069a2242be027b7bea0e7bb7e331c1ce jmg-2022-108929.R1_1.pdf.pdf f86b946cbfd650c3274214e51bab1e1c94b09ede jmg-2022-108929.R1_1.pdf.pdf bdc907295126d36e7113eb53f9c6793bed7e1a8e9a87188bb3829984aa9c168d jmg-2022-108929.R1_1.pdf.pdf Title: jmg-2022-108929.R1 (1).pdf Keywords: DAHNJOszkek,BAFE50m_4bA,0 Author: On Psicologia SCP J65847113 Creator: Canva Producer: Canva CreationDate: Sat Jun 20 22:48:35 2026 CEST ModDate: Tue Jun 23 14:39:48 2026 CEST Custom Metadata: no Metadata Stream: yes Tagged: yes UserProperties: no Suspects: no Form: none JavaScript: no Pages: 39 Encrypted: no Page size: 612 x 792 pts (letter) Page rot: 0 File size: 3596082 bytes Optimized: yes PDF version: 1.4 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- AAAAAA+Verdana-Bold CID TrueType Identity-H yes yes yes 1748 0 BAAAAA+Verdana CID TrueType Identity-H yes yes yes 1750 0 CAAAAA+Verdana-Italic CID TrueType Identity-H yes yes yes 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BAAAAA+Calibri-Bold CID TrueType Identity-H yes yes yes 1046 0 CAAAAA+Calibri-Italic CID TrueType Identity-H yes yes yes 1038 0 DAAAAA+IBMPlexSansCond CID TrueType Identity-H yes yes yes 1058 0 AAAAAA+Calibri CID TrueType Identity-H yes yes yes 1067 0 BAAAAA+Calibri-Bold CID TrueType Identity-H yes yes yes 1074 0 CAAAAA+Calibri-Italic CID TrueType Identity-H yes yes yes 1077 0 DAAAAA+IBMPlexSansCond CID TrueType Identity-H yes yes yes 1062 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-06-24 04:13:26 CEST RepresentationInformation: jmg-2022-108929.R1_1.pdf.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-06-23 14:40:14 CEST Size: 3596082 Format: PDF Version: 1.4 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf Profile: Linearized PDF, Tagged PDF PDFMetadata: Objects: 1791 FreeObjects: 1 IncrementalUpdates: 1 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: false CenterWindow: false DisplayDocTitle: true NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Language: es-ES Outlines: Item: Title: Journal of Medical Genetics Destination: 1 Item: Title: Clinical and psychological implications of secondary and incidental findings in cancer susceptibility genes after exome sequencing in patients with rare disorders Destination: 1 Children: Item: Title: https://mc.manuscriptcentral.com/jmedgenet Destination: 1 Item: Title: Page 1 of 36 Destination: 1 Item: Title: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Destination: 1 Item: Title: Journal of Medical Genetics Destination: 1 Item: Title: https://mc.manuscriptcentral.com/jmedgenet Destination: 1 Item: Title: Clinical and psychological implications of secondary and incidental findings susceptibility genes after exome sequencing in patients with rare disorders Destination: 1 Item: Title: in cancer Destination: 1 Children: Item: Title: E.Carrasco1,2,3, A.López-Fernández1,2, M.Codina4; I.Valenzuela4, A.M.Cueto-González4, G.Villacampa5, V.Navarro5, S.Torres-Esquius1,2, D.Palau4 M.Cruellas1, M.Torres1, B.Pérez- Dueñas6, A.Abulí4, O.Díez7, C.Sábado8, E.Garcia-Arumí4, E.F.Tizzano4, L.Moreno8,9, J. Balmaña1,2 Destination: 1 Item: Title: Affiliation: 1Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Spain, 2Medical Oncology Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 3Department of Pediatrics, Obstetrics, Gynecology, Preventative Medicine and Public Health. Universitat Autònoma de Barcelona, Barcelona, Spain; 4Genetics Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 5Oncology Data Science (ODysSey) Group, VHIO, Spain 6Neuropediatrics Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 7Department of Clinical and Molecular Genetics, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 8Pediatrics Oncology and Hematology Division, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 9Childhoood Cancer and Blood Disorders Group, Vall d’Hebron Institute of Research, Destination: 1 Item: Title: Corresponding author: Dr. Lucas Moreno, MD, PhD Head, Division of Pediatric Oncology and Hematology, Hospital Universitari Vall d’Hebron Vall d’Hebron Institute of Research Passeig de la Vall d’Hebron 119 08035 Barcelona (Spain) Destination: 1 Item: Title: Abstract Destination: 1 Children: Item: Title: Background/Objectives Exome sequencing may identify pathogenic variants unrelated with the purpose of the analysis. We investigated the frequency of secondary and incidental findings (SF/IF) in cancer susceptibility genes (CSG), their clinical actionability, and the psychological impact in individuals with an SF/IF (cases) compared with individuals tested due to their cancer history (controls). Methods 533 exomes ordered for non-cancer conditions. Medical records were reviewed for clinical actionability of SF/IF. Psychological impact was analyzed with the MICRA scale and compared between cases and controls with a propensity score weighting method. Destination: 1 Item: Title: Results The frequency of SF/IF in CSG was 2.1% (95% CI 1.1% - 3.8%): three BRCA2, three PMS2, two SDHB, and one each in BRCA1, MLH1, and RAD51C. Among relatives, 18 were carriers. Twenty enrolled for surveillance, and a neoplasm was diagnosed in 20%: three paragangliomas and one breast cancer. Cases presented higher MICRA mean scores than controls (21.3 versus 16.2 in MICRA total score, 6.3 versus 4.2 in distress subscale, and 8.3 versus 6.6 in uncertainty subscale; all p <0.001). Destination: 1 Item: Title: Conclusion SF/IF in CSG were identified in 2.1% of patients. Despite a numerically higher psychological impact, the identification of SF/IF allowed early detection and cancer prevention in families without cancer history. Destination: 1 Children: Item: Title: Key Words: genetic testing, genetics, medical, disease management, genetic predisposition to disease, genetic counseling- Destination: 1 Item: Title: SUMMARY BOX Destination: 1 Children: Item: Title: What is already known on this topic   summarise the state of scientific knowledge on this subject before you did your study and why this study needed to be done Destination: 1 Item: Title: The impact of disclosing a secondary/incidental finding in a cancer susceptibility gene after genomic analyses seems