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Mutational signatures are critical for proper estimation of purifying selection pressures in cancer somatic mutation data when using the dN/dS metric Ghent University
Large cancer genome sequencing initiatives have led to the identification of cancer driver genes based on signals of positive selection in somatic mutation data. Additionally, the identification of purifying (negative) selection has the potential to identify essential genes that may be of therapeutic interest. The most widely used way of quantifying selection pressures in protein-coding genes is the dN/dS metric, which compares non-synonymous to ...
New noncoding base pair mutation at the identical locus as the original NCMD/MCDR1 in a Mexican family, suggesting a mutational hotspot Ghent University
Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations KU Leuven
Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to ...
Long-term follow-up of retinal degenerations associated with LRAT mutations and their comparability to phenotypes associated with RPE65 mutations Ghent University
Purpose: To investigate the natural history in patients with LRAT-associated retinal degenerations (RDs), in the advent of clinical trials testing treatment options. Methods: A retrospective cohort of 13 patients with LRAT-RDs. Results: Twelve patients from a genetic isolate carried a homozygous c.12del mutation. One unrelated patient carried a homozygous c.326G>T mutation. The mean follow-up time was 25.3 years (SD 15.2; range 4.8-53.5). The ...
Borderline rpoB mutations transmit at the same rate as common rpoB mutations in a tuberculosis cohort in Bangladesh University of Antwerp Institute of Tropical Medicine
The spread of multidrug-resistant tuberculosis (MDR-TB) is a growing problem in many countries worldwide. Resistance to one of the primary first-line drugs, rifampicin, is caused by mutations in the Mycobacterium tuberculosis rpoB gene. So-called borderline rpoB mutations confer low-level resistance, in contrast to more common rpoB mutations which confer high-level resistance. While some borderline mutations show lower fitness in vitro than ...
Rare missense mutations and compound heterozygous mutations in ABCA7 contribute to Alzheimer's disease in Belgian patients. KU Leuven
BACKGROUND: Initially, ABCA7 was associated with Alzheimer's disease (AD) in large genome-wide association studies. Targeted resequencing of ABCA7 suggested a role for rare premature termination codon (PTC) mutations. We observed loss of ABCA7 in PTC carriers, although with high variability due to differences in transcript rescue. Additionally, rare missense mutations are present in ABCA7 with unknown effect on the protein. We aimed to ...
Breast cancer diagnosed during pregnancy is associated with enrichment of non-silent mutations, mismatch repair deficiency signature and mucin mutations KU Leuven
Breast cancer diagnosed during pregnancy (BCP) is a rare and highly challenging disease. To investigate the impact of pregnancy on the biology of breast cancer, we conducted a comparative analysis of a cohort of BCP patients and non-pregnant control patients by integrating gene expression, copy number alterations and whole genome sequencing data. We showed that BCP exhibit unique molecular characteristics including an enrichment of non-silent ...
SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors. KU Leuven
Defects in complex II of the mitochondrial respiratory chain are a rare cause of mitochondrial disorders. Underlying autosomal-recessive genetic defects are found in most of the 'SDHx' genes encoding complex II (SDHA, SDHB, SDHC, and SDHD) and its assembly factors. Interestingly, SDHx genes also function as tumor suppressor genes in hereditary paragangliomas, pheochromocytomas, and gastrointestinal stromal tumors. In these cases, the affected ...