Ultra-Rare Genetic Variation in the Epilepsies : A Whole-Exome Sequencing Study of 17,606 Individuals

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA(A) receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNAIG, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.Peer reviewe

Role of DNA methylation in head and neck cancer

Head and neck cancer (HNC) is a heterogenous and complex entity including diverse anatomical sites and a variety of tumor types displaying unique characteristics and different etilogies. Both environmental and genetic factors play a role in the development of the disease, but the underlying mechanism is still far from clear. Previous studies suggest that alterations in the genes acting in cellular signal pathways may contribute to head and neck carcinogenesis. In cancer, DNA methylation patterns display specific aberrations even in the early and precancerous stages and may confer susceptibility to further genetic or epigenetic changes. Silencing of the genes by hypermethylation or induction of oncogenes by promoter hypomethylation are frequent mechanisms in different types of cancer and achieve increasing diagnostic and therapeutic importance since the changes are reversible. Therefore, methylation analysis may provide promising clinical applications, including the development of new biomarkers and prediction of the therapeutic response or prognosis. In this review, we aimed to analyze the available information indicating a role for the epigenetic changes in HNC

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Assessment of Preoperative Risk Factors for Post-LASIK Ectasia Development

Mohamed Tarek El-Naggar,1 Rania Serag Elkitkat,2– 5 Hossam El-din Ziada,6 Louise Pellegrino Gomes Esporcatte,7– 9 Renato Ambrósio Jr7– 11 1Refractive Surgery Unit, Ophthalmology Department, Research Institute of Ophthalmology, Giza, Egypt; 2Ophthalmology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 3Watany Eye Hospital, Cairo, Egypt; 4Watany Research and Development Center, Cairo, Egypt; 5Ophthalmology Department, Modern University for Technology and Information, Cairo, Egypt; 6Cornea and Refractive Surgery Unit, Ophthalmology Department, Faculty of Medicine, AL-Azhar University, Cairo, Egypt; 7Rio de Janeiro Corneal Tomography and Biomechanics Study Group, Rio de Janeiro, Brazil; 8Instituto de Olhos Renato Ambrósio, Rio de Janeiro, Brazil; 9Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil; 10Brazilian Study Group of Artificial Intelligence and Corneal Analysis - BrAIN, Rio de Janeiro & Maceió, Brazil; 11Department of Ophthalmology, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, BrazilCorrespondence: Mohamed Tarek El-Naggar, Email [email protected]: To evaluate preoperative risk factors (mainly those related to corneal topography/tomography) for post-LASIK ectasia development.Methods: A retrospective case review for post-LASIK ectasia for myopia or myopic astigmatism. The evaluated data included preoperative subjective refraction, method of flap creation, and topometric/tomographic parameters from Oculus Pentacam, including subjective curvature pattern, topometric, elevation, and pachymetric indices from the Belin Ambrosio display “BAD”, and the Pentacam Random Forest Index (PRFI). Moreover, preoperative ectasia detection indices were calculated (including Percentage of Tissue Altered “PTA” index, Randleman Ectasia Risk Score System “ERSS”, and Navarro Index for Corneal Ectasia “NICE”).Results: Twenty-four eyes of 15 patients were enrolled. Concerning the risk factors, age was lower than 25 in 19 eyes (79%); flaps were created using a microkeratome in 17 eyes (70.8%); thinnest pachymetry was lower than 510μm in eight eyes (33%); total deviation from BAD was higher than 1.6 in 50%; Ambrósio’s relational thickness (ART) max was lower than 340 in 45.83%; PTA index was higher than 40% in 16%; ERSS was more than 3 points in 62.5%; NICE was higher than 8 points in three eyes (12.5%); PRFI index was more than 0.125 in 87.5%; two eyes (8%) had no identifiable risk factors.Conclusion: Current ectasia risk assessment criteria were insufficient for detecting a relatively large number of cases. There is an unequivocal need for more information, which may be derived from biomechanical assessment and epithelial thickness mapping. Novel corneal tomography indices derived from artificial intelligence may increase accuracy in characterizing ectasia susceptibility.Keywords: cornea ectasia, preoperative ectasia risk assessment, LASIK screening, Pentaca