The Importance of Copy Number Variant Analysis in Patients with Monogenic Kidney Disease.

Introduction: Genetic testing can reveal monogenic causes of kidney diseases, offering diagnostic, therapeutic, and prognostic benefits. Although single nucleotide variants (SNVs) and copy number variants (CNVs) can result in kidney disease, CNV analysis is not always included in genetic testing.

Methods: We investigated the diagnostic value of CNV analysis in 2432 patients with kidney disease genetically tested at the University Medical Centre Utrecht between 2014 and May 2022.

Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human.

Background: Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis.

Methods: We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM.

Recombinant Interleukin-1 Receptor Antagonist Is an Effective First-Line Treatment Strategy in New-Onset Systemic Juvenile Idiopathic Arthritis, Irrespective of HLA-DRB1 Background and IL1RN Variants.

Objective: Human leukocyte antigen (HLA)-DRB1*15:01 has been recently associated with interstitial lung disease (LD), eosinophilia, and drug reactions in systemic juvenile idiopathic arthritis (sJIA). Additionally, genetic variants in IL1RN have been linked to poor response to anakinra. We sought to reproduce these findings in a prospective cohort study of patients with new-onset sJIA treated with anakinra as first-line therapy.

Recommendations for IVDR compliant in-house software development in clinical practice: a how-to paper with three use cases.

Objectives: The Diagnostics Regulation (IVDR) will be effective in May 2022 by which in-house developed tests need to apply to the general safety and performance requirements defined in Annex I of the IVDR ruling. Yet, article 16 from Annex I about software can be hard to interpret and implement, particularly as laboratories are unfamiliar with quality standards for software development.

Methods: In this paper we provide recommendations on organizational structure, standards to use, and documentation, for IVDR compliant in-house software development.

FAIR Genomes metadata schema promoting Next Generation Sequencing data reuse in Dutch healthcare and research.

The genomes of thousands of individuals are profiled within Dutch healthcare and research each year. However, this valuable genomic data, associated clinical data and consent are captured in different ways and stored across many systems and organizations. This makes it difficult to discover rare disease patients, reuse data for personalized medicine and establish research cohorts based on specific parameters.

The end of the laboratory developed test as we know it? Recommendations from a national multidisciplinary taskforce of laboratory specialists on the interpretation of the IVDR and its complications.

The in vitro diagnostic medical devices regulation (IVDR) will take effect in May 2022. This regulation has a large impact on both the manufacturers of in vitro diagnostic medical devices (IVD) and clinical laboratories. For clinical laboratories, the IVDR poses restrictions on the use of laboratory developed tests (LDTs).

Cross-Omics: Integrating Genomics with Metabolomics in Clinical Diagnostics.

Next-generation sequencing and next-generation metabolic screening are, independently, increasingly applied in clinical diagnostics of inborn errors of metabolism (IEM). Integrated into a single bioinformatic method, these two -omics technologies can potentially further improve the diagnostic yield for IEM. Here, we present cross-omics: a method that uses untargeted metabolomics results of patient's dried blood spots (DBSs), indicated by Z-scores and mapped onto human metabolic pathways, to prioritize potentially affected genes.

Exploratory Study of Predicted Indirectly ReCognizable HLA Epitopes in Mismatched Hematopoietic Cell Transplantations.

HLA-mismatches in hematopoietic stem-cell transplantation are associated with an impaired overall survival (OS). The aim of this study is to explore whether the Predicted Indirectly ReCognizable HLA-Epitopes (PIRCHE) algorithm can be used to identify HLA-mismatches that are related to an impaired transplant outcome. PIRCHE are computationally predicted peptides derived from the patient's mismatched-HLA molecules that can be presented by donor-patient shared HLA.

Accuracy of NGS HLA typing data influenced by STR.

Next Generation Sequencing (NGS) has become a major technology in HLA typing. The expectations are that highly accurate and unambiguous typing results will be obtained. However, HLA typing by NGS has some limitations caused by imperfections in the PCR amplification.

Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy.

Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases.

Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes.

A Previous Miscarriage and a Previous Successful Pregnancy Have a Different Impact on HLA Antibody Formation during a Subsequent Successful Pregnancy.

Inherited paternal HLA antigens from the semi-allogeneic fetus may trigger maternal immune responses during pregnancy, leading to the production of child-specific HLA antibodies. The prevalence of these HLA antibodies increases with the number of successful pregnancies. In the present study, we investigated the effect of a single prior miscarriage on HLA antibody formation during a subsequent successful pregnancy.

A mutation in the glutamate-rich region of RNA-binding motif protein 20 causes dilated cardiomyopathy through missplicing of titin and impaired Frank-Starling mechanism.

Aim: Mutations in the RS-domain of RNA-binding motif protein 20 (RBM20) have recently been identified to segregate with aggressive forms of familial dilated cardiomyopathy (DCM). Loss of RBM20 in rats results in missplicing of the sarcomeric gene titin (TTN). The functional and physiological consequences of RBM20 mutations outside the mutational hotspot of RBM20 have not been explored to date.

Screening for pulmonary tuberculosis in a Tanzanian prison and computer-aided interpretation of chest X-rays.

Setting: Tanzania is a high-burden country for tuberculosis (TB), and prisoners are a high-risk group that should be screened actively, as recommended by the World Health Organization. Screening algorithms, starting with chest X-rays (CXRs), can detect asymptomatic cases, but depend on experienced readers, who are scarce in the penitentiary setting. Recent studies with patients seeking health care for TB-related symptoms showed good diagnostic performance of the computer software CAD4TB.

Genome-Wide Polyadenylation Maps Reveal Dynamic mRNA 3'-End Formation in the Failing Human Heart.

Rationale: Alternative cleavage and polyadenylation (APA) of mRNA represents a layer of gene regulation that to date has remained unexplored in the heart. This phenomenon may be relevant, as the positioning of the poly(A) tail in mRNAs influences the length of the 3'-untranslated region (UTR), a critical determinant of gene expression.

Objective: To investigate whether the 3'UTR length is regulated by APA in the human heart and whether this changes in the failing heart.

Predicted Indirectly Recognizable HLA Epitopes Presented by HLA-DRB1 Are Related to HLA Antibody Formation During Pregnancy.

Pregnancy can prime maternal immune responses against inherited paternal HLA of the fetus, leading to the production of child-specific HLA antibodies. We previously demonstrated that donor-specific HLA antibody formation after kidney transplantation is associated with donor-derived HLA epitopes presented by recipient HLA class II (predicted indirectly recognizable HLA epitopes presented by HLA class II [PIRCHE-II]). In the present study, we evaluated the role of PIRCHE-II in child-specific HLA antibody formation during pregnancy.

Zooming into the binding groove of HLA molecules: which positions and which substitutions change peptide binding most?

Human leukocyte antigen (HLA) genes are the most polymorphic genes in the human genome. Almost all polymorphic residues are located in the peptide-binding groove, resulting in different peptide-binding preferences. Whether a single amino acid change can alter the peptide-binding repertoire of an HLA molecule has never been shown.

Atrial fibrillation is an independent risk factor for ventricular fibrillation: a large-scale population-based case-control study.

Background: Atrial fibrillation (AF) is associated with sudden cardiac death. We aimed to study whether AF is associated with ventricular fibrillation (VF), the most common cause of sudden cardiac death and whether this association is independent of confounders, ie, concomitant disease, use of antiarrhythmic or QT-prolonging drugs, and acute myocardial infarction.

Methods And Results: We performed a community-based case-control study.

Refinement of the definition of permissible HLA-DPB1 mismatches with predicted indirectly recognizable HLA-DPB1 epitopes.

