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Conventionally, APOE genetic testing has not been recommended as a component of the standard diagnostic and management practices for Alzheimer's disease. However, recent research highlights the importance of this test, particularly for assessment of the safety profile of anti-amyloid-ß therapies. Therefore, the current United States guidelines for the administration of lecanemab explicitly advise APOE genetic testing. However, integration of this testing into clinical practice is associated with many clinical, ethical, legal, and economic challenges. It is important to initiate comprehensive discussions to address these multifaceted issues in Japan.

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INTRODUCTION: Genetic testing is used across medical disciplines leading to unprecedented demand for genetic services. This has resulted in excessive waitlists and unsustainable pressure on the standard model of genetic healthcare. Alternative models are needed; e-health tools represent scalable and evidence-based solution. We aim to evaluate the effectiveness of the Genetics Navigator, an interactive patient-centred digital platform that supports the collection of medical and family history, provision of pregenetic and postgenetic counselling and return of genetic testing results across paediatric and adult settings. METHODS AND ANALYSIS: We will evaluate the effectiveness of the Genetics Navigator combined with usual care by a genetics clinician (physician or counsellor) to usual care alone in a randomised controlled trial. One hundred and thirty participants (adults patients or parents of paediatric patients) eligible for genetic testing through standard of care will be recruited across Ontario genetics clinics. Participants randomised into the intervention arm will use the Genetics Navigator for pretest and post-test genetic counselling and results disclosure in conjunction with their clinician. Participants randomised into the control arm will receive usual care, that is, clinician-delivered pretest and post-test genetic counselling, and results disclosure. The primary outcome is participant distress 2 weeks after test results disclosure. Secondary outcomes include knowledge, decisional conflict, anxiety, empowerment, quality of life, satisfaction, acceptability, digital health literacy and health resource use. Quantitative data will be analysed using statistical hypothesis tests and regression models. A subset of participants will be interviewed to explore user experience; data will be analysed using interpretive description. A cost-effectiveness analysis will examine the incremental cost of the Navigator compared with usual care per unit reduction in distress or unit improvement in quality of life from public payer and societal perspectives. ETHICS AND DISSEMINATION: This study was approved by Clinical Trials Ontario. Results will be shared through stakeholder workshops, national and international conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT06455384.

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Standard of care genetic testing has undergone significant changes in recent years. The British Gynecological Cancer Society and the British Association of Gynecological Pathologists (BGCS/BAGP) has re-assembled a multidisciplinary expert consensus group to update the previous guidance with the latest standard of care for germline and tumor testing in patients with ovarian cancer. For the first time, the BGCS/BAGP guideline group has incorporated a patient advisor at the initial consensus group meeting. We have used patient focused groups to inform discussions related to reflex tumor testing - a key change in this updated guidance. This report summarizes recommendations from our consensus group deliberations and audit standards to support continual quality improvement in routine clinical settings.

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OBJECTIVE: To explore the genetic etiology of a Chinese pedigree affected with Branchio-oculo-facial syndrome (BOFS) and summarize the prenatal phenotype of BOFS patients. METHODS: A pedigree with BOFS which had presented at the Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University in December 2021 was selected as the study subject. Clinical data of the pedigree was collected. The fetus was subjected to routine prenatal ultrasound scan. Trio-whole exome sequencing (trio-WES) was carried out for the fetus and its parents, and candidate variant was verified by Sanger sequencing. Relevant literature was searched from the database to summarize the prenatal phenotype of BOFS patients. RESULTS: Ultrasound exam suggested the fetus had cleft lip and palate. Its father had presented with high palatal arch, prematurely grayed hair, occult cleft lip, congenital preauricular fistula, red-green color blindness and unilateral renal agenesis. Its grandfather also had high palatal arch, prematurely gray hair, protruding ears, congenital preauricular fistula and hearing disorders. Trio-WES revealed that the fetus and its father had both harbored a heterozygous c.890-1G>A variant of the TFAP2A gene. The same variant was not found in its mother. Sanger sequencing confirmed that its grandfather had also harbored the same variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PVS1+PM2_Supporting). Combined with 36 similar cases retrieved from the literature, the prenatal phenotypes of BOFS patients had included growth restriction (25/37), renal abnormalities (10/37), cleft lip and palate (5/37) and oligohydramnios (5/37). CONCLUSION: The c.890-1G>A variant of the TFAP2A gene probably underlay the pathogenesis of BOFS in this pedigree. Discovery of the novel variant has enriched the mutational spectrum of the TFAP2A gene. The common prenatal phenotypes of BOFS have included growth restriction, renal abnormalities, cleft lip and palate and oligohydramnios. Delineation of the intrauterine phenotype of BOFS may facilitate its prenatal diagnosis, clinical diagnosis, treatment and genetic counseling.

