPOSE: We conducted qualitative interviews with patients with cancer and providers to identify gaps in clinical care and highlight care delivery solutions for the return of secondary germline findings. METHODS: Twelve patients and 19 cancer providers from the United States were interviewed between January 2019 and May 2021. Interviews elicited feedback about patient information needs, emotional responses to secondary findings, and recommendations for improving pre-test education. RESULTS: Patients' responses ranged from gratitude to regret, depending on how much pre-test counseling they received before tumor testing. Providers cited insufficient clinic time as a major barrier to pretest education, favoring online support tools and standardized pre-test education models. Providers had differing perspectives on how pre-test education should be integrated into clinical workflows but agreed that it should include the differences between somatic and germline testing, the likelihood of medically actionable findings, and the possibility of being referred to a genetics provider. CONCLUSION: The spectrum of participants' responses to their secondary findings underscores the importance of adequate pre-test discussions before somatic sequencing. Although educational interventions could address patients' information needs and augment traditional pre-test counseling, health care systems, labs, and genetic providers may be called on to play greater roles in pre-test education.

Views of adults living with sickle cell disease on the theoretical return of secondary genomic findings.

PURPOSE: Although the body of research investigating research participants' opinions on the return of actionable secondary genomic findings grows, there has been limited study of individuals with genetic conditions, such as sickle cell disease (SCD). It is imperative that the views of diverse research participants on return of results (RoR) be investigated and rooted in the context of advancing health equity in genomics research. METHODS: We conducted qualitative, semi-structured interviews with 30 adults living with SCD with differing insurance coverages and utilized a directed content analysis to derive themes. RESULTS: Study findings show that living with SCD is a key influence on views of RoR. Participants were in favor of RoR while expressing concern regarding the burden RoR would place on their SCD management. Respondents also expressed an expectation for researchers to devote resources toward seeking ancillary care downstream and discussed how barriers faced when navigating SCD would inform their access to ancillary care. CONCLUSION: Research participants living with chronic genetic conditions such as SCD are generally in favor of RoR but anticipate experiencing barriers to care similar to those faced navigating their SCD. Understanding the views of diverse cohorts on RoR will help researchers better understand downstream barriers participants may face.

Additional findings from the 100,000 Genomes Project: A qualitative study of recipient perspectives.

PURPOSE: Participants in the 100,000 Genomes Project, a clinical/research initiative delivered through the UK National Health Service, were offered screening for "additional findings" (AFs): pathogenic/likely pathogenic secondary findings in genes associated with familial hypercholesterolemia or a cancer predisposition syndrome. Understanding the psychological and behavioral responses to secondary findings can inform the clinical utility of a search and disclose policy. METHODS: Thirty-two adult AF recipients took part in semi-structured interviews analyzed using deductive and inductive thematic analysis. RESULTS: Five themes were constructed: cognitive responses to an AF, emotional and psychological responses, personal control, perceived risk of AF-associated disease, and family implications. Many participants had misunderstood or incompletely remembered consent for AFs, and most were surprised or shocked to receive an AF. Although many ultimately appreciated knowing about the risk conferred, some struggled to make sense of their disease risk, which complicated decision making about risk management, particularly for women with a BRCA AF. Recipients sought control through seeking clinical evaluation and information, and informing relatives. Difficulties with conceptualizing risk and lack of AF-associated disease family history meant that some hesitated to inform relatives. CONCLUSION: Genome sequencing programs offering secondary findings require attention to consent processes. Post-disclosure care should aim to promote recipients' perceived personal control.

Implementing evidence-based assertions of clinical actionability in the context of secondary findings: Updates from the ClinGen Actionability Working Group.

PURPOSE: The ClinGen Actionability Working Group (AWG) developed an evidence-based framework to generate actionability reports and scores of gene-condition pairs in the context of secondary findings from genome sequencing. Here we describe the expansion of the framework to include actionability assertions. METHODS: Initial development of the actionability rubric was based on previously scored adult gene-condition pairs and individual expert evaluation. Rubric refinement was iterative and based on evaluation, feedback, and discussion. The final rubric was pragmatically evaluated via integration into actionability assessments for 27 gene-condition pairs. RESULTS: The resulting rubric has a 4-point scale (limited, moderate, strong, and definitive) and uses the highest-scoring outcome-intervention pair of each gene-condition pair to generate a preliminary assertion. During AWG discussions, predefined criteria and factors guide discussion to produce a consensus assertion for a gene-condition pair, which may differ from the preliminary assertion. The AWG has retrospectively generated assertions for all previously scored gene-condition pairs and are prospectively asserting on gene-condition pairs under assessment, having completed over 170 adult and 188 pediatric gene-condition pairs. CONCLUSION: The AWG expanded its framework to provide actionability assertions to enhance the clinical value of their resources and increase their utility as decision aids regarding return of secondary findings.