to be low. Nevertheless, the impact of these findings in families of pediatric patients undergoing genomic analysis for non-oncological conditions is still Destination: 1 Item: Title: largely unknown Destination: 1 Item: Title: What thisstudyadds Destination: 1 Children: Item: Title: know before Destination: 1 Item: Title:   summarise what we now know as a result of this study that we did not Destination: 1 Item: Title: This is the first case control study comparing the psychological impact of secondary/incidental findings in cancer susceptibility genes. We demonstrate a high clinical actionability for cancer surveillance in carriers, despite a numerically higher psychological impact compared to carriers identified due to their family history of cancer. Destination: 1 Item: Title: How this study might affect research, practice or policy   study Destination: 1 Item: Title: summarise the implications of this Destination: 1 Item: Title: It provides evidence to support the need of genetic counseling to help coping with secondary/incidental findings and it warrants further research on new genetic delivery models to lessen the psychological impact of secondary findings. Destination: 1 Item: Title: Words 2996; 3 figures; 4 Supplementary tables INTRODUCTION Exome sequencing is a next generation sequencing tool currently used in patients with suspected rare genetic conditions. In individuals with a clinical history of developmental delay or intellectual disability exome sequencing has become a routine testing practice and it is also used as one of the first-tier diagnostic test in disorders with an unclear phenotype[1],[2,3]. Although exome and genome sequencing might be useful to identify genetic alterations in individuals with rare diseases, it is relevant to highlight that these techniques may also identify unexpected variants not related with the purpose of the primary analysis and they may come as a surprise for clinicians, patients and their families. One of the paradigmatic examples is the identification of pathogenic variants in cancer susceptibility genes (CSG). Destination: 1 Item: Title: An issue of debate in the medical genetics community is whether and how this unintended information should be reported to the patient and/or family. Recently, several international scientific societies have published a policy statement for managing SF/IF. While the European Society of Human Genetics (ESHG)[4,5] recommended that genetic analysis should be restricted to the first purpose and follow a cautious approach in regards to opportunistic screening, other societies like the French Society[6], the 100,000 Genomes Project Protocol[7], the British Society of Genomic Medicine, and the American College of Medical Genetics[8,9] (ACMG) have published different lists of genes, mainly comprising hereditary cardiopathies genes and CSG, for which it is recommended to report the secondary findings (SF). According to ACMG[8], incidental findings (IF) comprise those variants found unexpectedly, while secondary findings (SF) include Destination: 1 Item: Title: those identified in genes that were analyzed intentionally, despite not being related to the primary indication. Destination: 1 Item: Title: Little is known about the clinical and psychological impact of SF/IF on CSG in patients and their families. The main concerns comprise the potential harm derived from the uncertain penetrance in the absence of a family history, and the psychological distress resulting from identifying genetic alterations that are not the targets of the genetic study. Destination: 1 Item: Title: In this study, our main objective was to describe the clinical actionability and the psychological impact of SF/IF disclosure in CSG in patients and their relatives. Specifically, we aimed to: 1) evaluate the frequency of pathogenic variants in CSG as SF/IF among a cohort of patients Destination: 1 Item: Title: undergoing clinical exome sequencing testing for a non-cancer condition, 2) analyze the uptake of predictive testing among family members, the adherence to screening and prevention recommendations, and the output of surveillance programs, and 3) compare the psychological impact of identifying pathogenic variants in CSG as SF/IF versus their identification in individuals with a cancer family history. Destination: 1 Item: Title: METHODS Destination: 1 Children: Item: Title: Study design Retrospective analysis of exome sequencing results ordered in 533 patients in the Department of Clinical and Molecular Genetics at University Hospital Vall d´Hebron, a tertiary care hospital, from January 1, 2018 to September 30, 2020. The psychological impact was analyzed with the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale[10,11] within a case-control study design. Cases involved those individuals who were carriers of a SF/IF identified through exome sequencing, as well as their relatives, in the absence of any cancer history (n=53). Controls (n=576) were identified among individuals undergoing CSG testing due to personal or family history of cancer. Family history was designated as positive when there were first or second-degree relatives with a type of cancer associated to the CSG identified in the family Destination: 1 Item: Title: Genetic testing and counseling Destination: 1 Children: Item: Title: Exome sequencing studies were ordered by health professionals of the Department of Clinical and Molecular Genetics to identify genetic causes for intellectual disability or congenital malformation, or to confirm a clinical suspicion of a syndrome not associated to cancer. Patients or their parents/guardians signed an informed consent and specified whether they opted-in to be disclosed SF(s). The IF was discussed in a multidisciplinary committee, which evaluated whether it should be disclosed based upon their penetrance and clinical actionability. Clinical recommendations for surveillance considered the overall health status of the carrier. A SF related to CSG was defined as the identification of a pathogenic or likely pathogenic variant in a CSG listed by ACMG (ACMG SF V2.0)[8]. Cancer-associated genes with