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OBJECTIVE: To analyze the clinical and genetic characteristics of a child featuring Dias-Logan syndrome. METHODS: A child with speech disorders and delayed psychomotor development from childhood who was admitted to the Rehabilitation Medicine Department of Children's Hospital Affiliated to Zhengzhou University in July 2022 was selected as the research subject. Clinical data of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his parents. Potential variant was screened by whole exome sequencing, and candidate variant was verified by Sanger sequencing. RESULTS: The child has presented with global developmental delay, microcephaly, special facial features and behavioral problems. Genetic testing revealed a de novo variant of the BCL11A gene, namely c.561_567delACACGCA (p.Q187fs*7), which was classified as pathogenic (PVS1+PS2+PM2_Supporting). CONCLUSION: The heterozygous variant of BCL11A gene probably underlay the Dias-Logan syndrome in this child. Above finding has enriched the phenotypic and mutational spectrum of the BCL11A gene and provides a basis for genetic counseling and clinical decision-making.

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OBJECTIVE: To explore the clinical phenotype and genetic etiology for a Chinese pedigree affected with Autosomal dominant polycystic kidney disease (ADPKD). METHODS: A pedigree with ADPKD diagnosed at the Department of Gynaecology of the First Affiliated Hospital of Zhengzhou University in December 2020 was selected as the study subject. Clinical data of the pedigree was collected, and whole exome sequencing (WES) was carried out for the proband. Candidate variants were verified by Sanger sequencing of the proband and her relatives. RESULTS: Fetal ultrasonography showed increased volume and parenchymal echogenicity in both kidneys. The fetus was found to harbor c.11098C>T (p.R3700C) and c.11039T>C (p.F3680S) compound heterozygous variants of the PKD1 gene, which were respectively inherited from its mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PM1+PM2_supporting+PP3). CONCLUSION: The c.11098C>T (p.R3700C) and c.11039T>C (p.F3680S) compound heterozygous variants of the PKD1 gene probably underlay the ADPKD in the fetus. Above finding has provided guidance for the genetic counseling and prenatal diagnosis for this pedigree.

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OBJECTIVE: To explore the genetic basis for a child with pachygyria. METHODS: A proband who had visited Qinzhou Maternal and Child Health Care Hospital for pachygyria and mental retardation in June 2020 was selected as the study subject. Clinical data was collected. The child was subjected to whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. RESULTS: The proband, a 4-year-and-6-month-old female, was clinically diagnosed with megagyrus deformity. WES revealed that she has harbored compound heterozygous variants of the ADGRG1 gene, namely c.781G>T (p.E261*) in exon 6 and c.1369A>C (p.S457R) in exon 11, which were verified by Sanger sequencing to be derived from her mother and father, respectively. Her younger sister was also heterozygous for the c.1369A>C (p.S457R) variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PVS1+PM2_ Supporting; PM1+PM2_Supporting+PM3+PP3). CONCLUSION: The c.781G>T (p.E261*) and c.1369A>C (p.S457R) compound heterozygous variants of the ADGRG1 gene probably underlay the pachygyria malformation in this child.

