Stefan H. Lelieveld
A5048292329- Genomics and Rare Diseases
- Genomic variations and chromosomal abnormalities
- Cystic Fibrosis Research Advances
- Immunodeficiency and Autoimmune Disorders
- Cancer Genomics and Diagnostics
- Genetics and Neurodevelopmental Disorders
- Genomics and Phylogenetic Studies
- Genomics and Chromatin Dynamics
- Acute Lymphoblastic Leukemia research
- Retinal Development and Disorders
- Chromatin Remodeling and Cancer
- Hearing, Cochlea, Tinnitus, Genetics
- RNA modifications and cancer
- DNA Repair Mechanisms
- T-cell and B-cell Immunology
- Advanced biosensing and bioanalysis techniques
- melanin and skin pigmentation
- Congenital heart defects research
- Retinal Diseases and Treatments
- Inflammasome and immune disorders
- Fetal and Pediatric Neurological Disorders
- Cancer-related molecular mechanisms research
- Connexins and lens biology
- Tuberous Sclerosis Complex Research
- Monoclonal and Polyclonal Antibodies Research
Princess Máxima Center
2019-2024
ENPICOM (Netherlands)
2024
Radboud University Medical Center
2015-2020
Radboud Institute for Molecular Life Sciences
2015-2020
Radboud University Nijmegen
2015-2020
University Medical Center
2015-2019
Vrije Universiteit Amsterdam
2013
For next-generation sequencing technologies, sufficient base-pair coverage is the foremost requirement for reliable detection of genomic variants. We investigated whether whole-genome (WGS) platforms offer improved coding regions compared with whole-exome (WES) platforms, and single-base a large set exome genome samples. find that WES have considerably in last years, but at comparable depth, WGS outperforms terms covered regions. At higher depth (95x–160x), successfully captures 95% minimal...
Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development malignancy. YY1 acts both as repressor an activator of gene expression. We have identified 23 individuals de novo mutations or deletions phenotypic features that define syndrome cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, various congenital malformations. Our combined clinical molecular data "YY1 syndrome" haploinsufficiency...
Inherited eye disorders have a large clinical and genetic heterogeneity, which makes diagnosis cumbersome. An exome-sequencing approach was developed in data analysis divided into two steps: the vision gene panel exome analysis. In analysis, variants genes known to cause inherited were assessed for pathogenicity. If no causative detected when patient consented, entire analyzed. A total of 266 Dutch patients with different types disorders, including retinal dystrophies, cataract,...
Abstract Introduction A minority of patients with sporadic early‐onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APP PSEN1 , or PSEN2 . We hypothesized that negatively screened may harbor somatic variants these genes. Methods applied an ultrasensitive approach based on single‐molecule molecular inversion probes followed by deep next generation sequencing 11 to 100 brain and 355 blood samples from 445 AD (>80% exhibited early...
Abstract De novo mutations in specific mTOR pathway genes cause brain overgrowth the context of intellectual disability (ID). By analyzing 101 mMTOR-related a large ID patient cohort and two independent population cohorts, we show that these modulate growth health disease. We report activator gene RHEB as an is associated with megalencephaly when mutated. Functional testing mutant vertebrate animal models indicates hyperactivation concomitant increase cell head size, aberrant neuronal...
Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management disease. Exome sequencing may provide a genetic diagnosis in significant number patients single test.
Gout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced monosodium urate crystals. Since IL-37 a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating role in pathogenesis treatment gout.Variant identification was performed DNA sequencing all coding bases IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) TaqMan genotyping...
Abstract Retinitis pigmentosa (RP) is a group of inherited progressive retinal dystrophies (RD) characterized by photoreceptor degeneration. RP highly heterogeneous both clinically and genetically, which complicates the identification causative genes mutations. Targeted next-generation sequencing (NGS) has been demonstrated to be an effective strategy for detection mutations in RP. In our study, in-house gene panel comprising 75 known was used analyze cohort 47 unrelated Spanish families...
Despite advances in next generation DNA sequencing (NGS), NGS-based single gene tests for diagnostic purposes require improvements terms of completeness, quality, speed, and cost. Single-molecule molecular inversion probes (smMIPs) are a technology with unrealized potential the area clinical genetic testing. In this proof-of-concept study, we selected 2 frequently requested tests, those breast cancer genes BRCA1 BRCA2, developed an automated work flow based on smMIPs.The BRCA2 smMIPs were...
Summary De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated only account for minority the observed excess such DNMs. To identify novel genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, developed simulation-based statistical test to gene-specific enrichments We identified 285 significantly including 28 not previously robustly associated with DDs. Despite...
Unraveling the causes and pathomechanisms of progressive disorders is essential for development therapeutic strategies. Here, we identified heterozygous pathogenic missense variants LMX1A in two families Dutch origin with nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo predicted to affect homeodomain LMX1A, which DNA binding. The second c.290G (p.Cys97Ser), a zinc-binding residue LIM domain that involved...
Krüppel-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family. ZNF encode proteins that recognize specific DNA motifs in promotors. They act as transcriptional co-activators or -repressors via interaction with chromatin remodeling and other transcription factors. Only few are currently linked to human disorders identification of gene-associated diseases may help understand their function. Here we provide genetic, statistical, clinical evidence...
Summary De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated only account for minority the observed excess such DNMs. To identify novel genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, developed simulation-based statistical test to gene-specific enrichments We identified 299 significantly including 49 not previously robustly associated with DDs. Despite...
Abstract Introduction One‐quarter of the relapses in children with B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) occur very early (within 18 months, before completion treatment), and prognosis these patients is worse compared to cases that relapse after treatment has ended. Methods In this study, we performed a genomic analysis diagnosis–relapse pairs 12 who relapsed early, followed by deep‐sequencing validation all identified mutations. addition, included one case good initial...
Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and characterized by clonal heterogeneity. Genomic mutations can increase proliferative potential of leukemic cells cause treatment resistance. However, mechanisms driving mutagenesis diversification in ALL are not fully understood. In this proof principle study, we performed whole genome sequencing two cases with multiple relapses order to investigate whether groups separated time show distinct mutational...
Eukaryotic gene expression is regulated by transcription factors (TFs) binding to promoter as well distal enhancers. TFs recognize short, but specific sites (TFBSs) that are located within the and enhancer regions. Functionally relevant TFBSs often highly conserved during evolution leaving a strong phylogenetic signal. While multiple sequence alignment (MSA) potent tool detect signal, current MSA implementations optimized align maximum number of identical nucleotides. This approach might...