Publications by authors named "A Hoischen"

177 Publications

Solving the unsolved rare diseases in Europe.

Eur J Hum Genet 2021 Jun 18. Epub 2021 Jun 18.

CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.

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http://dx.doi.org/10.1038/s41431-021-00924-8DOI Listing
June 2021

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Eur J Hum Genet 2021 Jun 1. Epub 2021 Jun 1.

CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.

Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics.
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http://dx.doi.org/10.1038/s41431-021-00852-7DOI Listing
June 2021

Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases.

Eur J Hum Genet 2021 Jun 1. Epub 2021 Jun 1.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe.
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http://dx.doi.org/10.1038/s41431-021-00859-0DOI Listing
June 2021

Pro-inflammatory Monocyte Phenotype During Acute Progression of Cerebral Small Vessel Disease.

Front Cardiovasc Med 2021 13;8:639361. Epub 2021 May 13.

Department of Internal Medicine, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, Netherlands.

The etiology of cerebral small vessel disease (SVD) remains elusive, though evidence is accumulating that inflammation contributes to its pathophysiology. We recently showed retrospectively that pro-inflammatory monocytes are associated with the long-term progression of white matter hyperintensities (WMHs). In this prospective high-frequency imaging study, we hypothesize that the incidence of SVD progression coincides with a pro-inflammatory monocyte phenotype. Individuals with SVD underwent monthly magnetic resonance imaging (MRI) for 10 consecutive months to detect SVD progression, defined as acute diffusion-weighted imaging-positive (DWI+) lesions, incident microbleeds, incident lacunes, and WMH progression. Circulating inflammatory markers were measured, cytokine production capacity of monocytes was assessed after stimulation, and RNA sequencing was performed on isolated monocytes in a subset of participants. 13 out of 35 individuals developed SVD progression (70 ± 6 years, 54% men) based on incident lesions ( = 7) and/or upper quartile WMH progression ( = 9). Circulating E-selectin concentration ( < 0.05) and the cytokine production capacity of interleukin (IL)-1β and IL-6 ( < 0.01) were higher in individuals with SVD progression. Moreover, RNA sequencing revealed a pro-inflammatory monocyte signature including genes involved in myelination, blood-brain barrier, and endothelial-leukocyte interaction. Circulating monocytes of individuals with progressive SVD have an inflammatory phenotype, characterized by an increased cytokine production capacity and a pro-inflammatory transcriptional signature.
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http://dx.doi.org/10.3389/fcvm.2021.639361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155247PMC
May 2021

Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of VEXAS patients.

J Allergy Clin Immunol 2021 May 25. Epub 2021 May 25.

Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, The Netherlands. Electronic address:

Background: A novel autoinflammatory syndrome was described recently in male patients who harboured somatic mutations in the X-chromosomal UBA1 gene. These patients were characterized by adult-onset, treatment-refractory inflammation with fever, cytopenias, dysplastic bone marrow, vacuoles in myeloid and erythroid progenitor cells, cutaneous and pulmonary inflammation, chondritis and vasculitis, abbreviated as VEXAS.

Objective: This study aimed to (retrospectively) diagnose VEXAS in patients that had been previously registered with unclassified autoinflammation. We furthermore aimed to describe clinical experiences with this multifaceted, complex disease.

Methods: A systematic re-analysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in the Netherlands was performed. When no sequencing data was available, targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS.

Results: A total of 12 male patients were identified that carried mutations in UBA1. These patients presented with adult-onset (mean age 67 years, range 47-79) autoinflammation with systemic symptoms, elevated inflammatory parameters, and multiorgan involvement, most typically involving the skin and bone marrow. Novel features of VEXAS included interstitial nephritis, cardiac involvement, stroke, and intestinal perforation related to treatment with tocilizumab. Although many types of treatment were initiated, most patients became treatment-refractory with a high mortality rate of 50%.

Conclusion: VEXAS should be considered in the differential diagnosis of males with adult-onset autoinflammation, characterized by systemic symptoms and multiorgan involvement. Early diagnosis can prevent unnecessary diagnostic procedures, and provide better prognostic information and more suitable treatment options, including stem cell transplantation.
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http://dx.doi.org/10.1016/j.jaci.2021.05.014DOI Listing
May 2021