搜索结果：Genetic counseling (Geneva, Switzerland)

Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive, fatal neurodegenerative disorder characterized by progressive loss of motor neurons. Approximately 15% of individuals diagnosed with ALS have a known genetic variant that contributes to disease. Herein, we present clinical and genetic data of a large Greek ALS cohort. The cohort consisted of 353 Greek consecutive index patients with ALS, including 16 patients with related motor neuron disease (MND) subtypes (nine with PLS, four with PBP, and three with PMA). Next generation sequencing raw data (obtained from the NYGC ALS Consortium) were further analyzed and used to screen for causative variants in known implicated genes. Repeat expansions in C9ORF72 and ATXN2 were investigated using ExpansionHunter software, repeat-primed PCR and fragment analysis. Pathogenic repeat expansions in C9ORF72 were detected in 41 patients (11.6%). In addition, 30 patients (8.5%) carried a causative variant in one of the genes studied. Known causative variants were identified in 27 cases (nine in SQSTM1, seven in TARDBP, five in SOD1, three in NEK1 and one each in SETX, VCP, FUS), whereas novel causative variants were identified in three cases (SOD1, FIG4, TBK1). In total, 71 cases received a molecular genetic diagnosis (20.1%). Additionally, seven cases (2.0%) carried an intermediate repeat expansion (30-33 CAG) in ATXN2. Our results reveal the distinct genetic profile of Greek ALS patients. These findings will have an impact on genetic counseling, the design of diagnostic gene panels for the Greek population and on genotype-specific therapeutic interventions. Understanding the genetic causes of ALS in different populations is becoming increasingly important, especially with the advent of personalized medicine.

We studied a retrospective cohort of children with developmental and epileptic encephalopathy (DEE), a group of neurological conditions characterized by early onset epilepsy and severe developmental delay. Cases were recruited from three university hospitals based on clinical criteria, after a blinded cross-validation process, and most were subject to both array-CGH and exome-based gene panel analyses. 155 subjects were included. A genetic diagnosis was identified in 105 (68 %). A majority of patients (71 %) had onset of symptoms before the age of one year. In this age group a disease-causing variant was identified in 73 % of children, the highest proportion of cases reported so far. Genetic heterogeneity was high, involving 40 different genes. The most prevalent gene was SCN1A. Eight genes were identified in multiple patients and accounted for 50 % of all diagnoses. The remaining genes represented ultra-rare disorders. In many cases, molecular diagnosis leads to treatment adaptation and allows for genetic counseling. Those results highlight the growing importance of genetic investigations especially in children with symptoms onset before the age of 1. Finally, we evaluated the disease-causing variants in an intention-to-treat approach and found that almost half would theoretically be amenable to personalized therapy using antisense oligonucleotides (ASOs).

Examining genetic literacy in families concerned with hereditary breast and ovarian cancer (HBOC) helps understand how genetic information is passed on from individuals who had genetic counseling to their at-risk relatives. This cross-study comparison explored genetic literacy both at the individual and the family level using data collected from three sequential studies conducted in the U.S. and Switzerland over ≥10 years. Participants were primarily females, at-risk or confirmed carriers of HBOC-associated pathogenic variants, who had genetic counselling, and ≥1 of their relatives who did not. Fifteen items assessed genetic literacy. Among 1933 individuals from 518 families, 38.5% had genetic counselling and 61.5% did not. Although genetic literacy was higher among participants who had counselling, some risk factors were poorly understood. At the individual level, genetic literacy was associated with having counselling, ≤5 years ago, higher education, and family history of cancer. At the family level, genetic literacy was associated with having counselling, higher education, and a cancer diagnosis. The findings suggest that specific genetic information should be emphasized during consultations, and that at-risk relatives feel less informed about inherited cancer risk, even if information is shared within families. There is a need to increase access to genetic information among at-risk individuals.