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Inherited retinal dystrophies/degenerations (IRDs) are the leading cause of visual impairment and incurable familial blindness in the Western world. Given the clinical and genetic heterogeneity, establishing a molecular diagnosis is especially relevant. The aim of this study was to perform the first nationwide survey to understand the prevalence and current management of IRDs in Portugal. A response was obtained from 26 healthcare providers (HCP) (76.5% response rate). Only 4 respondents reported not managing IRD patients. Most HCPs (68.1%) reported managing up to 100 patients, while three currently manage between 501 and 1000 patients. Based on the Portuguese population, an estimated IRD prevalence of 0.031%, i.e., about 1 in 3000 individuals, was calculated. In most HCPs (86.3%), most patients are adults, and non-syndromic retinitis pigmentosa is the most frequent diagnosis. Only 4 HCPs currently use the national, web-based IRD registry (IRD-PT). However, all but one respondent expressed interest in participating in such a registry. Genetic testing is available in 54.5%, with 58.3% HCPs reporting solved rates between 61-80%, but 4 to 9 months to get a genetic test result in 83.4% of cases. Based on this survey, the prevalence of biallelic RPE65-associated disease in Portugal is 0.00031%, i.e., approximately 1:300,000 individuals. Data from this study provide vital background information on national differences in the diagnosis and management of IRD patients. Nationwide implementation of the IRD-PT registry should be encouraged and supported to provide population-based reference data and to identify patients eligible for current and future therapies.

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As the heritability of abdominal aortic aneurysm (AAA) is high and AAA partially shares genetic architecture with other cardiovascular diseases, genetic information could help inform AAA screening strategies. Exploiting pleiotropy and meta-analysing summary data from large studies, we construct a polygenic risk score (PRS) for AAA. Leveraging related traits improves PRS performance (R2) by 22.7%, relative to using AAA alone. Compared with the low PRS tertile, intermediate and high tertiles have hazard ratios for AAA of 2.13 (95%CI 1.61, 2.82) and 3.70 (95%CI 2.86, 4.80) respectively, adjusted for clinical risk factors. Using simulation modelling, we compare PRS- and smoking-stratified screening with inviting men at age 65 and not inviting women (current UK strategy). In a futuristic scenario where genomic information is available, our modelling suggests inviting male current smokers with high PRS earlier than 65 and screening female smokers with high/intermediate PRS at 65 and 70 respectively, may improve cost-effectiveness.

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In 1996, Goggins and colleagues demonstrated the importance of germline BRCA2 pathogenic variants in the development of apparently sporadic pancreatic ductal adenocarcinoma (PDAC). Previously, the group identified homozygous deletion of the 13q region in PDACs, enabling the identification of the BRCA2 gene. This 1996 article first revealed loss of BRCA2, both germline and somatic, as a key driver of PDAC at a time when there was still doubt if PDAC even had an inherited component. Contrary to the prevailing wisdom, not all individuals with inherited pathogenic BRCA2 variants had a family history of cancer. The innovative bedside-to-bench nature of this work revealed that individuals with these variants would be missed if genetic testing was limited only to those meeting the family history criteria. Therefore, Goggins and colleagues advocated that universal genetic testing may be indicated for pancreatic cancer at a time when genetic testing was in its infancy. Twenty-three years later, in 2019, universal testing for pancreatic cancer became standard of care in the United States. Additionally, this work and future-related publications by the Kern Laboratory set the stage for targeting BRCA2 and related DNA repair mutations in pancreatic cancer via a synthetic lethal therapeutic approach. The provocative discussion initiated by this team in this publication is still inspiring the field today. In this seminal publication, Goggins and colleagues profoundly impacted the direction of pancreatic cancer research, leading to a more sophisticated approach to designing earlier detection and precision treatment strategies for pancreatic cancer. See related article by Goggins and colleagues, Cancer Res 1996;56:5360-4.

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BACKGROUND: Juvenile sudden cardiac death (SCD) remains unexplained in approximately 40% of cases, leading to a significant emotional burden for the victims' families and society. Comprehensive investigations are essential to uncover its elusive causes and enable cascade family screening. This study aimed to enhance the identification of likely causative variants in juvenile SCD cases (age ≤ 50 years), particularly when autopsy findings are inconclusive. RESULTS: Autopsy revealed diagnostic structural abnormalities in 46%, non-diagnostic findings in 23%, and structurally normal hearts in 31% of cases. Whole-exome sequencing (WES), refined through a customized virtual gene panel was used to identify variants. These variants were then evaluated using a multidisciplinary approach and a structured variant prioritization scheme. Our extended approach identified likely causative variants in 69% of cases, outperforming the diagnostic yields of both the cardio panel and standard susceptibility gene analysis (50% and 16%, respectively). The extended cardio panel achieved an 80% diagnostic yield in cases with structurally normal hearts, demonstrating its efficacy in challenging scenarios. Notably, half of the positive cases harboured a single variant, while the remainder had two or more variants. CONCLUSION: This study highlights the efficacy of a multidisciplinary approach employing WES and a tailored virtual gene panel to elucidate the aetiology of juvenile SCD. The findings support the expansion of genetic testing using tailored gene panels and prioritization schemes as part of routine autopsy evaluations to improve the identification of causative variants and potentially facilitate early diagnosis in first-degree relatives.