Secondary ACMG and non-ACMG genetic findings in a multiethnic cohort of 16,713 pediatric participants.

PURPOSE: Clinical next-generation sequencing is an effective approach for identifying pathogenic sequence variants that are medically actionable for participants and families but are not associated with the participant's primary diagnosis. These variants are called secondary findings (SFs). According to the literature, there is no report of the types and frequencies of SFs in a large pediatric cohort that includes substantial African-American participants. We sought to investigate the types (including American College of Medical Genetics and Genomics [ACMG] and non-ACMG-recommended gene lists), frequencies, and rates of SFs, as well as the effects of SF disclosure on the participants and families of a large pediatric cohort at the Center for Applied Genomics at The Children's Hospital of Philadelphia. METHODS: We systematically identified pathogenic (P) and likely pathogenic (LP) variants in established disease-causing genes, adhering to ACMG v3.2 secondary finding guidelines and beyond. For non-ACMG SFs, akin to incidental findings in clinical settings, we utilized a set of criteria focusing on pediatric onset, high penetrance, moderate to severe phenotypes, and the clinical actionability of the variants. This criteria-based approach was applied rather than using a fixed gene list to ensure that the variants identified are likely to affect participant health significantly. To identify and categorize these variants, we used a clinical-grade variant classification standard per ACMG/AMP recommendations; additionally, we conducted a detailed literature search to ensure a comprehensive exploration of potential SFs relevant to pediatric participants. RESULTS: We report a distinctive distribution of 1464 P/LP SF variants in 16,713 participants. There were 427 unique variants in ACMG genes and 265 in non-ACMG genes. The most frequently mutated genes among the ACMG and non-ACMG gene lists were TTR(41.6%) and CHEK2 (7.16%), respectively. Overall, variants of possible medical importance were found in 8.76% of participants in both ACMG (5.81%) and non-ACMG (2.95%) genes. CONCLUSION: Our study revealed that 8.76% of a large, multiethnic pediatric cohort carried actionable secondary genetic findings, with 5.81% in ACMG genes and 2.95% in non-ACMG genes. These findings emphasize the importance of including diverse populations in genetic research to ensure that all groups benefit from early identification of disease risks. Our results provide a foundation for expanding the ACMG gene list and improving clinical care through early interventions.

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.

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.

49,XXXXY PATIENT AND INCIDENTAL FINDING OF LOW LEVEL MOSAIC 45,X IN THE MOTHER.

Context: 49,XXXXY syndrome is an aneuploidy that affects males and is commonly referred to as a variant of Klinefelter Syndrome. It presents a frequency of 1:85,000 to 100,000 births and an etiology related to non-disjunction of homologous chromosomes. Findings include skeletal abnormalities, hypogonadism, and cognitive impairment. Turner syndrome is also an aneuploidy of the sex chromosomes, which affects women, and has a prevalence of 1:2000 to 2500 births and a phenotype characterized by short stature and sexual infantilism. Objective: The objective of this article was to study the literature, investigate the family members and report the case. Subjects and Methods: Data collection was based on medical records, family history, karyotype analysis, and FISH analysis. Results: The karyotype of the proband revealed mos 49, XXXXY[45]/46, XY[5]. The patient's mother is affected by mosaic Turner Syndrome low level and the maternal grandmother by inversion of chromosome 9. The father, the younger brother, and the paternal grandmother present variations in the normality of their chromosomes. Conclusions: It is important to highlight that the early diagnosis of the syndrome and the initiation of therapy reduce biopsychosocial impairment. Investigation of other family members makes genetic counseling more effective.

An incidental finding in prenatal exome sequencing-A case study and review of the clinical and ethical considerations.

