A5034006572- DNA Repair Mechanisms
- Genomics and Rare Diseases
- BRCA gene mutations in cancer
- Genomic variations and chromosomal abnormalities
- CRISPR and Genetic Engineering
- Genetics and Neurodevelopmental Disorders
- Cancer Genomics and Diagnostics
- PARP inhibition in cancer therapy
- Ovarian cancer diagnosis and treatment
- Genetic factors in colorectal cancer
- Microtubule and mitosis dynamics
- Colorectal Cancer Treatments and Studies
- Carcinogens and Genotoxicity Assessment
- Cancer-related Molecular Pathways
- Epigenetics and DNA Methylation
- Parkinson's Disease Mechanisms and Treatments
- Bacteriophages and microbial interactions
- Chromosomal and Genetic Variations
- Genomics and Chromatin Dynamics
- Gastric Cancer Management and Outcomes
- Genetic Neurodegenerative Diseases
- Connective tissue disorders research
- Peptidase Inhibition and Analysis
- RNA regulation and disease
- RNA modifications and cancer
Centogene (Germany)
2019-2024
University Medical Center
2006-2023
CS Diagnostics
2023
Amsterdam University Medical Centers
2020-2022
Centre Hospitalo-Universitaire Bab El Oued
2020
University Hospital of Oran
2020
Amsterdam UMC Location Vrije Universiteit Amsterdam
2006-2017
Vrije Universiteit Amsterdam
2002-2015
Cancer Center Amsterdam
2015
Hôpital Militaire Moulay Ismail
2009
Copy number changes and CpG methylation of various genes are hallmarks tumor development but not yet widely used in diagnostic settings. The recently developed multiplex ligation-dependent probe amplification (MLPA) method has increased the possibilities for detection gene copy aberrations a routine laboratory. Here we describe novel robust method: methylation-specific MLPA (MS-MLPA) that can detect both as well up to 40 chromosomal sequences simple reaction. In MS-MLPA, ligation...
Estimates of the spectrum and frequency pathogenic variants in Parkinson's disease (PD) different populations are currently limited biased. Furthermore, although therapeutic modification several genetic targets has reached clinical trial stage, a major obstacle conducting these trials is that PD patients largely unaware their status and, therefore, cannot be recruited. Expanding number investigated PD-related genes including related to disorders with overlapping features large,...
Abstract Purpose: Poly(ADP-ribose) polymerase (PARP) inhibitors are promising targeted treatment options for hereditary breast tumors with a homologous recombination (HR) deficiency caused by BRCA1 or BRCA2 mutations. However, the functional consequence of BRCA gene mutations is not always known and can be HR deficient other reasons than Therefore, we aimed to develop test determine activity in tumor samples facilitate selection patients eligible PARP inhibitor treatment. Experimental...
Abstract Fanconi anaemia (FA) is a hereditary disease featuring hypersensitivity to DNA cross-linker-induced chromosomal instability in association with developmental abnormalities, bone marrow failure and strong predisposition cancer. A total of 17 FA genes have been reported, all which act recessive mode inheritance. Here we report on de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation one allele the homologous recombination repair gene RAD51 an FA-like patient. This...
Retinoblastoma is a rare childhood cancer initiated by RB1 mutation or MYCN amplification, while additional alterations may be required for tumor development. However, the view on single nucleotide variants very limited. To better understand oncogenesis, we determined genomic landscape of retinoblastoma. We performed exome sequencing 71 retinoblastomas and matched blood DNA. Next, presence variants, copy number viruses. Aside from RB1, recurrent gene mutations were rare. Only limited...
Abstract Despite clear technical superiority of genome sequencing (GS) over other diagnostic methods such as exome (ES), few studies are available regarding the advantages its clinical application. We analyzed 1007 consecutive index cases for whom GS was performed in a setting 2-year period. reported pathogenic and likely (P/LP) variants that explain patients’ phenotype 212 (21.1%). In 245 additional (24.3%), variant unknown significance (VUS) related to reported. especially investigated...
Genetic stratification of Parkinson's disease (PD) patients facilitates gene-tailored research studies and clinical trials. The objective this study was to describe the design initial data from Rostock International Disease (ROPAD) study, an epidemiological observational aiming genetically characterize ~10,000 participants.Recruitment criteria included (1) diagnosis PD, (2) relative participant with a reportable LRRK2 variant, or (3) North African Berber Ashkenazi Jew. DNA analysis involved...
In multiple sclerosis (MS), brain atrophy depicted by magnetic resonance imaging reflects overall tissue loss, including axonal loss.To determine the course of studying rate development in patients who have different subtypes MS.Eighty-three with MS (42 relapsing-remitting, 21 secondary progressive, and 20 primary progressive) were studied longitudinally, an interval 2 to 4 years. Magnetic included T1- T2-weighted images obtain volume measurements: (1) parenchymal fraction as a marker global...
The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) can cause resistance to the alkylating drug temozolomide (TMZ). purpose of this study was determine relationship between MGMT status, determined by means several techniques and methods, cytotoxic response TMZ in 11 glioblastoma multiforme (GBM) cell lines 5 human tumour other origins. Cell survival analysed clonogenic assay. levels were assessed western blot analysis. promoter methylation using methylation-specific...