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With advances in genetic analysis technology, the genetic and molecular backgrounds of cerebrovascular diseases have become clearer. In moyamoya disease and intracranial artery stenosis, RNF213 p.Arg4810Lys has been identified as a disease susceptibility gene variant(germline variant), and various analyses have been conducted. PDGFRB mutations have been identified as characteristic somatic variants in cerebral aneurysms and are attracting attention. In addition, PIK3CA and MAP3K3 mutaions have been identified in cerebral cavernous malformations as somatic variants. Moreover, KRAS and BRAF mutations have been identified in arteriovenous malformations as somatic variants, respectively. Further studies are in progress. We reviewed the results of recent genetic analyses of cerebrovascular diseases, focusing particularly on genetic mutations.

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BACKGROUND: Cancer predisposition syndromes (CPS) impact about 10% of patients with pediatric cancer. Genetic testing (CPS-GT) has multiple benefits, but few studies have described parent and child knowledge and attitudes regarding CPS-GT decision-making. This study examined parent and patient CPS-GT decision-making knowledge and attitudes. PROCEDURE: English- or Spanish-speaking parents of children with pediatric cancer and patients with pediatric cancer ages 15-18 within 12 months of diagnosis or relapse were eligible to participate. Seventy-five parents and 19 parent-patient dyads (N = 94 parents, 77.7% female, 43.6% Latino/a/Hispanic; 19 patients, 31.6% female) completed surveys measuring CPS-GT-related beliefs. Independent samples t-tests compared parent responses across sociodemographic characteristics and parent-patient responses within dyads. RESULTS: Spanish-speaking parents were significantly more likely than English-speaking parents to believe that CPS-GT not being helpful (p < .001) and possibly causing personal distress (p = .002) were important considerations for deciding whether to obtain CPS-GT. Parents with less than four-year university education, income less than $75,000, or Medicaid (vs. private insurance) were significantly more likely to endorse that CPS-GT not being helpful was an important consideration for deciding whether to obtain CPS-GT (p < .001). Parents felt more strongly than patients that they understood what CPS-GT was (p = .01) and that parents should decide whether patients under 18 should receive CPS-GT (p = .002). CONCLUSIONS: Spanish-speaking parents and parents with lower socioeconomic statuses were more strongly influenced by the potential disadvantages of CPS-GT in CPS-GT decision-making. Parents felt more strongly than patients that parents should make CPS-GT decisions. Future studies should investigate mechanisms behind these differences and how to best support CPS-GT knowledge and decision-making.

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High-throughput sequencing technologies have increasingly led to discovery of disease-causing genetic variants, primarily in postnatal multi-cell DNA samples. However, applying these technologies to preimplantation genetic testing (PGT) in nuclear or mitochondrial DNA from single or few-cells biopsied from in vitro fertilised (IVF) embryos is challenging. PGT aims to select IVF embryos without genetic abnormalities. Although genotyping-by-sequencing (GBS)-based haplotyping methods enabled PGT for monogenic disorders (PGT-M), structural rearrangements (PGT-SR), and aneuploidies (PGT-A), they are labour intensive, only partially cover the genome and are troublesome for difficult loci and consanguineous couples. Here, we devise a simple, scalable and universal whole genome sequencing haplarithmisis-based approach enabling all forms of PGT in a single assay. In a comparison to state-of-the-art GBS-based PGT for nuclear DNA, shallow sequencing-based PGT, and PCR-based PGT for mitochondrial DNA, our approach alleviates technical limitations by decreasing whole genome amplification artifacts by 68.4%, increasing breadth of coverage by at least 4-fold, and reducing wet-lab turn-around-time by ~2.5-fold. Importantly, this method enables trio-based PGT-A for aneuploidy origin, an approach we coin PGT-AO, detects translocation breakpoints, and nuclear and mitochondrial single nucleotide variants and indels in base-resolution.

