Optimizing Gene Panels for Equitable Reproductive Carrier Screening: the "Goldilocks" Approach.

Background: Professional organizations recommend pan-ancestry carrier screening for autosomal recessive (AR) and X-linked (XL) conditions. Advances in DNA sequencing allow for analysis of hundreds of genes, but the optimal number of genes for carrier screening remains unclear. The American College of Medical Genetics and Genomics (ACMG) has proposed a tiered approach, recommending screening for 113 genes.

Calibrated Functional Data Decreases Clinical Uncertainty for Tier 1 Monogenic Disease: Application to Long QT Syndrome.

Rare missense variants are often classified as variants of uncertain significance (VUS) due to insufficient evidence for classification. These ambiguous findings create anxiety and frequently lead to inappropriate workup, colloquially referred to as the 'diagnostic odyssey'. Well-validated high-throughput experimental data have the potential to significantly reduce the number of VUS identified by clinical genetic testing, though the extent of this reduction and the optimal strategies to achieve it remain unclear.

Derivative and non-derivative aneuploidy rates in PGT tested blastocysts from carriers of structural rearrangements.

Research Question: What is the likelihood of having an euploid embryo when undergoing preimplantation genetic testing for structural rearrangements (PGT-SR)?

Design: PGT-SR data from 364 couples (2822 trophectoderm biopsies) with a reciprocal translocation (RecT, n = 263), Robertsonian translocation (RobT, n = 79) or inversion (Inv, n = 22) were analysed retrospectively. Rates of euploid, derivative aneuploid or non-derivative aneuploid were evaluated for each cycle, stratified by the type of rearrangement and parent of origin.

Results: Inv had the highest rate of euploid embryos (47.

Experience using conventional compared to ancestry-based population descriptors in clinical genomics laboratories.

Various scientific and professional groups, including the American Medical Association (AMA), American Society of Human Genetics (ASHG), American College of Medical Genetics (ACMG), and the National Academies of Sciences, Engineering, and Medicine (NASEM), have appropriately clarified that certain population descriptors, such as race and ethnicity, are social and cultural constructs with no basis in genetics. Nevertheless, these conventional population descriptors are routinely collected during the course of clinical genetic testing and may be used to interpret test results. Experts who have examined the use of population descriptors, both conventional and ancestry based, in human genetics and genomics have offered guidance on using these descriptors in research but not in clinical laboratory settings.

Clinical Variant Reclassification in Hereditary Disease Genetic Testing.

Importance: Because accurate and consistent classification of DNA sequence variants is fundamental to germline genetic testing, understanding patterns of initial variant classification (VC) and subsequent reclassification from large-scale, empirical data can help improve VC methods, promote equity among race, ethnicity, and ancestry (REA) groups, and provide insights to inform clinical practice.

Objectives: To measure the degree to which initial VCs met certainty thresholds set by professional guidelines and quantify the rates of, the factors associated with, and the impact of reclassification among more than 2 million variants.

Design, Setting, And Participants: This cohort study used clinical multigene panel and exome sequencing data from diagnostic testing for hereditary disorders, carrier screening, or preventive genetic screening from individuals for whom genetic testing was performed between January 1, 2015, and June 30, 2023.

Germline multigene panel testing in acute and chronic pancreatitis.

Background/objectives: Germline genetic testing is recommended for younger patients with idiopathic pancreatitis but there has been a lack of consensus in recommendations for those over age 35. We aimed to analyze the results of genetic testing among subjects of varying ages.

Methods: Individuals who underwent germline multigene testing for pancreatitis susceptibility genes (CASR, CFTR, CPA1, CTRC, PRSS1, SPINK1) through a large commercial laboratory between 2017 and 2022 were included.

Clinical utility of comprehensive gene panel testing for common and rare causes of skeletal dysplasia and other skeletal disorders: Results from the largest cohort to date.

Molecular genetics enables more precise diagnoses of skeletal dysplasia and other skeletal disorders (SDs). We investigated the clinical utility of multigene panel testing for 5011 unrelated individuals with SD in the United States (December 2019-April 2022). Median (range) age was 8 (0-90) years, 70.

Universal Germline-Genetic Testing for Breast Cancer: Implementation in a Rural Practice and Impact on Shared Decision-Making.

Background: Whereas the National Comprehensive Cancer Network (NCCN) criteria restrict germline-genetic testing (GGT) to a subset of breast cancer (BC) patients, the American Society of Breast Surgeons recommends universal GGT. Although the yield of pathogenic germline variants (PGV) in unselected BC patients has been studied, the practicality and utility of incorporating universal GGT into routine cancer care in community and rural settings is understudied. This study reports real-world implementation of universal GGT for patients with breast cancer and genetics-informed, treatment decision-making in a rural, community practice with limited resources.

Disruption of the HIF-1 pathway in individuals with Ollier disease and Maffucci syndrome.

Ollier disease (OD) and Maffucci Syndrome (MS) are rare disorders characterized by multiple enchondromas, commonly causing bone deformities, limb length discrepancies, and pathological fractures. MS is distinguished from OD by the development of vascular anomalies. Both disorders are cancer predisposition syndromes with malignancies developing in ~50% of the individuals with OD or MS.

Global Expansion of Jeffrey's Insights: Jeffrey Modell Foundation's Genetic Sequencing Program for Primary Immunodeficiency.

Genetic disorders that impair the immune system, known as Primary Immunodeficiencies (PI), include over 450 single-gene inborn errors of immunity. Timely and appropriate diagnosis and treatment is vital to quality of life (QOL) and sometimes survival, as patients are susceptible to frequent, persistent, severe, and sometimes life-threatening infections or autoimmunity. Suspected PI patients that do not have a genetic diagnosis often endure a prolonged, onerous, inefficient, and expensive experience, known as a diagnostic odyssey.

Measuring the patient experience in community mental health services for older people: A study of the Net Promoter Score using the Friends and Family Test in England.

Objectives: The research aimed to explore the value of the Net Promoter Score as a service improvement tool and an outcome measure. The study objectives were to (1) explore associations between the Net Promoter Score with patient and service-receipt characteristics; (2) evaluate the strength of association between the Net Promoter Score and a satisfaction score; and (3) evaluate its test-retest reliability.

Methods: A postal survey was sent to service users on caseloads of community mental health teams for older people in four localities of England.