clinical actionability beyond this list were listed as IF. Variant interpretation was based on the ACMG guidelines[12]. The sequencing methodology is reported as supplementary material. Destination: 1 Item: Title: All participants underwent pre and post-test counseling with a board-certified genetic counselor. The project was approved by the local IRB. Study Measurements Clinical actionability of SF/IF was assessed by a review of the electronic medical records of thosecarriers in whom surveillance had been indicated, from the date that their result was disclosed until December 2021. The psychological impact was assessed by the Spanish version of the MICRA scale, which is a validated tool to measure the specific impact of result disclosure after genetic testing. The MICRA scale includes 25-items measuring general and cancer-specific distress, and it includes three main subscales: Distress (range 0-30) evaluates feeling upset, sadness, guilt, problems with enjoying life, and loss of control; Uncertainty (range 0-45) evaluates difficulties in making decisions, family conflict, and frustration; and the Positive Experiences Destination: 1 Item: Title: subscale (range 0-20) evaluates relief, happiness and family communication. Carriers of a variant of uncertain significance, were excluded from the analysis of psychological impact. Satisfaction with the genetic counseling process, as well as the perceived feeling of regret for having disclosed an unexpected genetic finding were evaluated with three five Likert-type questions, with answers ranging from 0-10, or yes/no. Psychological impact and satisfaction with the genetic counseling process were analyzed at 3 months after results disclosure. Psychological impact was compared with a historical control population of individuals undergoing CSG testing due to their personal or family history at 3 months after results disclosure Statistical analysis Destination: 1 Item: Title: The Mann Whitney Wilcoxon test was used to assess differences between cases and controls for the different MICRA sub-scales. Standardized difference was used to study the associations of clinical characteristics and MICRA results between cases and controls. The propensity score Destination: 1 Children: Item: Title: weighting method was used to adjust for the imbalance in prognostic factors between cases and controls. We used ATT (average treatment effect among the treated method) to estimate the weights. The variables used for weighting the propensity scores were gender, age, study level, panel/exome or single pathogenic variant, positive or negative result. According to this approach, controls who were more similar to cases were those who had more influence in the analysis. Linear regression was used in order to evaluate which psychological impact (MICRA scale) variables had more impact in cases or controls. Statistical analyses were performed with R version 4.1.1. Destination: 1 Item: Title: RESULTS Frequency of secondary findings in cancer susceptibility genes Destination: 1 Children: Item: Title: Exome sequencing had been ordered in 582 individuals in the Clinical and Molecular Genetics Destination: 1 Item: Title: Department of our institution. Exome testing had been performed during the prenatal period (n=6), the postnatal period (n=494), or shortly after pregnancy termination (n=33). A total of 8% (49/582) of the index cases opted-out to the disclosure of a SF/IF (Figure 1, CONSORT diagram). Overall, 11 index cases (IC) were found to carry a pathogenic variant in a CSG, which results in a 2.1% (95% CI 1.1% - 3.8%) frequency (11/533). Ten SF belonged to the ACMG V2.0 genes list, distributed among six genes   three in BRCA2, three in PMS2, two in SDHB, one in BRCA1, and one in MLH1. One IF was identified in the RAD51C gene. Eight cases (73%) were children, two were young adults with intellectual disability, and one was an adult (Table S1). Two index cases had a family history of breast cancer Predictive genetic testing among relatives Destination: 1 Item: Title: Predictive genetic testing was performed in 42 relatives of the 11 index cases (Table S1). The median age was 47 years-old (range 6-78), with a 50% gender distribution. Among them, 23, 9 Destination: 1 Item: Title: and 10 (54%, 22% and 24%) were first, second and third degree relatives, pathogenic variant was identified in 18 (43%) relatives. Destination: 1 Item: Title: respectively. A Destination: 1 Item: Title: Clinical actionability in individuals with a pathogenic variant in a CSG Destination: 1 Children: Item: Title: Overall, there were 29 carriers of a pathogenic variant in a CSG identified as SF/IF (11 index cases and 18 relatives), of which 20 enrolled in a cancer surveillance program and nine were excluded because of their age (Table S2). The Median time of surveillance was 24 months (range 12-30). Among the seven SDHB carriers, three (43%) had a paraganglioma that was diagnosed after genetic testing. A middle childhood 6   11 years SDHB male carrier was diagnosed with a multisite para-aortic paraganglioma in his first imaging screening and two women were diagnosed with a localized paraganglioma between the ages 40 and 60. There were seven BRCA2 carriers (four men Destination: 1 Item: Title: and three women). Among them, an early 70s woman who had ended the population-based breast cancer screening was diagnosed with a localized breast cancer after her initial imaging screening post genetic testing. Two other women underwent prophylactic salpingo-oophorectomy. One male with metastatic prostate cancer was candidate for targeted therapy with a PARP inhibitor after the identification of a BRCA2 pathogenic variant. A woman with a pathogenic variant in the RAD51C gene underwent a prophylactic salpingo-oophorectomy. Among the three PMS2 carriers, two had a negative colonoscopy, and one had two colonic adenomatous polyps removed. Destination: 1 Item: Title: Psychological impact Destination: 1 Children: Item: Title: Within all cases (n=53), a total of 19 participants were excluded for this analysis (seven were younger than 16 years old, three had intellectual disability, one