Pancreatic ductal adenocarcinoma (PDAC) disproportionately impacts Black and Latino/a communities, who are less likely to receive genetic counseling/testing referrals, hindering early cancer detection/prevention access. This study aims to determine the barriers/facilitators to PDAC genetics care/surveillance among Black and Latino/a populations. This is a concurrent mixed-methods study that utilized electronic surveys and semi-structured focus groups/in-depth interviews (02/14/2022-12/21/2022). This was a volunteer sample of Black or Latino/a general participants with a&#xa0;personal or family history of PDAC and community leaders serving these groups. Participants discussed barriers/facilitators to PDAC cancer genetics care/surveillance. Health literacy, cancer worry, medical trust, and inherited cancer risk were assessed using electronic surveys. Discussions were recorded, transcribed, and analyzed using a content analysis approach. Chi-square tests, two-sample t-tests, and one-way analysis of variance were used to evaluate survey data using R v4.3.2. 55 participants (n&#x2009;=&#x2009;27 general participants, 28 leaders) completed surveys. 27 (49%) self-identified as Black and 23 (42%) as Latino/a. Leaders (74%) reported higher levels of perceived medical mistrust among their communities than general participants (Trust in Physician Scale mean/SD 29.9/4.2 vs. 38.4/5.2, p&#x2009;<&#x2009;0.001; Medical Mistrust Index&#x2009;=&#x2009;18.8/4.2 vs. 24.4/3.6; p&#x2009;<&#x2009;0.001, respectively). General participants self-reported higher digital health seeking capabilities than leaders' perception of that skillset (p&#x2009;<&#x2009;0.001). 24 of these participants completed a focus group/in-depth interview, emphasizing informed discussions with a trusted/established provider. Individuals impacted by PDAC are open to genetics care and desire resources to promote PDAC surveillance. It is also crucial that leaders and providers be engaged to facilitate access to this care.

We investigated the genetic landscape of Parkinson's disease (PD) on the island of Crete. DNA samples from 360 PD patients and 251 controls were analyzed using a combination of genotyping, whole-exome sequencing, and targeted screening for GBA1 variants p.N409S and p.L483P. A molecular diagnosis (heterozygous dominant/homozygous recessive pathogenic/likely pathogenic non-GBA1 variant) was identified in 3.1% of patients, including LRRK2-PD (n&#x2009;=&#x2009;4) and SNCA-PD (n&#x2009;=&#x2009;1). A novel homozygous PINK1 variant (p.Y295Ter) and a rare homozygous FIG4 variant (p.I41T) were detected in two early-onset cases. About 10.3% of patients carried a GBA1 variant, including four rare variants (p.C55S, p.H294Q, p.K237T, p.R502H), and had an adjusted earlier disease onset of 7.3 years. GBA1 carriers had a 4.3-fold higher risk for PD compared to non-carriers. The proportion of GBA1 in Crete is substantially higher than on the Greek mainland, highlighting the distinct genetic PD profile in this population and supporting targeted genetic testing and counseling.

Inherited mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2) confer high risks of breast and ovarian cancer. Because the contribution of BRCA1/2 germline mutations to BC in the Northeastern population of Morocco remains largely unknown, we conducted this first study to evaluate the prevalence and the phenotypic spectrum of two BRCA1/2 pathogenic mutations (the founder BRCA1 c.5309G>T and BRCA2 c.1310_1313delAAGA). This choice was also argued by the presence of an apparent specific geographical connection of these mutations and the Northeastern region of Morocco. Screening for the germline mutations c.5309G>T and BRCA2 c.1310_1313delAAGA was performed by sequencing on a total of 184 breast cancer (BC) patients originated from the Northeastern region of Morocco. The likelihood of identifying a BRCA mutation is calculated using the Eisinger scoring model. The clinical and pathologic features were compared between the BRCA-positive and BRCA-negative groups of patients. Difference in survival outcomes was compared between mutation carriers and non-carriers. BRCA1 c.5309G>T and BRCA2 c.1310_1313delAAGA are responsible for a significant proportion of all BC cases (12.5%) and at least 20% of familial BC. The screening of BRCA1/2 genes by NGS sequencing confirmed that there are no additional mutations detected among positive patients. The clinicopathological features in positive patients were in accordance with typical characteristics of BRCA pathogenic mutations. The mean features in the carriers were the early onset of the disease, familial history, triple negative status (for BRCA1 c.5309G>T) and worse prognosis in terms of overall surviving. Our study indicates that the Eisinger scoring model could be recommended to identify patients for referral to BRCA1/2 oncogenetic counseling. Our findings suggest that BRCA1 c.5309G>T and BRCA2 c.1310_1313delAAGA mutations may have a strong founder and/or recurrent effect on breast cancer among the Northeastern Moroccan population. There contribution to breast cancer incidence is certainly substantial in this subgroup. Therefore, we believe that BRCA1 c.5309G>T and BRCA2 c.1310_1313delAAGA mutations have to be included in the array of tests aimed at revealing cancer syndrome carriers among subjects of Moroccan origin.

