Publications by authors named "C F Tops"
SDHx variant carriers have an increased risk of developing head and neck paraganglioma. The Dutch guidelines state that these patients require lifelong follow-up, but no clear recommendation is made about the frequency of screening. To determine the annual risk of developing head and neck paraganglioma in SDHx variant carriers after a negative initial screening.
View Article and Find Full Text PDFFunctional analyses are the main method to classify mismatch repair (MMR) gene variants of uncertain significance (VUSs). However, the pathogenicity remains unclear for many variants because of conflicting results between clinical, molecular, and functional data. In this study, we evaluated whether whole exome sequencing (WES) could add another layer of evidence to elucidate the pathogenicity of MMR variants with conflicting interpretations.
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- - Pathogenic variants in the APC gene are responsible for familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome, prompting the development of specific classification criteria to aid in variant interpretation.
- - The study involved applying these APC-specific criteria to assess over 10,000 unique APC variants from databases like ClinVar and LOVD, leading to a significant reclassification of variants of uncertain significance (VUSs), with many being reassessed as (likely) benign or (likely) pathogenic.
- - The results showed that using these tailored criteria effectively reduced VUSs by 37%, highlighted the potential for systematic variant classification in large datasets, and established a model that could benefit future genetic variant interpretation efforts in
Two independent exome sequencing initiatives aimed to identify new genes involved in the predisposition to nonpolyposis colorectal cancer led to the identification of heterozygous loss-of-function variants in NPAT, a gene that encodes a cyclin E/CDK2 effector required for S phase entry and a coactivator of histone transcription, in two families with multiple members affected with colorectal cancer. Enrichment of loss-of-function and predicted deleterious NPAT variants was identified in familial/early-onset colorectal cancer patients compared to non-cancer gnomAD individuals, further supporting the association with the disease. Previous studies in Drosophila models showed that NPAT abrogation results in chromosomal instability, increase of double strand breaks, and induction of tumour formation.
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- The study focused on improving the classification of genetic variants linked to familial adenomatous polyposis using APC-specific criteria developed by an expert panel.
- A total of 10,228 unique variants were analyzed, resulting in 41% of VUS from ClinVar and 61% from LOVD being reclassified, primarily as (Likely) Benign, which reduced the overall VUS by 37%.
- The research highlighted a systematic approach to variant classification in large datasets that could be applied to other gene/disease interpretations and allowed for prioritization of VUS requiring further evidence collection.