had a psychiatric disorder, one was a non- Spanish speaker and seven underwent genetic testing after the cut-off date). Among the 34 Destination: 1 Item: Title: participants who were contacted to participate in this sub-study, 32 answered the MICRA scale (94%) (Figure 1). In all but one case the questionnaire was answered before their cancer diagnosis. The MICRA scale had previously been completed in the control population by 573 individuals Destination: 1 Item: Title: Comparison of the psychological impact with the MICRA scale between cases and controls Destination: 1 Children: Item: Title: There were some significant differences in clinical characteristics between cases and controls (Table S3). Among the control population, the frequency of females was higher (73% vs 56%), the educational level was higher (67% vs 56%), the median age was older (median age 48 vs 46,5 years), and the proportion of carriers was 29% and 41%, respectively. The propensity model adjusted for these differences (Table S3). The comparison between the MICRA scale scores in cases (n=32) and controls (n=573) is shown Destination: 1 Item: Title: in Figure 2 and Table S4. The mean ± SD in the total MICRA was 21.18±14.30 in cases vs 16.18±12.54 in controls (p=0.001), in the distress subscale the mean ± SD was 6.31±7.26 vs 4.16±5.31 (p=0.001), and in the uncertainty subscale the mean ± SD was 8.31±7.16 vs 6.58±6.32 (p=0.001). The positive experience score was higher in controls than in cases (14.74±5.18 vs 13.81±4.82, p=0.001). In the univariable linear regression (Figure 3), cases maintained higher scores in the total MICRA and each of the negative feeling subscales; however, no differences were observed in the score of the positive experiences’ subscale. Following the propensity score model, cases scored statistically significant higher values in the total MICRA scale (5.21 points above the mean of the controls), uncertainty (2.69 points above the mean of the controls) and distress (3.46 points above the mean of the controls) subscales. However, in the positive experience subscale the score was similar in both groups. Destination: 1 Item: Title: DISCUSSION Destination: 1 Children: Item: Title: In the present study, the analysis of 533 exomes ordered for non-oncological diagnoses yielded a 2% cancer-related SF/IF. These findings led to 20 individuals enrolling in a cancer surveillance program, which prompted a cancer diagnosis in 20% of them in the first round. Overall, the psychological impact of SF/IF disclosure was not clinically relevant, although the scores were significantly higher in individuals receiving a SF/IF than in individuals receiving similar genetic results within a family with cancer history. In this study, there was a 92% rate of acceptance for disclosure of SF/IF. This high rate highlights the importance of developing adequate delivery models of SF/IF disclosure to guarantee that those results turn into useful actions for the patients and their family members. The American College Destination: 1 Item: Title: of Medical Genetics (ACMG) recommend offering participants an informed consent process and the option to opt out of SF/IF´s disclosure[8]. Interestingly, in our study only 8% of the participants (or their legal representatives) chose to opt out for this type of disclosure, a slightly lower figure compared to a prior USA study that reported a non-acceptance in 17% of pediatric cases[13]. The 2% frequency of SF/IF in CSG in our study is in line with the frequency reported in other studies [14,15]. More specifically, the frequency of SF in a CSG was reported to range between 0.8% to 1.3%, mainly in the BRCA1/2 genes[15,16]. We also found that pathogenic variants in BRCA1/2 were the most frequent SF. In our study, we extended the genetic testing to blood relatives at risk to promote surveillance and prevention options among potential carriers. Cascade testing was successfully performed in 42 relatives older than 16 years, apart from a family with an SDHB pathogenic variant, in whom genetic testing was also recommended for minors. Eighteen carriers of a pathogenic variant in a CSG among relatives of the index case were diagnosed. Most of the CSG conferred an increased Destination: 1 Item: Title: risk of cancer in adulthood, except for one child with an SDHB pathogenic variant in whom a metastatic paraganglioma was diagnosed in his first round. In all cases the predictive cascade testing arrived to first degree relatives, in 55% families to second degree relatives, and in 45% to third degree relatives. We highlight that there are members of the same families in both cases and controls. It seems reasonable to hypothesize that these SF/IF findings might have a detrimental psychological impact on patients and their relatives[17,18]. One of the concerns raised among healthcare professionals is whether individuals who carry a pathogenic variant in a CSG without cancer family history may underestimate the susceptibility to develop cancer and consequently may not adhere to surveillance recommendations. However, in our study population, all carriers adhered to the follow-up. Destination: 1 Item: Title: Only two index cases had a familial history of cancer (not related with the pathogenic variant identified), and cancer surveillance recommendations were offered to 20 carriers. Surprisingly, four of them were diagnosed with a tumor in their first round. The tumor diagnoses were detected in three SDHB carriers and in one carrier of a BRCA2 pathogenic variant. Interestingly, none of these individuals were participating in a cancer surveillance program before undergoing the genetic testing. Focusing on the psychological impact after disclosure of SF/IF, some groups have reported a low impact after receiving these findings. In an Icelandic study led by deCODE Genetics[19], participants had the opportunity to receive information about the founder pathogenic variant in the BRCA2 gene. Little worries and anxiety were detected, and gratitude for the knowledge gained was reported by carriers. It may be the case that participants with no family history minimize their risk of developing