Clinical genetics

PURPOSE: Guidelines recommend germline genetic testing (GT) for patients with pancreatic ductal adenocarcinoma (PDAC). This study aims to evaluate the utilization and outcomes of multigene panel GT in patients with PDAC. METHODS: This retrospective, multisite study included patients with PDAC diagnosed between May 2018 and August 2020 at Mayo Clinic Arizona, Florida, and Minnesota. Discussion, uptake, and outcomes of GT were compared before (May 1, 2018-May 1, 2019) and after (August 1, 2019-August 1, 2020) the guideline update, accounting for a transition period...

The phase 2 CLL2-BAAG trial tested the measurable residual disease (MRD)-guided triple combination of acalabrutinib, venetoclax and obinutuzumab after an optional bendamustine debulking in 45 patients with relapsed/refractory CLL (one patient was excluded from the analysis due to a violation of exclusion criteria). MRD was measured by flow cytometry (FCM, undetectable MRD <10-4) in peripheral blood (PB) and circulating tumor DNA (ctDNA) by digital droplet PCR (ddPCR) of variable-diversity-joining (VDJ) rearrangements and CLL-related mutations in plasma...

G-quadruplex DNA structures (G4) are proven to interfere with most genetic and epigenetic processes. Small molecules binding these structures (G4 ligands) are invaluable tools to probe G4-biology and address G4-druggability in various diseases (cancer, viral infections). However, the large number of reported G4 ligands (> 1000) could lead to confusion while selecting one for a given application. Herein we conducted a systematic affinity ranking of 11 popular G4 ligands vs 5 classical G4 sequences using FRET-melting, G4-FID assays and SPR...

INTRODUCTION: Genetic mutations or inflammatory, degenerative, or neoplastic conditions can trigger amyloidosis. Hereditary gelsolin amyloidosis is a genetic disorder primarily marked by amyloid fibrils composed of misfolded gelsolin fragments. CASE REPORT: We present three sisters with AGel amyloidosis, illustrating its clinical diversity. Patient 1, a 51-year-old, had bilateral ptosis, ocular discomfort, and dry eye syndrome due to cranial nerve involvement. Patient 2, a 53-year-old, experienced progressive bilateral visual impairment...

BACKGROUND: Sickle cell disease (SCD) is a genetic hematological disorder associated with severe complications, such as vaso-occlusive crises, acute chest syndrome (ACS), and an increased risk of thromboembolic events, including pulmonary embolism (PE). The diagnosis of PE in SCD patients presents challenges due to the overlapping symptoms with other pulmonary conditions. Our previous study revealed that nearly 96% of computed tomography pulmonary angiography (CTPA) scans in SCD patients were negative for PE, highlighting a gap in understanding the significance of CTPA findings when PE is absent...

Genome-wide association studies have identified more than 290 single nucleotide variants (SNVs) associated with prostate cancer. These SNVs can be combined to generate a Polygenic Risk Score (PRS), which estimates an individual's risk to develop prostate cancer. Identifying individuals at higher risk for prostate cancer using PRS could allow for personalized screening recommendations, improve current screening tools, and potentially result in improved survival rates, but more research is needed before incorporating them into clinical use...

PURPOSE: Early dissemination of primary pancreatic ductal adenocarcinoma (PDAC) is the main cause of dismal prognosis as it highly limits possible treatment options. A number of PDAC patients experience distant metastasis even after treatment due to the metastatic clones. We aimed to demonstrate the molecular architecture of borderline resectable PDAC manifests cancer dissemination of PDAC. METHODS: Here, 36 organoids isolated from primary tumor masses of PDAC patients with diverse metastatic statues are presented...

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by its large heterogeneity in terms of clinical presentation and severity. The pathophysiology of SLE involves an aberrant autoimmune response against various tissues, an excess of apoptotic bodies, and an overproduction of type-I interferon. The genetic contribution to the disease is supported by studies of monozygotic twins, familial clustering, and genome-wide association studies (GWAS) that have identified numerous risk loci...

Glycogen storage diseases (GSDs) are a group of rare inherited metabolic disorders characterized by clinical, locus, and allele heterogeneity. This study aims to investigate the phenotype and genotype spectrum of GSDs in a cohort of 14 families from Iran using whole-exome sequencing (WES) and variant analysis. WES was performed on 14 patients clinically suspected of GSDs. Variant analysis was performed to identify genetic variants associated with GSDs. A total of 13 variants were identified, including six novel variants, and seven previously reported pathogenic variants in genes such as AGL, G6PC, GAA, PYGL, PYGM, GBE1, SLC37A4, and PHKA2...

Breast cancer is the most prevalent cancer among women, and its diagnosis requires the accurate identification and classification of histological features for effective patient management. Artificial intelligence, particularly through deep learning, represents the next frontier in cancer diagnosis and management. Notably, the use of convolutional neural networks and emerging Vision Transformers (ViT) has been reported to automate pathologists' tasks, including tumor detection and classification, in addition to improving the efficiency of pathology services...

