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 which 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 (CHOP). 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 secondary findings, 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 impact participant health significantly. To identify and categorize these variants, we employed a clinical-grade variant classification standard per ACMG/AMP recommendations; additionally, we conducted a detailed literature search to ensure a comprehensive exploration of potential secondary findings relevant to pediatric participants. RESULTS: We report a distinctive distribution of 1,464 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.

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.

Difficulties in disclosing secondary findings by facilities performing comprehensive germline genetic testing for rare diseases in Japan.

In Japan, a limited number of laboratories perform comprehensive genetic testing for rare diseases; this study investigated the attitudes of these laboratories toward the disclosure of secondary finding (SF). Following a preliminary survey, we identified laboratories conducting comprehensive genetic testing for participation. Subsequently, an online survey involving 20 selected facilities was conducted. The response rate was 80% (16/20). Of the 14 facilities, 71.4% had SFs. While 42.9% of them had a policy to disclose SFs with clinical utility, only 14.3% actively searched for actionable variants that could be included in the American College of Medical Genetics and Genomics list. Japan was less enthusiastic than the USA regarding SF disclosure. With regard to the reasons for not disclosing SFs, the factors "the thought that participants may have a low desire for SFs" and "uncertainty regarding their wish" were considered more important than in the USA. A content analysis of what was sought as a solution to this difficulty revealed a need to improve databases on pathogenicity and actionability and collect public thoughts on the issue. The factor "to promote entry in research" was not considered a critical reason for disclosing SFs, indicating that the thirst for information was not possibly due to anxiety but rather due to scientific interest. Japanese medical professionals may not be confident that society requires the disclosure of SFs. To improve the environment, it is necessary to survey the public regarding their thoughts on SF disclosure and discuss this issue in society.

SDHA secondary findings in germline testing: counseling and surveillance considerations.

This commentary explores the complexities faced by clinicians when encountering a secondary SDHA pathogenic variant (PV) in patients without a personal or family history of SDHA-related tumors. The increasing use of germline multi-gene panel testing has led to a rise in such secondary findings, necessitating a nuanced approach to counseling, surveillance, and decision-making. We aim to discuss the current data surrounding the penetrance of SDHA PVs, the spectrum of screening guidelines, recommendations for educating individuals and families about their secondary findings, and the need for future research to optimize care for these individuals. Practical recommendations for clinicians dealing with patients with secondary SDHA findings include acknowledging the limitations of existing guidelines, fostering shared decision-making, and considering specialist referrals. Overall, the evolving landscape of SDHA penetrance data warrants ongoing reassessment of surveillance approaches.

Parents and Provider Perspectives on the Return of Genomic Findings for Cleft Families in Africa.

BACKGROUND: Inadequate knowledge among health care providers (HCPs) and parents of affected children limits the understanding and utility of secondary genetic findings (SFs) in under-represented populations in genomics research. SFs arise from deep DNA sequencing done for research or diagnostic purposes and may burden patients and their families despite their potential health importance. This study aims to evaluate the perspective of both groups regarding SFs and their choices in the return of results from genetic testing in the context of orofacial clefts. METHODS: Using an online survey, we evaluated the experiences of 252 HCPs and 197 parents across participating cleft clinics in Ghana and Nigeria toward the return of SFs across several domains. RESULTS: Only 1.6% of the HCPs felt they had an expert understanding of when and how to incorporate genomic medicine into practice, while 50.0% agreed that all SFs should be returned to patients. About 95.4% of parents were willing to receive all the information from genetic testing (including SFs), while the majority cited physicians as their primary information source (64%). CONCLUSIONS: Overall, parents and providers were aware that genetic testing could help in the clinical management of diseases. However, they cited a lack of knowledge about genomic medicine, uncertain clinical utility, and lack of available learning resources as barriers. The knowledge gained from this study will assist with developing guidelines and policies to guide providers on the return of SFs in sub-Saharan Africa and across the continent.

Whole exome sequencing approach for identification of the molecular etiology in pediatric patients with hematuria.

BACKGROUND: Hematuria is a common condition in clinical practice of pediatric patients. It is related to a wide spectrum of disorders and has high heterogeneity both clinically and genetically, which contributes to challenges of diagnosis and lead many pediatric patients with hematuria not to receive accurate diagnosis and early management. METHODS: In this single center study, 42 children with hematuria were included in Tianjin Children's Hospital between 2019 and 2020. We analyzed the clinical information and performed WES (Whole exome sequencing) for all cases. Then the classification of identified variants was performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines for interpreting sequence variants. For the fragment deletion, qPCR was performed to validate and confirm the inherited pattern. RESULTS: For the 42 patients, 16 cases had gross hematuria and 26 had microscopic hematuria. Molecular genetic causes were uncovered in 9 (21.4%) children, including 7 with Alport syndrome (AS), one with polycystic nephropathy and one with lipoprotein glomerulopathy. The genetic causes for other patients were not related with hematuria. CONCLUSIONS: WES is a rapid and effective way to evaluate patients with hematuria. The analysis of genotype-phenotype correlations of patients with AS indicated that severe variants were associated with early kidney failure. Secondary findings were not rare in Chinese children, thus the clinician should pay more attention to the clinical interpretation of sequencing results and properly interaction with patients and their family.

