ABSTRACT
OBJECTIVES: Both clinical genomics and e-Health technology are changing the way medicine is being practiced. Although the basic clinical methodology of good medical care will remain unchanged, the combined power of genomics and electronic health records has the capability of enhancing, and in some cases transforming, the practice of medicine. This is particularly true in the care of patients with complex long-term medical conditions such as chronic refractory epilepsy, especially in those with related complex comorbidities including intellectual disability and psychiatric disease. METHODS: Herein we outline the development and integration of an epilepsy genomics module into a preexisting epilepsy electronic patient record (EPR) system. RESULTS: We describe how this EPR infrastructure is used to facilitate discussion at multidisciplinary clinical meetings around molecular diagnosis and resulting changes in management. SIGNIFICANCE: This work illustrates the role of eHealth technology in embedding genomics into the clinical pathway.
Subject(s)
Electronic Health Records , Epilepsy/genetics , Genomics , Epilepsy/therapy , Genomics/methods , Humans , Interdisciplinary Communication , Pedigree , Phenotype , PhotographyABSTRACT
Next generation sequencing provides an important opportunity for improved diagnosis in epilepsy. To date, the majority of diagnostic genetic testing is conducted in the paediatric arena, while the utility of such testing is less well understood in adults with epilepsy. We conducted whole exome sequencing (WES) and copy number variant analyses in an Irish cohort of 101 people with epilepsy and co-morbid intellectual disability to compare the diagnostic yield of genomic testing between adult and paediatric patients. Variant interpretation followed American College of Medical Genetics and Genomics (ACMG) guidelines. We demonstrate that WES, in combination with array-comparative genomic hybridisation, provides a diagnostic rate of 27% in unrelated adult epilepsy patients and 42% in unrelated paediatric patients. We observe a 2.7% rate of ACMG-defined incidental findings. Our findings indicate that WES has similar utility in both adult and paediatric cohorts and is appropriate for diagnostic testing in both epilepsy patient groups.
Subject(s)
Epilepsy/genetics , Genetic Testing/methods , Intellectual Disability/genetics , Adolescent , Adult , Child , Child, Preschool , Comorbidity , Comparative Genomic Hybridization/methods , Comparative Genomic Hybridization/standards , Epilepsy/diagnosis , Epilepsy/epidemiology , Female , Genetic Testing/standards , Humans , Infant , Intellectual Disability/diagnosis , Intellectual Disability/epidemiology , Male , Middle Aged , Mutation , Sensitivity and Specificity , Exome Sequencing/methods , Exome Sequencing/standardsABSTRACT
Statins are mainstream therapy in the treatment and prevention of cardiovascular disease through inhibitory effects on cholesterol synthesis. However, statins' beneficial effects in cardiovascular disease may also be attributable to their role as anti-inflammatory mediators. Here, we investigated the effects of simvastatin treatment on expression levels of interleukin (IL) 1ß in both patient with hyperlipidemia and healthy human peripheral blood mononuclear cells (PBMCs) using cholesterol crystals (CC), a cardiovascular pathogenic stimulus for activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome. Cholesterol crystal-induced NLRP3 inflammasome activation was used to trigger maturation and release of IL-1ß in PBMCs. Specifically, isolated PBMCs from patients with hyperlipidemia at baseline and following 8 weeks of in vivo treatment with simvastatin (10-20 mg) daily were stimulated with lipopolysaccharide (LPS; 100 ng/mL) for 3 hours to induce proIL-Iß expression followed by CC (2 mg/mL) stimulation for further 18 hours to activate the NLRP3 inflammasome complex to induce maturation/activation of IL-1ß. Peripheral blood mononuclear cells were also isolated from healthy donors and stimulated in vitro with simvastatin (50, 25, 5, and 2 µmol/L) prior to stimulation with LPS and CC as described above. The effects of simvastatin treatment on levels of IL-1ß expression were determined by enzyme-linked immunosorbent assay and western blot. Both in vitro and in vivo treatments with simvastatin led to a significant reduction in the levels of expression of IL-1ß in response to stimulation with CC. Simvastatin inhibits the expression and activation of IL-1ß induced by CC in PBMCs, which may contribute to its protective role in patients with cardiovascular disease.