The introduction of genomic testing into prenatal care has come at a rapid pace and has been met with significant clinical and ethical challenges, specifically when dealing with incidental findings. We present the case of a couple in their first pregnancy who were referred to our institution with isolated fetal cataracts on morphology scan. After an unremarkable infectious disease workup and microarray on an amniocentesis sample, the couple opted for fetal whole-exome sequencing to investigate the cataracts further. This investigation did not find any cause for the cataracts but yielded an incidental finding of a de novo pathogenic variant in the SCN1A gene unrelated to the cataracts. Pathogenic variants in the SCN1A gene are strongly associated with severe myoclonic epilepsy of infancy, or Dravet syndrome. After extensive genetic counseling, the couple decided to terminate the pregnancy at 28 weeks' gestation based on this finding. This case highlights some of the important clinical and ethical considerations in prenatal genetic diagnosis, particularly in the group of patients in which there is no phenotypic evidence in-utero of the incidental finding. The case demonstrates the value of frameworks and guidelines to guide management decisions for both clinicians and patients.

Research participants' perspectives regarding the feedback of secondary findings-A cohort from the DDD-Africa study, South Africa.

Genomic researchers face an ethical dilemma regarding feedback of individual results generated from genomic studies. In the African setting, genomic research is still not widely implemented and, coupled with this, the limited African-specific guidelines on how to feedback on individual research findings. A qualitative study was performed to assess participants' expectations and preferences regarding the feedback of secondary findings from genomic research. Participants were parents of children with a developmental disorder, enrolled in the Deciphering Developmental Disorders in Africa (DDD-Africa) research project, and were purposefully selected. Three deliberative focus group discussions were conducted with 14 participants. Each deliberative focus group consisted of two separate audio-recorded interviews and presented different case scenarios for different types of secondary findings that could be theoretically detected during genomic research. We aimed to explore participants' preferences for the extent, nature, timing, and methods for receiving individual study results, specifically pertaining to secondary findings. Thematic content analysis was done, with a deductive approach to coding. Four themes emerged which included participants' perception of readiness to receive secondary findings, queries raised around who has access to research findings and feedback of findings consent, responsibilities of the researcher, and reasons for not wanting/wanting secondary findings. Overall, participants expressed that they want to receive feedback on secondary findings irrespective of disease severity and treatment availability. Lifestyle changes, early prevention or treatment, impact on future generations, and preparedness were strong motivations for wanting feedback on results. Participants felt that when the research involved minors, it was the parents' right to receive results on behalf of their children. This study provides new insights into participants' preferences around feedback on genomic research results and could serve as an important basis for creating guidelines and recommendations for feedback on genomic results in the African context.

Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations.

BACKGROUND: Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. OBJECTIVES: This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option. CONCLUSIONS: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.

[Medical ethics in genomic medicine].

Recently, utilization of genetic data has become routine in medicine. It is important to consider the use of genetic information in different situations based on the principles of medical ethics. Furthermore, it is necessary to understand the features of genetic information and to adhere to various guidelines in research and clinical practices. In genomic medicine, which will become the mainstream of medicine using comprehensive genetic information, it will be crucial to fully comprehend the suitable handling of secondary results, and to prioritize benefits to the patients. Moreover, developing a system that incorporates appropriate legislation to ensure nondiscrimination of patients on the basis of their genetic information and to provide a forum for ethical issues that will arise in the future is essential.

Analyzing and Reanalyzing the Genome: Findings from the MedSeq Project.

Although genome sequencing is increasingly available in clinical and research settings, many questions remain about the interpretation of sequencing data. In the MedSeq Project, we explored how much effort is required to evaluate and report on more than 4,500 genes reportedly associated with monogenic conditions, as well as pharmacogenomic (PGx) markers, blood antigen serotyping, and polygenic risk scores in 100 individuals (50 with cardiomyopathy and 50 healthy) randomized to the sequencing arm. We defined the quality thresholds for determining the need for Sanger confirmation. Finally, we examined the effort needed and new findings revealed by reanalyzing each genome (6-23 months after initial analysis; mean 13 months). Monogenic disease risk and carrier status were reported in 21% and 94% of participants, respectively. Only two participants had no monogenic disease risk or carrier status identified. For the PGx results (18 genotypes in six genes for five drugs), the identified diplotypes prompted recommendation for non-standard dosing of at least one of the analyzed drugs in 95% of participants. For blood antigen studies, we found that 31% of participants had a rare blood antigen genotype. In the cardiomyopathy cohort, an explanation for disease was identified in 48% of individuals. Over the course of the study, 14 variants were reclassified and, upon reanalysis, 18 new variants met criteria for reporting. These findings highlight the quantity of medically relevant findings from a broad analysis of genomic sequencing data as well as the need for periodic reinterpretation and reanalysis of data for both diagnostic indications and secondary findings.