cancer and are less worried[20]. However, in our study the total MICRA score, Destination: 1 Children: Item: Title: the uncertainty and the distress after the genetic result were higher in those individuals in whom a SF/IF was identified compared to those from the control group, in whom a family history of cancer Destination: 1 Item: Title: such as upset, sadness, guilt, indecision and frustration could be more frequently found in cases with unexpected cancer genetic findings in whom the genetic result is less expected and who are living within a rare disease. The psychological impact after cancer panel testing has largely been analyzed in several cancer cohorts[21 23]. Overall, the psychological impact is higher than in controls, but it is not Destination: 1 Item: Title: was triggering the genetic analyses. Feelings Destination: 1 Item: Title: Genetic counselors and geneticists should be cautious when conveying this information in the pre-test and post-test. This reinforces the need to guarantee genetic counseling in complex genetic analyses. Given the increased psychological impact of SF/IF reporting in non-cancer families, future Destination: 1 Item: Title: detrimental. Destination: 1 Item: Title: research should focus on developing strategies to minimise the impact of such results. It is crucial to emphasize the opt in/opt out decision of being disclosed SF/IF during the informed consent process in order to promote individual’s autonomy and provide an adequate counseling framework to enhance the understanding of the implications of SF/IF detection in index cases and healthy relatives. Destination: 1 Item: Title: LIMITATIONS Destination: 1 Children: Item: Title: Some limitations of our study include: 1) Despite the size differences between two groups, we minimized this with the propensity weighting score model were those controls which were more similar to cases had higher weight in the statistical analysis. Moreover, both cases and controls could be members of the same families so this bias was present. In both groups. Althoug we mitigated imbalance in prognostic factors between cases and controls with the use of the propensity Destination: 1 Item: Title: score weighting method, there is still some imbalance between both groups that might impact the results; 2) the 3-month post disclosure follow-up for all participants might not provide sufficient time to manifest some of the psychosocial outcomes, despite our prior data suggests that psychological impact measured by MICRA does not change between 3- and 12-month post disclosure; 3) as primary and secondary findings were reported simultaneously, the distinction between them might not have been fully clear among study participants and thus generate a mixed impact in the MICRA score; 4) the number of cases was relatively small and this did not allow to provide precise estimations in this group. Destination: 1 Item: Title: CONCLUSION Destination: 1 Children: Item: Title: The frequency of SF/IF in CSG was 2% in a large cohort of patients undergoing genetic testing Destination: 1 Item: Title: due to non-oncological conditions without cancer family history. The identification of SF/IF after exome sequencing leads to the recognition of unaffected carriers at risk of developing cancer, with a high actionability as shown in our work. This demonstrates the importance of cascade testing in relatives. Our findings indicate that the participants who receive a SF/IF in CSG after exome sequencing have a numerically higher distress and uncertainty compared with those who undergo genetic testing due to a family history of cancer. Our study offers substantial insight for other clinicians who will need to address secondary findings and provide adequate genetic counseling. It also emphasizes the importance of the potential psychological effects of expanded genetic testing. Destination: 1 Item: Title: DATA AVAILABILITY Destination: 1 Children: Item: Title: All data and methods used in the analysis are described or included in this article and in the electronic supplementary information. Raw data is available upon request. Destination: 1 Item: Title: ACKNOWLEDGMENTS Destination: 1 Children: Item: Title: We want to acknowledge all patients and their families participating in the study. This work has been carried out within the framework of the Doctorate Program of Pediatrics, Obstetrics and Gynecology of Universitat Autònoma de Barcelona. Destination: 1 Item: Title: COMPETING INTEREST Destination: 1 Children: Item: Title: J.B has received a speaker’s fee from AstraZeneca and Pfizer and has served AstraZeneca in an Destination: 1 Item: Title: advisory role; G.V has received a speaker’s fee from MSD and Pierre Fabre and has served AstraZeneca in an advisory role. L.M. is member of data monitoring committees for clinical trials sponsored by Novartis, Actuate Therapeutics, Shionogi, Incyte, the University of Southampton and the Royal Marsden NHS Foundation Trust; had a consulting role for Novartis, Norgine, Boehringer, Ymabs and Shionogi and participated in educational activities organized by Bayer and Eusa Pharma. L.M. is member of the Executive Committee of SIOPEN (European neuroblastoma research cooperative group), an organization which receives royalties for the sales of dinutuximab beta. EFT has received grant support to conduct clinical trials on SMA from Ionis/Biogen and serves as a consultant to Biogen, Novartis,AveXis, Roche, Biologix, and Cytokinetics. GV has received research honoraria for speakers bureau from MSD and Pierre Fabrer and advisory role from Astrazeneca The other authors declare no conflict of interest. Destination: 1 Item: Title: FUNDINGS Destination: 1 Children: Item: Title: We have not received any funding for this work Destination: 1 Item: Title: ETHICS DECLARATION Destination: 1 Children: Item: Title: This study was reviewed by the Institutional Review Board of our institution. All individuals participating in the study or their parents/legal representatives signed the informed consent approved by the Institutional Review Board. Destination: 1 Item: Title: CONTRIBUTORSHIP STATEMENT Destination: 1 Children: Item: Title: Conceptualization: E.C., J.B., L.M.; Data curation: E.C., S.T, MC, IV AMC, DP, AA; Formal Analysis: G.V., V.N., E.C..; Funding acquisition: J.B; Investigation: E.C., J.B., L.M.; Methodology: E.C., J.B., L.M., G.V., V.N.; Project administration: E.C.; Resources: A.D., S.T, M.C; C.S, O.D, D.P, A.C, I.V, B.P, E.FT, M.T, E.GA, Genetica.; Software: S.T.; G.V.; V.N;Supervision: J.B., L.M.; EGA, EFT;Validation: E.C., J.B., L.M.; Visualization: E.C., G.V; Destination: 1 Item: Title: Writing: E.C; V.N; J.B; L.M.; ALF ;Writing review & editing: All authors . Destination: 1 Item: Title: REFERENCES Destination: 1 Children: Item: Title: 1 2 3 Destination: 1 Item: Title: Retterer K, Juusola J, Cho MT, et al. Original Research Article Clinical application of whole-exome sequencing across clinical indications. Genet Med 2015;:1 9. Manolio TA, Chisholm RL, Ozenberger B, et al. 