The principle of non-directiveness remains an important tenet in genetics. However, the concept has encountered growing criticism over the last two decades. There is an ongoing discussion about its appropriateness for specific situations in genetics, especially in light of recent significant advancements in genetic medicine. Despite the debate surrounding non-directiveness, there is a notable lack of up-to-date international research empirically investigating the issue from the perspective of those who actually do genetic counselling. Addressing this gap, our article delves into the viewpoints and experiences of medical geneticists in Germany and Switzerland. Twenty qualitative interviews were analysed employing reflexive thematic analysis. Participants' responses revealed substantial uncertainties and divergences in their understanding and application of the concept. It seems to cause distress since many geneticists stated that the principle was difficult to put into clinical practice and was no longer ethically justified given the increasing likelihood of therapeutic implications resulting from genomic testing outcomes. The insights provided by our qualitative empirical study accord with the ongoing theoretical debate regarding the definition, legitimacy, and feasibility of the principle. An adequately nuanced understanding and application of non-directiveness seems crucial to circumvent the risks inherent in the principle, while promoting patient autonomy and beneficence.

Decision-making concerning predictive genetic testing for hereditary cancer syndromes is inherently complex. This study aims to investigate what kind of complexities adults undergoing genetic counseling in Switzerland experience, how they deal with them, and what heuristics they use during the decision-making process. Semi-structured qualitative interviews with eighteen Swiss adults seeking genetic counseling for hereditary cancer syndrome genetic testing and two counseling physicians were conducted and analyzed using a grounded theory approach. Counselees stated that once they were aware of their eligibility for genetic testing they perceived an inevitable necessity to make a decision in a context of uncertainties. Some counselees perceived this decision as simple, others as very complex. High emotional involvement increased perceived complexity. We observed six heuristics that counselees used to facilitate their decision: Anticipating the test result; Focusing on consequences; Dealing with information; Interpreting disease risk; Using external guidance; and (Re-)Considering the general uncertainty of life. Our findings are limited to the context of predictive genetic testing for hereditary cancer syndromes. This qualitative study does not allow extrapolation of the relative frequency of which heuristics occur. The use of heuristics is an inherent part of decision-making, particularly in the complex context of genetic testing for inherited cancer predisposition. However, some heuristics increase the risk of misinterpretation or exaggerated external influences. This may negatively impact informed decision-making. Thus, this study illustrates the importance of genetic counselors and medical professionals being aware of these heuristics and the individual manner in which they might be applied in the context of genetic testing decision-making. Findings may offer practical support to achieve this, as they inductively focus on the counselees' perspective.