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Pancreatic neuroendocrine tumors (pNETs) are the second most prevalent neoplasms of the pancreas with variable prognosis and clinical course. Our knowledge of the genetic alterations in patients with pNETs has expanded in the past decade with the availability of whole-genome sequencing and germline testing. This review will focus on potential clinical applications of the genetic testing in patients with pNETs. For somatic testing, we discuss the commonly prevalent somatic mutations and their impact on prognosis and treatment of patients with pNET. We also highlight the relevant genomic biomarkers that predict response to specific treatments. Previously, germline testing was only recommended for high-risk patients with syndromic features (MEN1, VHL, TSC, and NF1), we review the evolving paradigm of germline testing in pNETs as recent studies have now shown that sporadic-appearing pNETs can also harbor germline variants.

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Importance: Between 5% and 10% of breast cancer cases are associated with an inherited germline pathogenic or likely pathogenic variant (GPV) in a breast cancer susceptibility gene (BCSG), which could alter local and systemic therapy recommendations. Traditional genetic testing criteria misses a proportion of these cases. Objective: To evaluate the prevalence and clinicopathological associations of GPVs in 2 groups of BCSGs among an ethnically diverse cohort of women with newly diagnosed breast cancer. Design, Setting, and Participants: This cross-sectional study, conducted at 3 Montreal hospitals between September 2019 and April 2022, offered universal genetic counseling and testing to all women with a first diagnosis of invasive breast cancer. Women were offered an obligatory primary panel of BRCA1, BRCA2, and PALB2 (B1B2P2) and an optional secondary panel of 14 additional BCSGs. Eligible participants were women 18 years of age or older who received a diagnosis of a first primary invasive breast cancer not more than 6 months before the time of referral to the study. Data were analyzed from November 2023 to June 2024. Results: Of 1017 referred patients, 805 were eligible and offered genetic counseling and testing, and 729 of those 805 (90.6%) consented to be tested. The median age at breast cancer diagnosis was 53 years (range, 23-91 years), and 65.4% were White and of European ancestry. Fifty-four GPVs were identified in 53 patients (7.3%), including 39 patients (5.3%) with B1B2P2 and 15 patients (2.1%) with 6 of the 14 secondary panel BCSGs (ATM, BARD1, BRIP1, CHEK2, RAD51D, and STK11). On multivariable analysis, clinical factors independently associated with B1B2P2-positive status included being younger than 40 years of age at diagnosis (odds ratio [OR], 6.83; 95% CI, 2.22-20.90), triple-negative breast cancer (OR, 3.19; 95% CI, 1.20-8.43), high grade disease (OR, 1.68; 95% CI, 1.05-2.70), and family history of ovarian cancer (OR, 9.75; 95% CI, 2.65-35.85). Of 39 B1B2P2-positive patients, 13 (33.3%) were eligible for poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. Conclusions and Relevance: In this cross-sectional universal genetic testing study of women with newly diagnosed invasive breast cancer, the prevalence of GPVs was 7.3%, with 5.3% of patients testing positive for B1B2P2. Among B1B2P2-women women, one-third were eligible for PARP inhibitors.

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Over the last 75 years, the field of Human Genetics has developed enormously. One of the recent developments involves health-related direct-to-consumer genetic tests (DTC-GTs), through which consumers gain insight in their genetic information and personal health risks without involvement of a health care professional. The DTC-GT market is diverse and dynamic, testing for continuously changing combinations of traits and DNA-variants that can affect personal health and disease. DTC-GTs can have positive and negative consequences for individuals, health care, society, and science. Notably, consumers are presently not optimally empowered for informed decision making regarding health-related DTC-GT usage. It is important to protect them from negative impact, given the present lack of actionable legislation. Insight in which citizens buy these tests, and why they do so, will help to properly inform and empower consumers to make informed decisions both before and after purchasing health-related DTC-GTs. Projects answering these questions are ongoing.

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