PurposeWithin this study, we aimed to discover novel gene–disease associations in patients with no genetic diagnosis after exome/genome sequencing (ES/GS).MethodsWe followed two approaches: (1) a patient-centered approach, which routine diagnostic analysis systematically interrogates variants genes not yet associated human diseases; and (2) gene variant centered approach. For the latter, focused on de novo that presented neurodevelopmental delay (NDD) and/or intellectual disability (ID), are...
Abstract Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies vacuolar sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation macromolecules organelles are linked to human disease. VPS proteins function as part complexes such the homotypic fusion vacuole (HOPS) tethering composed VPS11, VPS16, VPS18, VPS33A, VPS39 VPS41. The HOPS-specific subunit VPS41 has been reported...
Fanconi anemia (FA) is a recessively inherited syndrome with predisposition to bone marrow failure and malignancies. Hypersensitivity cross-linking agents cellular feature used confirm the diagnosis. The mode of inheritance autosomal recessive (12 subtypes) as well X-linked (one subtype). Most genetic subtypes have initially been defined "complementation groups" by cell fusion studies. Here we report comprehensive subtyping approach for FA that primarily based on mutation screening,...
Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein residual function at the cellular level. Patient-derived cell lines exhibit sensitivity topoisomerase PARP inhibitors, defective sister chromatid cohesion reduced DNA replication fork speed. Deleting RPE1-TERT cells inhibits proliferation survival...
Fanconi anemia (FA) is a rare genetic instability syndrome characterized by developmental defects, bone marrow failure, and high cancer risk. Fifteen subtypes have been distinguished. The majority of patients (≈85%) belong to the A (≈60%), C (≈15%) or G (≈10%), while minority distributed over remaining 12 subtypes. All seem fit within “classical” FA phenotype, except for D1 N patients, who more severe clinical symptoms. Since need special management, diagnosis should be firmly established,...
Fanconi anemia (FA) is a rare inherited disease characterized by developmental defects, short stature, bone marrow failure, and high risk of malignancies. FA heterogeneous: 15 genetic subtypes have been distinguished so far. A clinical diagnosis needs to be confirmed testing cells for sensitivity cross-linking agents in chromosomal breakage test. As second step, DNA can employed elucidate the subtype patient identify familial mutations. This knowledge allows preimplantation (PGD) enables...
We implemented a collaborative diagnostic program in Lahore (Pakistan) aiming to establish the genetic diagnosis, and asses yield clinical impact patients with suspected diseases. Local physicians ascertained pediatric who had no previous access testing. More than 1586 tests were performed 1019 individuals (349 index cases, 670 relatives). Most frequently exome/genome sequencing (ES/GS, 284/78 cases) specific gene panels (55 cases). In 61.3% of (n = 214) diagnosis was established based on...
Summary. Fanconi anaemia (FA) is a chromosomal instability disorder associated with high risk of acute myeloid leukaemia (AML). Previous work has shown that the AML cell line CHRF‐288, derived from sporadic AML‐M7 patient, does not express FANCF protein and exhibits cellular FA phenotype. We show this phenotype corrected by ‐expressing plasmid absence explained hypermethylation promoter region gene. As localized in hot‐spot for somatic (11p15), silencing might be an early step...
Fanconi anemia (FA) is a rare genomic instability syndrome. Disease-causing are biallelic mutations in any one of at least 15 genes encoding members the FA/BRCA pathway DNA-interstrand crosslink repair. Patients diagnosed based upon phenotypical manifestations and diagnosis FA confirmed by hypersensitivity cells to DNA interstrand crosslinking agents. Customary molecular diagnostics has become increasingly cumbersome, time-consuming expensive more have been identified. We performed Whole...
Fanconi anemia is an inherited cancer predisposition disease characterized by cytogenetic and cellular hypersensitivity to cross-linking agents. Seeking evidence of protein dysfunction in women at risk ovarian cancer, we screened surface epithelial cells from 25 primary cultures established 22 patients using cross-linker assays. Samples were obtained (a) high for with histologically normal ovaries, (b) patients, (c) a control group no family history breast or cancer. In chromosomal breakage...
Inactivation of the FA-BRCA pathway results in chromosomal instability. Fanconi anaemia (FA) patients have an inherited defect this and are strongly predisposed to development acute myeloid leukaemia (AML). Studies sporadic cancers shown promoter methylation FANCF gene a significant proportion various solid tumours. However, only single leukaemic case with one genes has been described date, i.e. cell line CHRF-288. We investigated presence aberrant 11 cases leukaemia.We analyzed 143 AML bone...
Abstract Failure to repair DNA damage or defective sister chromatid cohesion, a process essential for correct chromosome segregation, can be causative of chromosomal instability (CIN), which is hallmark many types cancers. We investigated how frequent this occurs in head and neck squamous cell carcinoma (HNSCC) whether specific mechanisms genes could linked these phenotypes. The genomic syndrome Fanconi anemia caused by mutations any at least 16 regulating interstrand crosslink (ICL) repair....