This study aims to clinically and genetically assess 30 unrelated consanguineous Pakistani families from various ethnic backgrounds, all exhibiting features of neurodevelopmental disorders (NDDs). We conducted clinical, genetic, biochemical, and molecular analyses on 30 consanguineous families with NDDs enrolled from various regions of Pakistan. The likely molecular causes of primary microcephaly and NDDs were identified. Detailed clinical investigations and molecular diagnoses were performed using whole exome sequencing (WES) of the proband, followed by Sanger sequencing for validation and segregation in the available family members of the affected families. WES identified likely disease-causing homozygous variants in 30 unrelated consanguineous families. Six families presented newly described variants in known NDD-related genes: ABAT (c.1439&#x2009;T&#x2009;>&#x2009;G; p.Phe480Cys) [OMIM613163], SLC12A6 (c.2865_2865insT; p.Glu955Asnfs*5) [OMIM 218000], SHANK3 (c.1305-3_1,305-2delTT; p.Gln29-_Gly305del) [OMIM 606232], BCKDK (c.356_356insC; p.Gly119Alafs*24) [OMIM 614923], DDHD2 (c.2065G&#x2009;>&#x2009;T; p.Asp689Tyr) [OMIM 615033], ERCC2 (c.1255G&#x2009;>&#x2009;A; p.Glu419Lys) [OMIM 610756]. Additionally, 12 families had previously reported disease-causing variants associated with different types of NDDs: ATRX (c.109C&#x2009;>&#x2009;T; p.Arg37*) [OMIM 309580], GPR56 [ADGRG1] (c.1423C&#x2009;>&#x2009;T; p.Arg475*) [OMIM 606854], NAGLU (c.1694G&#x2009;>&#x2009;A; p.Arg565Gln) [OMIM 252920], DOLK (c.3G&#x2009;>&#x2009;A; p.Met1Ile) [OMIM 610768], GPT2 (c.815C&#x2009;>&#x2009;T; p.Ser272Leu) [OMIM 616281], DYNC1I2 (c.607&#x2009;+&#x2009;1G&#x2009;>&#x2009;A; p.?) [OMIM 618492], FBXL3 (c.885delT; p.Leu295Phefs25*) [OMIM 606220], LINGO1 (c.869G&#x2009;>&#x2009;A; p.Arg290His) [OMIM 618103], and ASPM (c.3978G&#x2009;>&#x2009;A; Trp1326*, c.9557C&#x2009;>&#x2009;G; p.Ser3186*, c.6994C&#x2009;>&#x2009;T; p.Arg2332*) [OMIM 608716]. All the identified variants showed segregation compatible with autosomal recessive inheritance. In the present study, we observed a high frequency of ASPM variants in the genetic analysis of 30 consanguineous families exhibiting features of NDDs, particularly those associated with autosomal recessive primary microcephaly. These findings contribute to studies on genotype-phenotype correlation, genetic counseling for families, and a deeper understanding of human brain function and development.

Due to its importance for treatment and potential prevention in family members, germline testing for&#xa0;BRCA1/2&#xa0;in patients with newly diagnosed ovarian cancer is decisive and considered a standard of care. Maintenance therapy with poly(ADP-ribose) polymerase (PARP) inhibitors substantially improves progression-free survival in patients with&#xa0;BRCA&#xa0;mutations and homologous recombination-deficient tumours by inducing synthetic lethality. In Switzerland, they are licensed only for these patients. Therefore, it is crucial to test patients early while they are receiving adjuvant chemotherapy. This study aimed to determine whether genetic counselling followed by homologous recombination deficiency testing is feasible for initialising maintenance therapy within eight weeks and cost-effective in daily practice in Switzerland compared to somatic tumour analysis of all patients at diagnosis. This single-centre retrospective study included 44 patients with newly diagnosed high-grade serous ovarian cancer of a Federation of Gynaecology and Obstetrics (FIGO) stage of IIIA-IVB diagnosed between 12/2020 and 12/2022. It collected the outcomes of genetic counselling, germline testing, and somatic Geneva test for homologous recombination deficiency. Delays in initiating maintenance therapy, total testing costs per patient, and progression-free survival were examined to assess feasibility and cost-effectiveness in clinical practice. Thirty-seven of 44 patients (84%) with newly diagnosed ovarian cancer received counselling, of which 34 (77%) were tested for germline&#xa0;BRCA&#xa0;and other homologous recombination repair gene mutations. Five (15%)&#xa0;BRCA&#xa0;and three (9%) other homologous recombination deficiency mutations were identified. Eleven of the remaining 26 patients (42%) had tumours with somatic homologous recombination deficiency. The mean time to the initiation of maintenance therapy of 5.2 weeks was not longer than in studies for market authorisation (SOLO1, PAOLA, and PRIMA). The mean testing costs per patient were 3880 Swiss Franks (CHF), compared to 5624 CHF if all patients were tested at diagnosis with the myChoice CDx test (p <0.0001). Using genetic counselling to consent patients with newly diagnosed ovarian cancer for germline testing fulfils the international gold standard. Subsequent somatic homologous recombination deficiency analysis complements testing and identifies more patients who will benefit from PARP inhibitor maintenance therapy. Contrary to previous health cost model studies, the procedure does not increase testing costs in the Swiss population and does not delay maintenance therapy. Therefore, all patients should be offered a primary germline analysis. The challenge for the future will be to ensure sufficient resources for prompt genetic counselling and germline testing.

