A structure-based analysis of the Kell blood group system.

Kell is one of the most complex blood group systems, with a highly polymorphic genetic background. Extensive allelic variations in the gene affect the encoded erythrocyte surface protein Kell. Genetic variants causing aberrant splicing, premature termination of protein translation, or specific amino acid exchanges lead to a variety of different phenotypes with altered Kell expression levels or changes in the antigenic properties of the Kell protein.

Functional Variation in Human CAZyme Genes in Relation to the Efficacy of a Carbohydrate-Restricted Diet in IBS Patients.

Background & Aims: Limiting the dietary intake of certain carbohydrates has therapeutic effects in some but not all irritable bowel syndrome (IBS) patients. We investigated genetic variation in human Carbohydrate-Active enZYmes (hCAZymes) genes in relationship to the response to a FODMAP-lowering diet in the DOMINO study.

Methods: hCAZy polymorphism was studied in patients with IBS from the dietary (FODMAP-lowering; n = 196) and medication (otilonium bromide; n = 54) arms of the DOMINO trial via targeted sequencing of 6 genes of interest (AMY2B, LCT, MGAM, MGAM2, SI, and TREH).

Stratified analyses refine association between TLR7 rare variants and severe COVID-19.

Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.

Genome interpretation in a federated learning context allows the multi-center exome-based risk prediction of Crohn's disease patients.

High-throughput sequencing allowed the discovery of many disease variants, but nowadays it is becoming clear that the abundance of genomics data mostly just moved the bottleneck in Genetics and Precision Medicine from a data availability issue to a data interpretation issue. To solve this empasse it would be beneficial to apply the latest Deep Learning (DL) methods to the Genome Interpretation (GI) problem, similarly to what AlphaFold did for Structural Biology. Unfortunately DL requires large datasets to be viable, and aggregating genomics datasets poses several legal, ethical and infrastructural complications.

Genetic Variation in and and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia.

Background: Acute pancreatitis (AP) is a serious, mechanistically not entirely resolved side effect of L-asparaginase-containing treatment for acute lymphoblastic leukemia (ALL). To find new candidate variations for AP, we conducted a genome-wide association study (GWAS).

Methods: In all, 1,004,623 single-nucleotide variants (SNVs) were analyzed in 51 pediatric ALL patients with AP (cases) and 1388 patients without AP (controls).

Artificial intelligence enables comprehensive genome interpretation and nomination of candidate diagnoses for rare genetic diseases.

Background: Clinical interpretation of genetic variants in the context of the patient's phenotype is becoming the largest component of cost and time expenditure for genome-based diagnosis of rare genetic diseases. Artificial intelligence (AI) holds promise to greatly simplify and speed genome interpretation by integrating predictive methods with the growing knowledge of genetic disease. Here we assess the diagnostic performance of Fabric GEM, a new, AI-based, clinical decision support tool for expediting genome interpretation.

Exome Sequencing of 5 Families with Severe Early-Onset Periodontitis.

Periodontitis is characterized by alveolar bone loss leading to tooth loss. A small proportion of patients develop severe periodontitis at the juvenile or adolescent age without exposure to the main risk factors of the disease. It is considered that these cases carry rare variants with large causal effects, but the specific variants are largely unknown.

Current Developments of Clinical Sequencing and the Clinical Utility of Polygenic Risk Scores in Inflammatory Diseases.

In this mini-review, we highlight selected research by the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence "Precision Medicine in Chronic Inflammation" focusing on clinical sequencing and the clinical utility of polygenic risk scores as well as its implication on precision medicine in the field of the inflammatory diseases inflammatory bowel disease, atopic dermatitis and coronary artery disease. Additionally, we highlight current developments and discuss challenges to be faced in the future. Exemplary, we point to residual challenges in detecting disease-relevant variants resulting from difficulties in the interpretation of candidate variants and their potential interactions.

A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease without clear etiology or effective treatment. Genetic factors contribute to PSC pathogenesis, but so far, no causative mutation has been found. We performed whole-exome sequencing in a family with autosomal dominant inheritance of PSC and identified a heterozygous germline missense mutation in , encoding a K849T variant of CD100.

SETDB1 is required for intestinal epithelial differentiation and the prevention of intestinal inflammation.

Objective: The intestinal epithelium is a rapidly renewing tissue which plays central roles in nutrient uptake, barrier function and the prevention of intestinal inflammation. Control of epithelial differentiation is essential to these processes and is dependent on cell type-specific activity of transcription factors which bind to accessible chromatin. Here, we studied the role of SET Domain Bifurcated Histone Lysine Methyltransferase 1, also known as ESET (SETDB1), a histone H3K9 methyltransferase, in intestinal epithelial homeostasis and IBD.

Exome sequencing in 38 patients with intracranial aneurysms and subarachnoid hemorrhage.

Objective: Genetic risk factors for unruptured intracranial aneurysms (UIA) and aneurysmal subarachnoid hemorrhage (aSAH) are poorly understood. We aimed to verify recently reported risk genes and to identify novel sequence variants involved in the etiology of UIA/aSAH.

Methods: We performed exome sequencing (ES) in 35 unrelated individuals and 3 family members, each with a history of UIA and/or aSAH.

Leptin induces TNFα-dependent inflammation in acquired generalized lipodystrophy and combined Crohn's disease.

Leptin has been shown to modulate intestinal inflammation in mice. However, clinical evidence regarding its immune-stimulatory potential in human Crohn's disease remains sparse. We here describe a patient with the unique combination of acquired generalized lipodystrophy and Crohn's disease (AGLCD) featuring a lack of adipose tissue, leptin deficiency and intestinal inflammation.

"Positive Examples": a bottom-up approach to identifying best practices in HIV care and treatment based on the experiences of peer educators.

Literature describing the roles and activities of peers working in HIV care is limited. Evaluations of the impact of peer-based behavior-change interventions reveal mixed results, due in part to varied program aims, structure, evaluation mechanisms, and training. Peers themselves are important resources to address these concerns and lay the groundwork for developing improved programs and evaluation strategies.

[Effect of combined treatment with cisplatin and irradiation on the survival of kidney cells in the Syrian hamster].

During combined treatment of hamster kidney cells with cisplatin and irradiation under aerobic conditions, there appear interactions between the two treatment modalities. The presence of cisplatin during irradiation leads to an increased bending, pretreatment or posttreatment with cisplatin to a gradual adaption of the shape of the survival curve to a straight line. Simultaneous treatment of hamster kidney cells with cisplatin and irradiation in hypoxia does not change the survival curve in contrast to simultaneous treatment under aerobic conditions.