Hematopoietic stem cell transplantation with HLA-DPB1-mismatched donors leads to an increased risk of acute graft-versus-host disease (GVHD). Studies have indicated a prognostic value for classifying HLA-DPB1 mismatches based on T cell-epitope (TCE) groups. The aim of this study was to determine the contribution of indirect recognition of HLA-DP-derived epitopes, as determined with the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) method.

Summary of the Dutch S3-guidelines on the treatment of psoriasis 2011. Dutch Society of Dermatology and Venereology.

This document provides a summary of the Dutch S3-guidelines on the treatment of psoriasis. These guidelines were finalized in December 2011 and contain unique chapters on the treatment of psoriasis of the face and flexures, childhood psoriasis as well as the patient's perspective on treatment. They also cover the topical treatment of psoriasis, photo(chemo)therapy, conventional systemic therapy and biological therapy.

Tuberculosis control in big cities and urban risk groups in the European Union: a consensus statement.

In low-incidence countries in the European Union (EU), tuberculosis (TB) is concentrated in big cities, especially among certain urban high-risk groups including immigrants from TB high-incidence countries, homeless people, and those with a history of drug and alcohol misuse. Elimination of TB in European big cities requires control measures focused on multiple layers of the urban population. The particular complexities of major EU metropolises, for example high population density and social structure, create specific opportunities for transmission, but also enable targeted TB control interventions, not efficient in the general population, to be effective or cost effective.

HIV-1 evolution in patients undergoing immunotherapy with Tat, Rev, and Nef expressing dendritic cells followed by treatment interruption.

Objectives: This study aimed to evaluate HIV sequence evolution in whole genes and in CD8 T-cell epitope regions following immunotherapy and subsequent analytical treatment interruption (ATI). A second objective of this study was to analyze associations between vaccine-specific immune responses and epitope mutation rates.

Design: HIV-1-infected patients on combined antiretroviral therapy (cART) were subjected to immunotherapy by the administration of an autologous dendritic cell-based therapeutic vaccine expressing Tat, Rev, and Nef and subsequent ATI.

The rate of immune escape vanishes when multiple immune responses control an HIV infection.

During the first months of HIV infection, the virus typically evolves several immune escape mutations. These mutations are found in epitopes in viral proteins and reduce the impact of the CD8⁺ T cells specific for these epitopes. Recent data show that only a subset of the epitopes escapes, that most of these escapes evolve early, and that the rate of immune escape slows down considerably.

Inferring patient to patient transmission of Mycobacterium tuberculosis from whole genome sequencing data.

Background: Mycobacterium tuberculosis is characterised by limited genomic diversity, which makes the application of whole genome sequencing particularly attractive for clinical and epidemiological investigation. However, in order to confidently infer transmission events, an accurate knowledge of the rate of change in the genome over relevant timescales is required.

Methods: We attempted to estimate a molecular clock by sequencing 199 isolates from epidemiologically linked tuberculosis cases, collected in the Netherlands spanning almost 16 years.

Role of the QuantiFERON(R)-TB Gold In-Tube assay in screening new immigrants for tuberculosis infection.

This study aimed to estimate the risk of progression to active tuberculosis (TB) within 2 yrs after entry in newly arriving immigrants who were screened with the QuantiFERON®-TB Gold In-Tube assay (QFT-GIT; Cellestis, Carnegie, Australia). In a case-base design, we determined the prevalence QFT-GIT-positive subjects among a representative sample of immigrants aged ≥ 18 yrs who arrived between April 2009 and March 2011 (the base cohort). Active TB patients (cases) within 2 yrs post-arrival in 2005, 2006 or 2007 were extracted from the Netherlands Tuberculosis Register.

High sensitivity of chest radiograph reading by clinical officers in a tuberculosis prevalence survey.

Background: Chest radiographs (CXRs) are used in tuberculosis (TB) prevalence surveys to identify participants for bacteriological examination. Expert readers are rare in most African countries. In our survey, clinical officers scored CXRs of 19 216 participants once.