A consensus protocol for genetic counselling and testing of familial dementia, the Italian Dominantly Inherited Alzheimer's and Frontotemporal Network (IT-DIAfN) protocol, has been developed in Italy by a network of expert dementia centres. The aim of this study is to evaluate feasibility and acceptability of the genetic counselling and testing process, as undertaken according to the IT-DIAfN protocol in one of the IT-DIAfN dementia research centres. The protocol was tested by a multidisciplinary team at the IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy, on affected individuals with suspected inherited forms of Alzheimer's disease (AD) or frontotemporal dementia (FTD), and to healthy at-risk relatives. The genetic counselling and testing process consisted of (i) pre-test consultation and psychological assessment (ii) genetic testing, (iii) genetic test result disclosure and (iv) follow-up consultation and psychological assessment. Twenty affected individuals from 17 families fulfilled the family history criteria of the IT-DIAfN protocol for suspected inherited dementia (17 for AD, 2 for FTD, 1 for inclusion body myopathy with Paget disease of bone and frontotemporal dementia) and were included in the protocol. Nineteen out of 20 affected individuals received the genetic test result (one left after the pre-test consultation being not ready to cope with an unfavourable outcome). A pathogenic mutation was found in 6 affected individuals (1 in PSEN1, 2 in PSEN2, 1 in GRN, 1 in MAPT, 1 in VCP). Eleven healthy at-risk relatives asked to undergo predictive testing and were included in the protocol. Three completed the protocol, including follow-up; one did not ask for the genetic test result after genetic testing; and eight withdrew before the genetic testing, mainly due to an increased awareness about the possible consequences of an unfavourable test result. To date, no catastrophic reactions were reported at the follow-up. Our case series shows that a structured genetic counselling and testing protocol for inherited dementia can be implemented in both affected individuals and at-risk relatives in a research setting. The procedure was shown to be safe in terms of occurrence of catastrophic events. A formal validation in larger cohorts is needed.

There is a need to standardise, within a coordinated Swiss framework, the practical aspects of genetic testing and genetic counselling on possibly inherited cardiovascular disorders in relatives of a sudden cardiac death (SCD) victim. Because of the major advances in genetic investigation techniques and recent publication of international guidelines in the field of cardiology, genetics and pathology, we consider it important to summarise the current evidence and propose an optimal approach to post-mortem genetic investigation for SCD victims and their families in Switzerland. In this article, we discuss important technical, financial and medico-ethical aspects, and provide updated information on specific situations in which forensic pathologists, general practitioners and cardiologists should suspect a genetic origin of the SCD. At present, the principles of benefit, the duty to warn and the impact of genetic information for family members at risk are considered as strong justifications for post-mortem disclosure and prevail over the arguments of respect for a deceased person's privacy and confidentiality. This paper underlines also the need to update and improve the general knowledge concerning the genetic risk of cardiovascular pathologies, the importance to perform an autopsy and post-mortem genetic testing in SCD victims, and to develop standardized post-mortem disclosure policy at national and international levels for SCD cases and relatives.

Cancer predisposition syndromes (CPSs), including genetic tumour risk syndromes (genturis), are a heterogeneous group of genetic disorders characterised by an increased risk of developing tumours compared to the general population. CPSs raise reproductive issues for affected individuals because of the risk of passing the disease-causing genetic alterations on to offspring. The demand for reproductive counselling is often unmet due to the lack of sufficient healthcare professionals with the specialised knowledge, experience and skill. Based on a comprehensive literature review of 851 publications and expert consensus (multidisciplinary medical experts and patient representatives), the European Reference Network on genetic tumour risk syndromes (ERN GENTURIS) developed a guideline providing 16 recommendations for reproductive counselling in CPSs. The central recommendation is to offer reproductive counselling proactively to all individuals with a CPS and their relevant family members, together with psychological support and in multidisciplinary collaborations. This guideline aims to standardize the offer of reproductive counselling for individuals with a CPS across Europe, empowers healthcare professionals for their specific tasks, and helps patients dealing with their own challenges.