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder. Its etiology may be associated with genetic, environmental, and lifestyle factors. With the advancement of technology, the integration of genomics, transcriptomics, and imaging data related to AD allows simultaneous exploration of molecular information at different levels and their interaction within the organism. This paper proposes a hypergraph-regularized joint deep semi-non-negative matrix factorization (HR-JDSNMF) algorithm to integrate positron emission tomography (PET), single-nucleotide polymorphism (SNP), and gene expression data for AD...

MiRNAs (microRNAs) constitute a group of diminutive molecules of non-coding RNA intricately involved in regulating gene expression. This regulation is primarily accomplished through the binding of miRNAs to complementary sequences situated in the 3'-UTR of the messenger RNA (mRNA) target; as a result, they are degraded or repressed. The multifaceted biogenesis of miRNAs is characterized by a meticulously orchestrated sequence of events encompassing transcription, processing, transportation, and decay. Colorectal cancer stands as a pervasive and formidable ailment, afflicting millions across the globe...

The molecular landscape of chronic lymphocytic leukemia (CLL) has been extensively characterized, and various potent prognostic biomarkers were discovered. The genetic composition of the B-cell receptor (BCR) immunoglobulin (IG) was shown to be especially powerful for discerning indolent from aggressive disease at diagnosis. Classification based on the IG heavy chain variable gene (IGHV) somatic hypermutation status is routinely applied. Additionally, BCR IGH stereotypy has been implicated to improve risk stratification, through characterization of subsets with consistent clinical profiles...

PRCIS: This article delves into the imperative of screening family members of patients with glaucoma due to the disease's hereditary nature. It discusses the significant risks faced by first-degree relatives, approaches for identification, and challenges in implementing effective screening strategies. Emphasizing education, targeted campaigns, community involvement, and collaborative healthcare approaches, the article highlights the potential for mitigating undiagnosed glaucoma cases through strategic interventions targeting high-risk individuals...

This study offers a detailed exploration of lung adenocarcinoma (LUAD), addressing its heterogeneity and treatment challenges through a multi-faceted analysis that includes gene expression, genetic subtyping, pathway analysis, immune assessment, and drug sensitivity. It identifies 165 genes with significant expression differences and 46 genes associated with survival, revealing insights into oxidative stress and autophagy. LUAD samples were divided into three subtypes using consensus clustering on these 46 genes, with distinct survival outcomes...

PURPOSE: The inherent genetic heterogeneity of acute myeloid leukemia (AML) has challenged the development of precise and effective therapies. The objective of this study was to elucidate the genomic basis of drug resistance or sensitivity, identify signatures for drug response prediction, and provide resources to the research community. EXPERIMENTAL DESIGN: We performed targeted sequencing, high-throughput drug screening, and single-cell genomic profiling on leukemia cell samples derived from patients with AML...

Pseudomonas aeruginosa is a ubiquitous Gram-negative opportunistic pathogen with remarkable phylogenetic and phenotypic variabilities. In this work, we applied classical molecular networking analysis to secondary metabolite profiling data from seven Pseudomonas aeruginosa strains, including five clinical isolates from the lung secretions of people with cystic fibrosis (CF). We provide three vignettes illustrating how secondary metabolite profiling aids in the identification of rare genomics traits in P. aeruginosa ...

BACKGROUND: Opioids are widely used in chronic non-cancer pain (CNCP) management. However, they remain controversial due to serious risk of causing opioid use disorder (OUD). Our main aim was to develop a predictive model for future clinical translation that include pharmacogenetic markers. METHODS: An observational study was conducted in 806 pre-screened Spanish CNCP patients, under long-term use of opioids, to compare cases (with OUD, N.=137) with controls (without OUD, N...

In recent years, the incidence of autism spectrum disorder (ASD) has increased, but the etiology and pathogenesis remain unclear. In this narrative review, we review and systematically summarize the methods used to construct animal models to study ASD and the related behavioral studies based on recent literature. Utilization of various ASD animal models can complement research on the etiology, pathogenesis, and core behaviors of ASD, providing information and a foundation for further basic research and clinical treatment of ASD...

INTRODUCTION: Ehlers-Danlos syndromes (EDS) are genetic connective tissue disorders affecting multiple organ systems that frequently result in connective tissue hyperlaxity and early osteoarthritis. Short- and long-term outcomes after primary total hip arthroplasty (THA) in this patient population remain poorly characterised. The primary purpose of this study is to compare postoperative outcomes and survivorship after primary THA in patients with and without EDS. METHODS: The New York Statewide Planning and Research Cooperative System (SPARCS) database was queried for all patients undergoing primary elective THA between September 2009 and December 2020...