Perspectives and preferences regarding genomic secondary findings in underrepresented prenatal and pediatric populations: A mixed-methods approach.

PURPOSE: Patients undergoing clinical exome sequencing (ES) are routinely offered the option to receive secondary findings (SF). However, little is known about the views of individuals from underrepresented minority pediatric or prenatal populations regarding SF. METHODS: We explored the preferences for receiving hypothetical categories of SF (H-SF) and reasons for accepting or declining actual SF through surveying (n = 149) and/or interviewing (n = 47) 190 families undergoing pediatric or prenatal ES. RESULTS: Underrepresented minorities made up 75% of the probands. In total, 150 families (79%) accepted SF as part of their child/fetus's ES. Most families (63%) wanted all categories of H-SF. Those who declined SF as part of ES were less likely to want H-SF across all categories. Interview findings indicate that some families did not recall their SF decision. Preparing for the future was a major motivator for accepting SF, and concerns about privacy, discrimination, and psychological effect drove decliners. CONCLUSION: A notable subset of families (37%) did not want at least 1 category of H-SF, suggesting more hesitancy about receiving all available results than previously reported. The lack of recollection of SF decisions suggests a need for alternative communication approaches. Results highlight the importance of the inclusion of diverse populations in genomic research.

ORCA, a values-based decision aid for selecting additional findings from genomic sequencing in adults: Efficacy results from a randomized trial.

PURPOSE: Individuals having genomic sequencing can choose to be notified about pathogenic variants in genes unrelated to the testing indication. A decision aid can facilitate weighing one's values before making a choice about these additional results. METHODS: We conducted a randomized trial (N = 231) comparing informed values-choice congruence among adults at risk for a hereditary cancer syndrome who viewed either the Optional Results Choice Aid (ORCA) or web-based additional findings information alone. ORCA is values-focused with a low-literacy design. RESULTS: Individuals in both arms had informed values-choice congruence (75% and 73% in the decision aid and web-based groups, respectively; odds ratio [OR] = 1.10, 95% CI = 0.58-2.08). Most participants had adequate knowledge (79% and 76% in the decision aid and web-based groups, respectively; OR = 1.20, 95% CI = 0.61-2.34), with no significant difference between groups. Most had information-seeking values (97% and 98% in the decision aid and web-based groups, respectively; OR = 0.59, 95% CI = 0.10-3.61) and chose to receive additional findings. CONCLUSION: The ORCA decision aid did not significantly improve informed values-choice congruence over web-based information in this cohort of adults deciding about genomic results. Both web-based approaches may be effective for adults to decide about receiving medically actionable additional results.

ClinGen's Pediatric Actionability Working Group: Clinical actionability of secondary findings from genome-scale sequencing in children and adolescents.

PURPOSE: Synthesis and curation of evidence regarding the clinical actionability of secondary findings (SFs) from genome-scale sequencing are needed to support decision-making on reporting of these findings. To assess actionability of SFs in children and adolescents, the Clinical Genome Resource established the Pediatric Actionability Working Group (AWG). METHODS: The Pediatric AWG modified the framework of the existing Adult AWG, which included production of summary reports of actionability for genes and associated conditions and consensus actionability scores for specific outcome-intervention pairs. Modification of the adult framework for the pediatric setting included accounting for special considerations for reporting presymptomatic or predictive genetic findings in the pediatric context, such as maintaining future autonomy by not disclosing conditions not actionable until adulthood. The Pediatric AWG then applied this new framework to genes and associated conditions with putative actionability. RESULTS: As of September 2021, the Pediatric AWG applied the new framework to 70 actionability topics representing 143 genes. Reports and scores are publicly available at www.clinicalgenome.org. CONCLUSION: The Pediatric AWG continues to curate gene-condition topics and build an evidence-based resource, supporting clinical communities and decision-makers with policy development on the return of SFs in pediatric populations.