Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants.

Congenital Hypodysfibrinogenemia due to γ326Cys→Tyr Mutation: Third Ever-Described Case Associated with Recurrent Venous Thrombosis and COVID Vaccine.

Introduction: Congenital fibrinogen disorders are a heterogenous group of fibrinogen defects.

Case Presentation: Here, we describe hypodysfibrinogenemia in a 33-year-old female patient with provoked recurrent deep vein thrombosis (DVT) diagnosed based on decreased functional and antigenic fibrinogen levels with a decreased functional/antigenic fibrinogen ratio. Definitive diagnosis of congenital hypodysfibrinogenemia is done by genotyping using whole-exome sequencing, which identified the γ326Cys→Tyr mutation combined with single-nucleotide polymorphisms: rs2070011 and rs2070018 in FGA and rs1049636 in FGG.

Biochemical Changes in Adult Male Gamers During Prolonged Gaming: Pilot Study.

Background: Gaming has become an integrated part of life for children and adults worldwide. Previous studies on the impact of gaming on biochemical parameters have primarily addressed the acute effects of gaming. The literature is limited, and the study designs are very diverse.

Homologous Recombination Deficiency Detection Algorithms: A Systematic Review.

Homologous recombination deficiency (HRD) can arise from germline or somatic pathogenic variants as well as other genomic damage and epigenetic alterations in the HR repair pathway. Patients with tumors presenting with an HRD phenotype can show sensitivity to Poly (ADP-ribose) polymerase inhibitors (PARPis). Several promising tests to detect HRD have been developed based on different HRD definitions, biomarkers, and algorithms.

National clinical Genetic Networks - GENets - Establishment of expert collaborations in Denmark.

Genetic conditions are often familial, but not all relatives receive counseling from the same institution. It is therefore necessary to ensure consistency in variant interpretation, counseling practices, and clinical follow up across health care providers. Furthermore, as new possibilities for gene-specific treatments emerge and whole genome sequencing becomes more widely available, efficient data handling and knowledge sharing between clinical laboratory geneticists and medical specialists in clinical genetics are increasingly important.

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Polygenic risk scores (PRS) identify at-risk individuals for many common diseases. A discussion of strengths and limitations is carried out in this review. PRS complement traditional genetic testing and have shown utility in establishing a proper diagnosis and guiding primary and secondary prevention.

Colorectal cancer detected by liquid biopsy 2 years prior to clinical diagnosis in the HUNT study.

Background: Colorectal cancer (CRC) is often diagnosed in advanced stages. Circulating tumour DNA (ctDNA) has been proposed as an early diagnostic biomarker. However, as a screening tool, ctDNA has mainly been studied in selected populations at the time of clinical diagnosis.

Promoter hypermethylation of SFRP1 as a prognostic and potentially predictive blood-based biomarker in patients with localized pancreatic ductal adenocarcinoma.

Introduction: Current prognostic blood-based biomarkers for pancreatic adenocarcinoma (PDAC) are limited. Recently, promoter hypermethylation of SFRP1 (phSFRP1) has been linked to poor prognosis in patients with gemcitabine-treated stage IV PDAC. This study explores the effects of phSFRP1 in patients with lower stage PDAC.

Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2.

Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.

Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies.

Feasibility and early clinical impact of precision medicine for late-stage cancer patients in a regional public academic hospital.

Aim: Our goal was to describe a precision medicine program in a regional academic hospital, characterize features of included patients and present early data on clinical impact.

Materials And Methods: We prospectively included 163 eligible patients with late-stage cancer of any diagnosis from June 2020 to May 2022 in the Proseq Cancer trial. Molecular profiling of new or fresh frozen tumor biopsies was done by WES and RNAseq with parallel sequencing of non-tumoral DNA as individual reference.

Early diagnosis of ovarian cancer based on methylation profiles in peripheral blood cell-free DNA: a systematic review.

