With the continued expansion and commercialisation of fertility treatments, the selection and matching of donors have become more sophisticated and technologised. As part of this landscape, new form of genetic screening: \'expanded carrier screening\' (ECS) is being offered as a technique to avoid the risk of donors passing on genetic conditions to future offspring. Allowing donors to be tested for hundreds of genetic conditions simultaneously, ECS marks a considerable departure from traditional \'family history\' models of screening, which rely on an individual\'s knowledge of family health. There is growing evidence of a drive towards the use of ECS within the fertility sector, and a growing number of clinics are offering it for a fee, as part of an egg or sperm donation cycle or as an add-on to IVF treatment. In this article, we use methods of critical reflection to synthesise data from two studies to explore how ECS is being used to avoid genetic risk in IVF treatment using donor gametes. We suggest that ECS is a new form of repro-genetic selection-a selective reproductive technology-with specific and important implications for donors, recipients and clinicians and with the potential to reconfigure the scope and application of gamete donation. We examine these implications and conclude that the existing policy blind spot relating to this development in fertility treatment practice needs to be urgently addressed.

Multiple endocrine neoplasia syndromes are a rare but potentially fatal pathology due to the lack of early diagnosis. We have performed a narrative review of the medical literature, summarizing the main clinical concepts useful in current clinical practice, showing the importance of screening and early diagnosis during childhood.

The Brugada pattern is associated with a genetic disorder characterized by ST-segment elevation in the right precordial leads on electrocardiogram (EKG) in the absence of structural heart disease. Patients with the Brugada pattern have an increased risk for ventricular tachyarrhythmia and sudden cardiac death. Loss-of-function mutations in the SCN5A gene which encodes the alpha subunit of the cardiac sodium channel have been associated with Brugada syndrome (BrS). We report a case of a patient who was found to have a spontaneous type 1 Brugada pattern on a routine EKG done prior to travel. He underwent electrophysiological testing (EPS) which provoked ventricular tachycardia and underwent implantable cardioverter defibrillator (ICD) placement. His family history revealed a history of sudden cardiac death, abnormal EKG, syncope, dilated cardiomyopathy, and BrS. Genetic testing revealed a variant of uncertain significance (VUS) in the SCN5A gene in the proband and six of his relatives. The SCN5A VUS in this clinical context and segregation with the disease in his family supports its reclassification to pathogenic.

Congenital generalized lipodystrophy type 2 (CGL2) is a rare autosomal recessive disorder characterized by the near-total absence of adipose tissue, leading to various metabolic complications. We present the case of a one-year-old male who exhibited progressive abdominal distension from six months of age. Physical examination revealed distinctive features including triangular facies, hypertelorism, an emaciated appearance with absent buccal fat, and hepatosplenomegaly. Laboratory investigations showed elevated transaminases and a deranged lipid profile, while imaging confirmed hepatosplenomegaly without systemic anomalies. A liver biopsy indicated macrovesicular steatosis and impending cirrhosis. Genetic testing revealed a homozygous pathogenic variant in the BSCL2 gene (c.604C>T), confirming CGL2. The child is under regular follow-up, with genetic counseling provided to the parents. This case underscores the importance of early recognition, genetic diagnosis, and regular monitoring in managing this rare condition.

The endomembrane system in plants is composed of interconnected membrane organelles that contribute to intracellular structure and function. These organelles include the endoplasmic reticulum (ER), Golgi apparatus, vacuole, trans-Golgi network, and prevacuolar compartment or multivesicular body. Through vesicle-mediated transport, secreted proteins are synthesized in the ER and subsequently transported along the secretory pathway to the vacuole or outside of cells to fulfill specialized functions. Genetic screening is a crucial method for studying plant protein secretion. It entails identifying phenotypic differences resulting from genetic mutations, such as ethyl methanesulfonate, T-DNA insertion, and RNAi, to investigate gene function and discover mutants with specific traits or gene functions. Significant progress has been achieved in the study of plant protein secretion through genetic screening. In this protocol, we provide a step-by-step guide to studying the protein secretion pathway using a genetic screen approach. We use the example of the free 1 suppressor of Arabidopsis thaliana and oil body mutants of Marchantia polymorpha. Additionally, we offer an overview of genetic screening and briefly summarize the emerging technologies in the field of protein secretion research.

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Li-Fraumeni syndrome (LFS) is caused by a pathogenic germline variant at the TP53 locus and is associated with an increased predisposition to a variety of cancers. The neoplasms most frequently associated with LFS are sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. In this case report, we present a 43-year-old male diagnosed with an ocular adnexal sebaceous carcinoma of the right upper eyelid who was confirmed to have LFS with subsequent genetic testing. The mutational profile of both the patient\'s genetic screen and tumor sequencing were congruent, demonstrating the same pathogenic loss-of-function TP53 variant. This case report highlights the importance of pursuing genetic testing in patients with a history of multiple tumor types, particularly those with uncommon diagnoses. In this case, confirmation of LFS had important implications for personalized patient care, including identification of contraindicated treatment interventions and the imaging modalities necessary for vigilant follow-up screening.

CRISPR technologies have revolutionized research areas ranging from fundamental science to translational medicine. CRISPR-based genetic screens offer a powerful platform for unbiased screening in various fields, such as cancer immunology. Immune checkpoint blockade (ICB) therapy has been shown to strongly affect cancer treatment. However, the currently available ICBs are limited and do not work in all cancer patients. Pooled CRISPR screens enable the identification of previously unknown immune regulators that can regulate T-cell activation, cytotoxicity, persistence, infiltration into tumors, cytokine secretion, memory formation, T-cell metabolism, and CD4+ T-cell differentiation. These novel targets can be developed as new immunotherapies or used with the current ICBs as new combination therapies that may yield synergistic efficacy. Here, we review the progress made in the development of CRISPR technologies, particularly technological advances in CRISPR screens and their application in novel target identification for immunotherapy.

UNASSIGNED: Genomic disorders caused by copy number variations (CNVs) are prevalent in patients with kidney disease; however, their contribution to chronic kidney failure (KF) of undetermined aetiology (uKF) is unclear. We screened patients with uKF aged 50 years or younger to establish the prevalence of causative CNVs.
UNASSIGNED: We enrolled patients with an onset of KF ≤50 years from suspected undetermined aetiology for initial review of medical records to exclude patients with clear-cut clinical or histopathological kidney diagnoses or patients with already established genetic kidney diseases. Next, we performed single nucleotide polymorphism (SNP) array-based CNV screening. All the detected CNVs were systematically classified and evaluated as possible causes of the patient\'s kidney disease. Patients with CNVs not explaining the kidney phenotype were additionally screened for causal variants in 540 genes using whole-genome sequencing.
UNASSIGNED: We enrolled 172 patients, of whom 123 underwent SNP-array. Pathogenic CNVs corresponding to known genomic disorders were identified in 12 patients (9.8%). The identified genomic disorders provided a causative kidney diagnosis in three patients, all of whom had reached KF by age 18 years. The remaining nine patients had CNVs with unclear kidney disease causality. Subsequently, whole-genome sequencing provided a causative genetic diagnosis in an additional four patients, including two diagnostic sequence variants unrelated to the detected CNVs.
UNASSIGNED: Genomic disorders were prevalent in this cohort with uKF, and causative CNVs were identified in 5 of 123 patients. Further studies combining the analysis of CNVs and sequence variants are needed to clarify the causal role of genomic disorders in kidney disease.

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