Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes

Objective: The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods: We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation: We identified 8 known missense mutations, previously reported as path

Marinesco-Sjogren syndrome due to SIL1 mutations with a comment on the clinical phenotype

Item does not contain fulltextBACKGROUND: Marinesco-Sjogren syndrome is an autosomal recessive cerebellar ataxia, characterised by cerebellar ataxia, myopathy, cataracts and intellectual disability, due to mutations in the SIL1 gene. METHODS: The clinical features and two novel SIL1 mutations of four Dutch patients with Marinesco-Sjogren syndrome are described and compared to the literature on genetically proven Marinesco-Sjogren patients. RESULTS: The core phenotype of this syndrome appears homogeneous, but: [1] cataract can develop later than the motor and cognitive signs; [2] myopathy is an early feature that seems progressive during the course of the disease; [3] serum creatine kinase is normal or only mildly elevated; [4] peripheral neuropathy is absent; and [5] a variable degree of intellectual disability is present in most Marinesco-Sjogren patients. CONCLUSIONS: Because the late appearance of some hallmarks and the uncertainty as to whether incomplete phenotypes occur, SIL1 mutation analysis is helpful early in the diagnostic work-up of children with suspected inherited ataxias

Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease.

BACKGROUND: Three rare autosomal recessive disorders share the combination of congenital muscular dystrophy and brain malformations including a neuronal migration defect: muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), and Fukuyama congenital muscular dystrophy (FCMD). In addition, ocular abnormalities are a constant feature in MEB and WWS. Lack of consistent ocular abnormalities in FCMD has allowed a clear clinical demarcation of this syndrome, whereas the phenotypic distinction between MEB and WWS has remained controversial. The MEB gene is located on chromosome 1p32-p34. OBJECTIVES: To establish distinguishing diagnostic criteria for MEB and WWS and to determine whether MEB and WWS are allelic disorders. METHODS: The authors undertook clinical characterization followed by linkage analysis in 19 MEB/WWS families with 29 affected individuals. With use of clinical diagnostic criteria based on Finnish patients with MEB, each patient was categorized as having either MEB or WWS. A linkage and haplotype analysis using 10 markers spanning the MEB locus was performed on the entire family resource. RESULTS: Patients in 11 families were classified as having MEB and in 8 families as WWS. Strong evidence in favor of genetic heterogeneity was obtained in the 19 families. There was evidence for linkage to 1p32-p34 in all but 1 of the 11 pedigrees segregating the MEB phenotype. In contrast, linkage to the MEB locus was excluded in seven of eight of the WWS families. CONCLUSION: These results allow the classification of MEB and WWS as distinct disorders on both clinical and genetic grounds and provide a basis for the mapping of the WWS gene(s)

Variation of CNV distribution in five different ethnic populations.

Item does not contain fulltextRecent studies have revealed a new type of variation in the human genome encompassing relatively large genomic segments ( approximately 100 kb-2.5 Mb), commonly referred to as copy number variation (CNV). The full nature and extent of CNV and its frequency in different ethnic populations is still largely unknown. In this study we surveyed a set of 12 CNVs previously detected by array-CGH. More than 300 individuals from five different ethnic populations, including three distinct European, one Asian and one African population, were tested for the occurrence of CNV using multiplex ligation-dependent probe amplification (MLPA). Seven of these loci indeed showed CNV, i.e., showed copy numbers that deviated from the population median. More precise estimations of the actual genomic copy numbers for (part of) the NSF gene locus, revealed copy numbers ranging from two to at least seven. Additionally, significant inter-population differences in the distribution of these copy numbers were observed. These data suggest that insight into absolute DNA copy numbers for loci exhibiting CNV is required to determine their potential contribution to normal phenotypic variation and, in addition, disease susceptibility

THE CONCEPT OF AEOS WITHIN THE CONTEXT OF THEORY OF LAW

Development of integration processes in the Customs Union (CU) of the Republic of Belarus, Kazakhstan and the Russian Federation at the present stage requires reshaping of customs administration in accordance with best practices and enforcement standards of the World Customs Organization. The legal institution of Authorized Economic Operator (AEO) is currently the subject of study of Russian and foreign researchers, due to the need to improve customs control through the use of modern tools and technologies designed for providing effective customs control and secure supply chain. The subject institution is based on introduced models of special customs simplifications (customs benefits) in exchange for compliance with economic operator specific requirements and conditions established by the customs legislation. In view of the forthcoming transformation of the Customs Union into the Eurasian EconomicUnion by2015,the AEO institution is acquiring new content and requires further study.To obtain the most objective data on the subject under examination the authors used general scientific methods, such as induction, deduction, analysis, synthesis. In addition, they used such particular scientific methods as comparative legal, historical legal, formal logic, system analysis, etc. In order to create an optimal balance between the rights and obligations of bona fide traders and the state represented by the customs authorities, the customs administration needs constant improvement. The authors exploring the AEO institution, come to the conclusion that its further development needs the improvement of special AEO status in terms of revising its administrative powers. This conclusion is based not only on the analysis of areas of concern related to the assignment of administrative and legal status to the AEO and its subsequent activities but also on the investigation into national AEO programs implemented by foreign customs administrations. The definition of the AEO legal institution is unquestionably has both theoretical and practical value; it constitutes a significant contribution to the theory of administrative law and customs law as well as to the practice of public administration