Patients diagnosed with epithelial ovarian cancer (OC) have a 5-year survival rate of 49%. For early-stage disease, the 5-year survival rate is above 90%. However, advanced-stage disease accounts for most cases as patients with early stages often are asymptomatic or present with unspecific symptoms, highlighting the need for diagnostic tools for early diagnosis.

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers.

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation.

The Physiological and Cardiologic Effects of Long Video Gaming Sessions in Adult Males.

The effect of long gaming sessions on energy intake, caffeine intake, blood pressure, heart rate, heart rate variability, and biochemical cardiac injury markers is unknown. The objective of this exploratory study was to investigate the changes in healthy male adults during two consecutive 18-hour sedentary video gaming sessions. Nine participants were enrolled in the study.

Cancer Risks Associated With and Pathogenic Variants.

Purpose: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in and for effective cancer risk management.

Methods: We used data from 3,184 and 2,157 families in the Consortium of Investigators of Modifiers of to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.

Results: PVs were associated with risks of male breast (RR = 4.

Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction.

Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants.

Purpose: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants.

Methods: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2.

[Preimplantation genetic testing].

Preimplantation genetic testing (PGT) for known familial monogenetic disease (PGT-M) or structural chromosomal rearrangements (PGT-SR) has evolved into a well-established alternative to prenatal diagnosis. PGT significantly reduces the risk of a pregnancy with an affected foetus. Screening for aneuploidy (PGT-A) used as an add-on to standard IVF treatment of infertile couples is widely used internationally, although its benefit is highly debated.

Validation of SFRP1 Promoter Hypermethylation in Plasma as a Prognostic Marker for Survival and Gemcitabine Effectiveness in Patients with Stage IV Pancreatic Adenocarcinoma.

No reliable predictive blood-based biomarkers are available for determining survival from pancreatic adenocarcinoma (PDAC). This combined discovery and validation study examines promoter hypermethylation (ph) of secreted frizzled-related protein 1 (SFRP1) in plasma-derived cell-free DNA as an independent prognostic marker for survival and Gemcitabine effectiveness in patients with stage IV PDAC. We conducted methylation-specific polymerase chain reaction analysis of the promoter region of the SFRP1 gene, based on bisulfite treatment.

DNA Methylation Changes in Fibromyalgia Suggest the Role of the Immune-Inflammatory Response and Central Sensitization.

Fibromyalgia (FM) has been explained as a result of gene-environment interactions. The present study aims to verify DNA methylation differences in eleven candidate genome regions previously associated to FM, evaluating DNA methylation patterns as potential disease biomarkers. DNA methylation was analyzed through bisulfite sequencing, comparing 42 FM women and their 42 healthy sisters.

Prevalence and type distribution of human papillomavirus infections in Danish patients diagnosed with vulvar squamous cell tumors and precursors.

Objective: To study the prevalence and type distribution of human papillomavirus (HPV) in patients with vulvar high-grade precancerous lesions and vulvar squamous cell carcinoma (VSCC).

Methods: Formalin-fixed and paraffin-embedded (FFPE) tissue samples from Danish patients diagnosed with vulvar precancerous lesions or VSCC in the period from 2010 to 2012 were obtained. HPV-DNA detection was carried out by the use of polymerase chain reaction (PCR) using GP5+/GP6+ primers and genotyped by sequencing.

DNA methylation changes in genes involved in inflammation and depression in fibromyalgia: a pilot study.

Objectives: The present pilot study aims to investigate DNA methylation changes of genes related to fibromyalgia (FM) development and its main comorbid symptoms, including sleep impairment, inflammation, depression and other psychiatric disorders. Epigenetic modifications might trigger or perpetuate complex interplay between pain transduction/transmission, central pain processing and experienced stressors in vulnerable individuals.

Methods: We conducted DNA methylation analysis by targeted bisulfite NGS sequencing testing differential methylation in 112 genomic regions from leukocytes of eight women with FM and their eight healthy sisters as controls.