This study aims to assess information needs and information sources and seeks to illustrate what at-risk individuals consider motivators of and barriers to information-seeking before and after genetic testing for cancer predisposition. Semi-structured interviews with people seeking genetic counseling in Switzerland were analyzed qualitatively using thematic analysis. Wilson's model of information behavior was the theoretical framework. We identified four themes that illustrate motivators of and barriers to information-seeking: attitudes and emotions; knowledge; social environment; and demographic factors. We also elucidated information needs and collected participants' information sources. This study&#xa3;s empirical approach helps healthcare professionals to understand their patients' behaviors and wishes concerning information-seeking more concretely than theoretical models alone. The study also identifies information gaps, especially outside the genetic counseling setting. Genetic counselors and other healthcare professionals need to purposefully assist patients in finding trustworthy and accessible information. Healthcare professionals in all disciplines need to be educated about predictive genetic testing.

Our aim was to evaluate the psychological impact of predictive genetic testing in individuals at-risk for inherited dementia who underwent a structured counseling and testing protocol. Participants were healthy at-risk relatives from families with at least one affected patient, in whom a disease-associated genetic variant had been ascertained. A comprehensive psychological assessment (personality, anxiety and depression, quality of life, coping strategies, resilience and health-related beliefs) was administered at baseline, at 6 months and 12 months follow-up. Twenty-four participants from 13 families were included. Sixteen participants underwent blood sampling and genetic analysis; 6 resulted to be carriers of pathogenic variants (1 in PSEN1, 1 in PSEN2, 4 in GRN). Carriers showed higher score on the Resilience Scale for Adults (RSA) - social competence, and on Multidimensional Health Locus of Control - internal, than noncarriers (P=0.03 for both). Ten at-risk relatives who completed the follow-up showed improvement in RSA - planned future (P=0.01) with respect to baseline. Our case series showed that at-risk individuals undergoing predictive testing showed benefit on personal life and no detrimental impact on a broad range of psychological outcomes. Higher social skills and lower internal health locus of control in carriers may be an early psychological correlate of preclinical dementia.

The development of high-throughput technologies has enabled Expanded Carrier screening (ECS) as a more comprehensive and extensive approach for high-risk populations. The available methods of ECS are population-targeted gene-panels according to ethnicity, however these panels should be planned according to a real-world data evaluation. In this study, we estimate the frequency of pathogenic variants for autosomal-recessive and X-linked conditions in Exome Sequencing-ES data for a 176 gene panel proposed from ACMG and ACOG in a Greek cohort. ES data from 1000 unrelated individuals was evaluated for pathogenic SNVs and CNVs. Variants were filtered using 5% Minor Frequency Allele (MAF), ClinVar submissions, and classification with ACMG criteria. For the at-risk couple rate, we hypothesized that both parents carried variants in the same gene. It is noted that many common conditions (hemoglobinopathies, SMA, Fragile-X) may escape NGS-based detection as they require alternative methods for optimal detection. Amongst 1000 participants, 32% were heterozygous for at least one disorder and 14% for two or more, whereby 393 unique pathogenic/likely pathogenic heterozygous variants were identified. We calculated that 1.6% of couples have a risk for at least one AR condition, which means that for 85,000 births per year, 1380 couples require genetic counseling. This study provides data confirming that the ACMG/ACOG ECS list of 176 genes is suitable for carrier screening in Greece, and aids counseling prospective parents for residual risk, however it should be supported by appropriate interpretation and reproductive options, as well as ancillary genetic testing methods.

