Targeted exonic sequencing identifies novel variants in a cerebral small vessel disease cohort.

Background And Aims: Cerebral small vessel diseases (CSVDs) are a set of conditions that affect the small blood vessels in the brain and can cause severe neurological pathologies such as stroke and vascular dementia. The most common monogenic CSVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) which is caused by mutations in NOTCH3. However, only 15-20% of CADASIL cases referred for genetic testing have pathogenic mutations in NOTCH3.

Exonic mutations in cell-cell adhesion may contribute to CADASIL-related CSVD pathology.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition caused by mutations in NOTCH3 and results in a phenotype characterised by recurrent strokes, vascular dementia and migraines. Whilst a genetic basis for the disease is known, the molecular mechanisms underpinning the pathology of CADASIL are still yet to be determined. Studies conducted at the Genomics Research Centre (GRC) have also identified that only 15-23% of individuals clinically suspected of CADASIL have mutations in NOTCH3.

GSTM1 and GSTT1 polymorphisms associated with pain in a chemotherapy-induced peripheral neuropathy cohort.

Purpose: Chemotherapy induced peripheral neuropathy (CIPN) is a debilitating condition that is a direct consequence of receiving cancer treatment. The molecular aetiology of CIPN is not well understood, and it is theorised that there may be a genetic component. Genetic polymorphisms in Glutathione-S Transferase (GST) genes, including GSTT1, GSTM1 and GSTP1, encode for enzymes known to metabolise drugs used in chemotherapy, and have been theorised to be associated with CIPN.

Investigating a Genetic Link Between Alzheimer's Disease and CADASIL-Related Cerebral Small Vessel Disease.

Monogenic forms of Alzheimer's disease (AD) have been identified through mutations in genes such as APP, PSEN1, and PSEN2, whilst other genetic markers such as the APOE ε carrier allele status have been shown to increase the likelihood of having the disease. Mutations in these genes are not limited to AD, as APP mutations can also cause an amyloid form of cerebral small vessel disease (CSVD) known as cerebral amyloid angiopathy, whilst PSEN1 and PSEN2 are involved in NOTCH3 signalling, a process known to be dysregulated in the monogenic CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The overlap between AD genes and causes of CSVD led to the hypothesis that mutations in other genes within the PANTHER AD-presenilin pathway may be novel causes of CSVD in a cohort of clinically suspicious CADASIL patients without a pathogenic NOTCH3 mutation.

Tiered analysis of whole-exome sequencing for epilepsy diagnosis.

It is thought that despite highly variable phenotypic expression, 70-80% of all epileptic cases are caused by one or more genetic mutations. Next generation sequencing technologies, such as whole exome sequencing (WES), can be used in a diagnostic or research setting to identify genetic mutations which may have significant prognostic implications for patients and their families. In this study, 398 genes associated with epilepsy or recurrent seizures were stratified into tiers based on genotype-phenotype concordance, tissue gene expression, frequency of affected individuals with mutations and evidence from functional and family studies.

Variant Call Format-Diagnostic Annotation and Reporting Tool: A Customizable Analysis Pipeline for Identification of Clinically Relevant Genetic Variants in Next-Generation Sequencing Data.

In this article, we introduce the variant call format-diagnostic annotation and reporting tool (VCF-DART), a customized analysis pipeline tool for the rapid annotation of variants from exome or genome sequencing and the generation of reports for genetic diagnostics. VCF-DART uses custom gene lists to categorize variants into specific analysis tiers and to subcategorize them on the basis of standard parameters to facilitate the rapid interrogation of potentially pathogenic variants by human operators. The tool uses publicly available databases to identify a range of data to assist with variant classification and curation processes and includes robust logging of parameters and database versions to allow comparison of analyses performed at different times.

Three cases of an unusual pattern of invasion in malignant Brenner tumors.

Ovarian malignant Brenner tumors are rare neoplasms that are typically admixed with benign and borderline Brenner tumor elements. We report 3 cases of an unusual variant of malignant Brenner tumor where the infiltrative malignant component arose directly from a benign Brenner tumor rather than from borderline elements and did not exhibit a desmoplastic stromal response. Borderline elements were present in 1 case, but the invasive component did not arise from these.

Epstein-Barr virus-positive mucocutaneous ulcer of the oral cavity: the importance of having a detailed clinical history to reach a correct diagnosis.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a recently recognized clinicopathological entity. It presents as an ulcerative lesion with lymphoma-like histologic features and is clinically associated with various types of immunosuppression. EBVMCU lesions respond well to conservative measures aimed at correcting the underlying immunosuppression.