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Impacto psic漀氀最椀挀漀 搀攀氀 䌀漀渀猀攀樀漀 最攀渀琀椀挀漀 瘀愀氀漀爀愀搀漀 瀀漀爀 攀氀 挀甀攀猀琀椀漀渀愀爀椀漀 搀攀 攀瘀愀氀甀愀挀椀渀 洀甀氀琀椀搀椀洀攀渀猀椀漀渀愀氀 搀攀氀 椀洀瀀愀挀琀漀 搀攀 爀椀攀猀最漀 搀攀 挀渀挀攀爀  䴀椀挀爀愀⸀ 䔀猀琀甀搀椀漀 搀攀 氀愀猀 瀀爀漀瀀椀攀搀愀搀攀猀 瀀猀椀挀漀洀琀爀椀挀愀猀 搀攀氀 䴀椀挀爀愀⸀ 倀猀椀挀漀漀渀挀漀氀漀最椀愀 ㈀　㄀㄀㬀㠀㨀㄀㈀㔠ጀ 㐀㈀⸀  刀椀挀栀愀爀搀猀 匀Ⰰ 䄀稀椀稀 一Ⰰ 䈀愀氀攀 匀Ⰰ 攀琀 愀氀⸀ 匀琀愀渀搀愀爀搀猀 愀渀搀 最甀椀搀攀氀椀渀攀猀 昀漀爀 琀栀攀 椀渀琀攀爀瀀爀攀琀愀琀椀漀渀 漀昀 猀攀焀甀攀渀挀攀 瘀愀爀椀愀渀琀猀㨀 䄀 樀漀椀渀琀 挀漀渀猀攀渀猀甀猀 爀攀挀漀洀洀攀渀搀愀琀椀漀渀 漀昀 琀栀攀 䄀洀攀爀椀挀愀渀 䌀漀氀氀攀最攀 漀昀  edical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–24. Swanson K, Sparks TN, Lian漀最氀漀甀 䈀刀Ⰰ 攀琀 愀氀⸀ 倀爀攀昀攀爀攀渀挀攀 昀漀爀 猀攀挀漀渀搀愀爀礀 昀椀渀搀椀渀最猀 椀渀  瀀爀攀渀愀琀愀氀 愀渀搀 瀀攀搀椀愀琀爀椀挀 攀砀漀洀攀 猀攀焀甀攀渀挀椀渀最⸀ 倀爀攀渀愀琀 䐀椀愀最渀 倀甀戀氀椀猀栀攀搀 伀渀氀椀渀攀 䘀rst: 2021. Ragan Hart M, Biesecker BB, Blout CL, et al. Secondary findings from clinical genomic sequencing: prevalence, patien琀 瀀攀爀猀瀀攀挀琀椀瘀攀猀Ⰰ 昀愀洀椀氀礀 栀椀猀琀漀爀礀 愀猀猀攀猀猀洀攀渀琀Ⰰ 愀渀搀 栀攀愀氀琀栀ⴀ挀愀爀攀 挀漀猀琀猀 昀爀漀洀 愀 洀甀氀琀椀猀椀琀攀 猀琀甀搀礀⸀ 䜀攀渀攀琀 䴀攀搀 ㈀　㄀㤀㬀㈀㄀㔀㨀㄀㄀　〠ጀ㄀　⸀  䜀漀爀搀漀渀AS, Zouk H, Venner E, et al. Frequency of genomic secondary findings among 21,915 eMERGE network participants. Genet Med 2020;2㈀㨀㄀㐀㜀〠ጀ㜀⸀  䬀椀洀 䨀Ⰰ 䰀甀漀 圀Ⰰ 圀愀渀最 䴀Ⰰ 攀琀 愀氀⸀ 倀爀攀瘀愀氀攀渀挀攀 漀昀 瀀愀琀栀漀最攀渀椀挀⼀氀椀欀攀氀礀 瀀愀琀栀漀最攀渀椀挀 瘀愀爀椀愀渀琀猀 椀渀 琀栀攀 ㈀㐀 挀愀渀挀攀爀 最攀渀攀猀 漀昀 琀栀攀 䄀䌀䴀䜀 econdary Findings v2.0 list in a large cancer cohort and ethnicity-matched controls. Destination: 1 Item: Title: 13 14 Destination: 1 Item: Title: 15 16 Destination: 1 Item: Title: 17 18 Destination: 1 Item: Title: 20 21 Destination: 1 Item: Title: 22 23 Destination: 1 Item: Title: Sapp JC, Dong D, Stark C, et al. Parental attitudes, values, and beliefs toward the return of results from exome sequencing in children. Clin Genet 2014;85:120 6. Krabbenborg L, Vissers LELM, Schieving J, et al. Understanding the Psychosocial Effects of WES Test Results on Parents of Children with Rare Diseases. J Genet Couns 2016;25:1207 14. Stefansdottir V, Thorolfsdottir E, Hognason HB, et al. Web-based return of BRCA2 research results: one-year genetic counselling experience in Iceland. Eur J Hum Genet Published Online First: 2020. Lewis KL, Hooker GW, Connors PD, et al. Participant use and communication of findings from exome sequencing: a mixed-methods study. Published Online First: 2016. Esteban I, Vilaró M, Adrover E, et al. Psychological impact of multigene cancer panel testing in patients with a clinical suspicion of hereditary cancer across Spain. Psychooncology 2018;27:1530 7. Lumish HS, Steinfeld H, Koval C, et al. Cancer on Patients. 2020;26:1116 29. Culver JO, Ricker CN, Bonner J, et al. Psychosocial Outcomes Following Germline Multigene Panel Testing in an Ethnically and Economically Diverse Cohort of Patients. Cancer 2021;127:1275 85. Destination: 1 Item: Title: Figure 1. CONSORT Diagram of study population Destination: 1 Item: Title: Figure 2.Univariable analysis of psychological impact (MICRA scale) in cases (n=32) and controls (n=576) Destination: 1 Item: Title: Figure 3. Distribution of MICRA scores scales and subscales betweencases (n=32) and controls (n=576). Total MICRA score (range 0-105), Uncertainty (range 0-45),Distress (range 0-30), Positive experiences (range 0-20) Destination: 1 Item: Title: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Destination: 1 Item: Title: Journal of Medical Genetics Destination: 1 Item: Title: https://mc.manuscriptcentral.com/jmedgenet Destination: 1 Item: Title: Page 22 of 36 Destination: 1 Item: Title: Page 23 of 36 Destination: 1 Item: Title: Journal of Medical Genetics Destination: 1 Item: Title: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Destination: 1 Item: Title: https://mc.manuscriptcentral.com/jmedgenet Destination: 1 Item: Title: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Destination: 1 Item: Title: Journal of Medical Genetics Destination: 1 Item: Title: Page 24 of 36 Destination: 1 Item: Title: https://mc.manuscriptcentral.com/jmedgenet Destination: 1 Item: Title: RESPONSE TO REVIEWERS Destination: 1 Children: Item: Title: We are grateful for the careful review of our submitted manuscript. Destination: 1 Item: Title: Reviewer: 2 Destination: 1 Children: Item: Title: We highly appreciate the positive feedback of the reviewer with the objective criticism to improve the quality of the manuscript Destination: 1 Item: Title: The reviewer brings up a good point. Initially, the 2 groups are not comparable due to differences in baseline characteristics. For that reason, we used the propensity score weighting method to correct for the imbalance. The method mitigated these differences to obtain groups with similar characteristics, that could be compared (Supplementary Table 3). However, we agree that there are still some imbalances that could impact the results. The following sentence has been added in the limitation section: Destination: 1 Item: Title: We agree with the reviewer that the sample size of cases is quite small and that present a clear limitation of the study. Smaller sample sizes are associated with a lack of statistical power to detect real difference. On one hand, this study does not have a problem with lack of statistical power because differences in MICRA scores were detected even with the small size (mainly because differences in MICRA values seem to be large and consistent between cases and controls). On the other hand, it is true that the small sample