Prenatal Exome Sequencing Analysis in Fetuses with Various Ultrasound Findings.

OBJECTIVES: To evaluate the use of Exome Sequencing (ES) for the detection of genome-wide Copy Number Variants (CNVs) and the frequency of SNVs-InDels in selected genes related to developmental disorders in a cohort of consecutive pregnancies undergoing invasive diagnostic procedures for minor or simple ultrasound findings with no indication of ES. METHODS: Women undergoing invasive diagnostic testing (chorionic villus sampling or amniocentesis) for QF-PCR and chromosomal microarray analysis (CMA) due to prenatal ultrasound findings without an indication for ES were selected over a five-month period (May-September 2021). ES was performed to compare the efficiency of genome-wide CNV detection against CMA analysis and to detect monogenic disorders. Virtual gene panels were selected to target genes related to ultrasound findings and bioinformatic analysis was performed, prioritizing variants based on the corresponding HPO terms. The broad Fetal Gene panel for developmental disorders developed by the PAGE group was also included in the analysis. RESULTS: A total of 59 out of 61 women consented to participate in this study. There were 36 isolated major fetal anomalies, 11 aneuploidy markers, 6 minor fetal anomalies, 4 multiple anomalies, and 2 other ultrasound signs. Following QF-PCR analysis, two uncultured samples were excluded from this study, and six (10%) common chromosome aneuploidies were detected. In the remaining 51 cases, no pathogenic CNVs were detected at CMA, nor were any pathogenic variants observed in gene panels only targeting the ultrasound indications. Two (3.9%) monogenic diseases, apparently unrelated to the fetal phenotype, were detected: blepharo-cheilo-odontic syndrome (spina bifida) and Duchenne muscular dystrophy (pyelocaliceal dilation). CONCLUSIONS: In our series of pregnancies with ultrasound findings, common aneuploidies were the only chromosomal abnormalities present, which were detected in 10% of cases. ES CNV analysis was concordant with CMA results in all cases. No additional findings were provided by only targeting selected genes based on ultrasound findings. Broadening the analysis to a larger number of genes involved in fetal developmental disorders revealed monogenic diseases in 3.9% of cases, which, although apparently not directly related to the indications, were clinically relevant.

Hallazgos incidentales en medicina genómica / Incidental Findings in Genomic Medicine

Las técnicas de Biología Molecular de última generación, como es la secuenciación masiva en paralelo o NGS (Next Generation Sequencing), permite obtener gran cantidad de información genómica, la cual muchas veces va más allá de la detección de una variante patogénica en un gen que explique la patología (hallazgo primario). Es así como surgió desde hace años la discusión internacional respecto a la decisión a tomar frente a los hallazgos secundarios accionables, es decir, aquellos hallazgos de variantes clasificadas como patogénicas o probablemente patogénicas que no están relacionadas con el fenotipo del paciente, pero que tiene alguna medida preventiva o tratamiento posible y, por lo tanto, podría ser de utilidad para la salud del paciente. Luego de revisar la bibliografía internacional y debatir entre los expertos del Hospital de Pediatría Garrahan, se logró establecer una política institucional y reforzar el hecho de que se trata de una disciplina multidisciplinaria. Así, fue posible definir que solo se atenderá las cuestiones relacionadas con la edad pediátrica, dejando para un tratamiento posterior aquellas variantes detectadas en genes que sean accionables en edad adulta. En el Hospital Garrahan, ha sido posible definir claramente cómo proceder frente a los hallazgos secundarios, al adaptar el consentimiento informado a esta necesidad, definiendo cuándo serán informados, y sabiendo que serán buscados intencionalmente en los genes clínicamente accionables enlistados en la última publicación del American College of Medical Genetics and Genomics, siempre y cuando el paciente/padre/tutor lo consienta (AU)

The latest generation of molecular biology techniques, including massive parallel sequencing or NGS (Next Generation Sequencing), allows us to obtain a whealth of genomic information, which often goes beyond the detection of a pathogenic variant in a gene that explains the pathology (primary finding). As a result, an international discussion has arisen over the years regarding the decision-making concerning actionable secondary findings, it means, those findings of variants classified as pathogenic or probably pathogenic that are not related to the patient's phenotype, but which have some possible preventive measure or treatment and, therefore, could be useful for the patient's health. After reviewing the international literature and discussing among the experts of the Hospital de Pediatría Garrahan, an institutional policy was established and the concept that this is a multidisciplinary discipline was reinforced. Consequently, it has been defined that only issues related to children will be addressed, reserving those variants detected in genes that are actionable in adulthood for later treatment. At Garrahan Hospital, we were able to clearly define how to proceed with secondary findings by adapting the informed consent to this need, defining when they will be reported, and knowing that they will be intentionally searched for in the clinically actionable genes listed in the latest publication of the American College of Medical Genetics and Genomics, as long as the patient/parent/guardian consents (AU)