The study adapted the Family Gene Toolkit and developed a customized web application for Swiss and Korean families harboring BRCA1 or BRCA2 pathogenic variants to support family communication of genetic testing results and promote cascade genetic testing among at-risk relatives. In the first step, narrative data from 68 women with BRCA1/BRCA2 pathogenic variants and clinician feedback informed a culturally sensitive adaptation of the content consistent with current risk management guidelines. In the second step, the Information Technology team developed the functions and the interface of the web application that will host the intervention. In the third step, a new sample of 18 women from families harboring BRCA1/BRCA2 pathogenic variants tested the acceptability and usability of the intervention using "think-aloud" interviews and a questionnaire. Participants expressed high levels of satisfaction with the intervention. They provided positive feedback for the information regarding active coping, strategies to enhance family communication, interactive elements, and illustrative stories. They reported that the information was useful and the web application was easy to navigate. Findings suggest that the Family Gene Toolkit is well-designed and can increase rates of cascade testing among at-risk relatives. Its efficacy will be tested in a subsequent randomized trial.

Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment. To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. In this international, multicenter diagnostic accuracy study, 1071 pediatric (<19 years of age) oncology patients who had a confirmed CPS (12 oncology referral centers) or who underwent germline DNA sequencing through precision medicine programs (6 centers) from January 1, 2000, to July 31, 2020, were studied. Exposures were MIPOGG application in patients with cancer and a confirmed CPS (diagnosed through routine clinical care; n&#x2009;=&#x2009;413) in phase 1 and MIPOGG application in patients with cancer who underwent germline DNA sequencing (n&#x2009;=&#x2009;658) in phase 2. Study phases did not overlap. Data analysts were blinded to genetic test results. The performance of MIPOGG in CPS recognition was compared with that of routine clinical care, including identifying a CPS earlier than practitioners. The tool's test characteristics were calculated using next-generation germline DNA sequencing as the comparator. In phase 1, a total of 413 patients with cancer (median age, 3.0 years; range, 0-18 years) and a confirmed CPS were identified. MIPOGG correctly recognized 410 of 412 patients (99.5%) as requiring referral for CPS evaluation at the time of primary cancer diagnosis. Nine patients diagnosed with a CPS by a practitioner after their second malignant tumor were detected by MIPOGG using information available at the time of the first cancer. In phase 2, of 658 children with cancer (median age, 6.6 years; range, 0-18.8 years) who underwent comprehensive germline DNA sequencing, 636 had sufficient information for MIPOGG application. When compared with germline DNA sequencing for CPS detection, the MIPOGG test characteristics for pediatric-onset CPSs were as follows: sensitivity, 90.7%; specificity, 60.5%; positive predictive value, 17.6%; and negative predictive value, 98.6%. Tumor DNA sequencing data confirmed the MIPOGG recommendation for CPS evaluation in 20 of 22 patients with established cancer-CPS associations. In this diagnostic study, MIPOGG exhibited a favorable accuracy profile for CPS screening and reduced time to CPS recognition. These findings suggest that MIPOGG implementation could standardize and rationalize recommendations for CPS evaluation in children with cancer.

BRCA1/2 genetic testing offers tremendous opportunities for prevention, diagnosis and treatment of breast and ovarian cancer. Women acquire valuable information that can help them to make informed decisions about their health. However, knowing one's susceptibility to developing cancer may be burdensome for several women, as this risk needs to be managed over time through a continuous dialogue with multiple healthcare professionals. We explored how communication between physicians and unaffected women carrying BRCA1/2 germline pathogenic variants was experienced by women in relation to their genetic risk. Data came from qualitative interviews conducted in Switzerland with 32 unaffected women carrying BRCA1/2 pathogenic variants and aware of their genetic status for at least 3 years. We identified three different types of message as conveyed by physicians to women: (1) a normative message, (2) an over-empowering message, and (3) a minimizing message. On one hand, we found that women are exposed to contradictory messages, often simultaneously, in their interactions with healthcare professionals during their post-genetic testing journey. On the other hand, women's reports highlighted the absence of shared decision-making in such interactions. The combination of these two findings resulted in a strong sense of disorientation, frustration, and powerlessness among participants. Healthcare professionals interacting with high cancer risk women are urged to align in favor of a both concerted and shared decision-making approach when discussing options for managing genetic risk.