size did not allow to provide precise estimations in this group. This limitation has been added in the current version of the manuscript. Destination: 1 Item: Title: The positive result was one of the variables used to adjust the imbalance between cases and controls. Initially the percentage of positive results for cases and controls was 40.6% and 29.5%, Destination: 1 Item: Title: respectively. The adjusted analysis allocated more weight in the control group with positive results to create a more comparable population (40.6% vs 40.63%) (Supplementary Table 3). Based on this, the difference in the MICRA results should not be impacted for the percentage of positive results. Destination: 1 Item: Title: This study was done in a public hospital within a national health system. Participants did not have to pay for their clinical management nor received any payment to participate in the research study. Both cases and controls included relatives of the proband, therefore the same bias is shared in both groups. We have added this point in the discussion (page 12). Destination: 1 Item: Title: To improve the quality of the manuscript, we have sent it for revision to a native English teacher. 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ToUnicode: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT Encoding: Identity-H ToUnicode: true Font: BaseFont: CAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+Verdana Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT Encoding: Identity-H ToUnicode: true Font: BaseFont: CAAAAA+TimesNewRomanPS-BoldMT Encoding: Identity-H ToUnicode: true Font: BaseFont: CAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT Encoding: Identity-H ToUnicode: true Font: BaseFont: CAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+Verdana-Bold Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+Verdana Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT Encoding: Identity-H ToUnicode: true Font: BaseFont: CAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: CAAAAA+Verdana-Italic Encoding: Identity-H ToUnicode: true Font: BaseFont: CAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+Verdana Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+TimesNewRomanPS-ItalicMT Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+TimesNewRomanPS-ItalicMT Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: DAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT Encoding: Identity-H ToUnicode: true Font: BaseFont: DAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT Encoding: Identity-H ToUnicode: true Font: BaseFont: DAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: CAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+Verdana Encoding: Identity-H ToUnicode: true Font: BaseFont: CAAAAA+TimesNewRomanPS-BoldMT Encoding: Identity-H ToUnicode: true Font: BaseFont: CAAAAA+TimesNewRomanPS-BoldMT Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+Verdana Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT Encoding: Identity-H ToUnicode: true Font: BaseFont: CAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT Encoding: Identity-H ToUnicode: true Font: BaseFont: AAAAAA+Calibri-Bold Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+TimesNewRomanPS-ItalicMT Encoding: Identity-H ToUnicode: true Font: BaseFont: EAAAAA+IBMPlexSansCond Encoding: Identity-H ToUnicode: true Font: BaseFont: CAAAAA+TimesNewRomanPS-BoldMT Encoding: Identity-H ToUnicode: true Font: BaseFont: BAAAAA+Calibri Encoding: Identity-H ToUnicode: true CIDFontType2: Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: BAAAAA+Calibri CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+Calibri Flags: Symbolic FontBBox: -502, -312, 1240, 1026 FontFile2: true Font: BaseFont: DAAAAA+Arimo-Regular CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: DAAAAA+Arimo-Regular Flags: Symbolic FontBBox: -543, -303, 1301, 979 FontFile2: true Font: BaseFont: CAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: DAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: DAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: CAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: CAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: CAAAAA+Calibri-Italic CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+Calibri-Italic Flags: Symbolic, Italic FontBBox: -724, -275, 1259, 1026 FontFile2: true Font: BaseFont: EAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: EAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: AAAAAA+Calibri CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+Calibri Flags: Symbolic FontBBox: -502, -312, 1240, 1026 FontFile2: true Font: BaseFont: BAAAAA+Calibri-Bold CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+Calibri-Bold Flags: Symbolic FontBBox: -518, -349, 1262, 1039 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: CAAAAA+TimesNewRomanPS-ItalicMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+TimesNewRomanPS-ItalicMT Flags: Symbolic, Italic FontBBox: -497, -306, 1333, 1023 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: CAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-ItalicMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-ItalicMT Flags: Symbolic, Italic FontBBox: -497, -306, 1333, 1023 FontFile2: true Font: BaseFont: CAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: DAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: DAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: DAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: DAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: DAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: DAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: AAAAAA+Calibri CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+Calibri Flags: Symbolic FontBBox: -502, -312, 1240, 1026 FontFile2: true Font: BaseFont: BAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: DAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: DAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: BAAAAA+Calibri-Bold CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+Calibri-Bold Flags: Symbolic FontBBox: -518, -349, 1262, 1039 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-ItalicMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-ItalicMT Flags: Symbolic, Italic FontBBox: -497, -306, 1333, 1023 FontFile2: true Font: BaseFont: CAAAAA+Calibri-Italic CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+Calibri-Italic Flags: Symbolic, Italic FontBBox: -724, -275, 1259, 1026 FontFile2: true Font: BaseFont: AAAAAA+Verdana CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+Verdana Flags: Symbolic FontBBox: -559, -303, 1522, 1050 FontFile2: true Font: BaseFont: CAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: BAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: CAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: DAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: DAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-ItalicMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-ItalicMT Flags: Symbolic, Italic FontBBox: -497, -306, 1333, 1023 FontFile2: true Font: BaseFont: CAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: CAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: CAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: CAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: BAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: AAAAAA+Verdana CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+Verdana Flags: Symbolic FontBBox: -559, -303, 1522, 1050 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: BAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-ItalicMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-ItalicMT Flags: Symbolic, Italic FontBBox: -497, -306, 1333, 1023 FontFile2: true Font: BaseFont: DAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: DAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: AAAAAA+Verdana CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+Verdana Flags: Symbolic FontBBox: -559, -303, 1522, 1050 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: AAAAAA+Verdana-Bold CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+Verdana-Bold Flags: Symbolic FontBBox: -549, -303, 1707, 1071 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: BAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: CAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: BAAAAA+Verdana CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+Verdana Flags: Symbolic FontBBox: -559, -303, 1522, 1050 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-ItalicMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-ItalicMT Flags: Symbolic, Italic FontBBox: -497, -306, 1333, 1023 FontFile2: true Font: BaseFont: CAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: CAAAAA+Verdana-Italic CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+Verdana-Italic Flags: Symbolic, Italic FontBBox: -453, -303, 1584, 1050 FontFile2: true Font: BaseFont: DAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: DAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: CAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: AAAAAA+Verdana CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+Verdana Flags: Symbolic FontBBox: -559, -303, 1522, 1050 FontFile2: true Font: BaseFont: DAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: DAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: BAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: AAAAAA+TimesNewRomanPSMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+TimesNewRomanPSMT Flags: Symbolic FontBBox: -568, -306, 2045, 1039 FontFile2: true Font: BaseFont: CAAAAA+TimesNewRomanPS-ItalicMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+TimesNewRomanPS-ItalicMT Flags: Symbolic, Italic FontBBox: -497, -306, 1333, 1023 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true Font: BaseFont: AAAAAA+Calibri-Bold CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: AAAAAA+Calibri-Bold Flags: Symbolic FontBBox: -518, -349, 1262, 1039 FontFile2: true Font: BaseFont: CAAAAA+IBMPlexSansCond CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+IBMPlexSansCond Flags: Symbolic FontBBox: -241, -246, 1122, 1126 FontFile2: true Font: BaseFont: BAAAAA+TimesNewRomanPS-ItalicMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BAAAAA+TimesNewRomanPS-ItalicMT Flags: Symbolic, Italic FontBBox: -497, -306, 1333, 1023 FontFile2: true Font: BaseFont: CAAAAA+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: CAAAAA+TimesNewRomanPS-BoldMT Flags: Symbolic FontBBox: -558, -327, 2000, 1055 FontFile2: true XMP: application/pdf es-ES jmg-2022-108929.R1 (1).pdf jmg-2022-108929.R1 (1).pdf On Psicologia SCP J65847113 Canva DAHNJOszkek,BAFE50m_4bA,0 False Canva 2026-06-20T20:48:35.721Z 2026-06-23T14:39:48+02:00 2026-06-23T14:39:48+02:00 1 uuid:0d7b6d44-9c46-449c-999b-e90fb91d7152 uuid:83ec3bb8-868f-4975-9854-0086ef8ff77f Pages: Page: Sequence: 1 Page: Sequence: 2 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 386, 641, 416, 651 Flags: Print Annotation: Subtype: Link Rect: 390, 629, 418, 639 Flags: Print Annotation: Subtype: Link Rect: 418, 629, 420, 639 Flags: Print Annotation: Subtype: Link Rect: 307, 555, 387, 565 Flags: Print Annotation: Subtype: Link Rect: 307, 543, 386, 553 Flags: Print Annotation: Subtype: Link Rect: 386, 543, 389, 553 Flags: Print Page: Sequence: 4 Page: Sequence: 5 Page: Sequence: 6 Page: Sequence: 7 Page: Sequence: 8 Page: Sequence: 9 Page: Sequence: 10 Page: Sequence: 11 Page: Sequence: 12 Page: Sequence: 13 Page: Sequence: 14 Page: Sequence: 15 Page: Sequence: 16 Page: Sequence: 17 Page: Sequence: 18 Page: Sequence: 19 Page: Sequence: 20 Page: Sequence: 21 Page: Sequence: 22 Page: Sequence: 23 Page: Sequence: 24 Page: Sequence: 25 Page: Sequence: 26 Page: Sequence: 27 Page: Sequence: 28 Page: Sequence: 29 Page: Sequence: 30 Page: Sequence: 31 Page: Sequence: 32 Page: Sequence: 33 Page: Sequence: 34 Page: Sequence: 35 Page: Sequence: 36 Page: Sequence: 37 Page: Sequence: 38 Page: Sequence: 39 Checksum: a1b2bc58 Type: CRC32 Checksum: 069a2242be027b7bea0e7bb7e331c1ce Type: MD5 Checksum: f86b946cbfd650c3274214e51bab1e1c94b09ede Type: SHA-1 Checksum: bdc907295126d36e7113eb53f9c6793bed7e1a8e9a87188bb3829984aa9c168d Type: SHA-256