Методы и механизмы геттерирования кремниевых структур в производстве интегральных микросхем

Увеличение степени интеграции элементной базы предъявляет все более жесткие требования к уменьшению концентрации загрязняющих примесей и окислительных дефектов упаковки в исходных кремниевых пластинах с ее сохранением в технологическом цикле изготовления ИМС. Это обуславливает высокую актуальность применения геттерирования в современной технологии микроэлектроники. В статье рассмотрены существующие методы геттерирования кремниевых пластин и механизмы их протекания.Збільшення ступеня інтеграції елементної бази пред'являє все більш жорсткі вимоги до зменшення концентрації забруднюючих домішок та окислювальних дефектів упаковки у вихідних кремнієвих пластинах за її збереження у технологічному циклі виготовлення ІМС. Це обумовлює високу актуальність застосування гетерування в сучасній технології мікроелектроніки. Розглянуто існуючі методи гетерування кремнієвих пластин та розглянуто механізми їх перебігу.Increasing the degree of integration of hardware components imposes more stringent requirements for the reduction of the concentration of contaminants and oxidation stacking faults in the original silicon wafers with its preservation in the IC manufacturing process cycle. This causes high relevance of the application of gettering in modern microelectronic technology. The existing methods of silicon wafers gettering and the mechanisms of their occurrence are considered

Rare coding variants in genes encoding GABA_A receptors in genetic generalised epilepsies: an exome-based case-control study

BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors. INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy. FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund)

Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies : an exome-based case-control study

Background: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41–4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05–2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02–2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors. Interpretation: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy. Funding: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund)

Rare exonic deletions of the <em>RBFOX1</em> gene increase risk of idiopathic generalized epilepsy.

PURPOSE: Structural variations disrupting the gene encoding the neuron-specific splicing regulator RBFOX1 have been reported in three patients exhibiting epilepsy in comorbidity with other neuropsychiatric disorders. Consistently, the Rbfox1 knockout mouse model showed an increased susceptibility of seizures. The present candidate gene study tested whether exon-disrupting deletions of RBFOX1 increase the risk of idiopathic generalized epilepsies (IGEs), representing the largest group of genetically determined epilepsies. METHODS: Screening of microdeletions (size: &gt;40&nbsp;kb, coverage&nbsp;&gt;20 markers) affecting the genomic sequence of the RBFOX1 gene was carried out by high-resolution single-nucleotide polymorphism (SNP) arrays in 1,408 European patients with idiopathic generalized epilepsy (IGE) and 2,256 population controls. Validation of RBFOX1 deletions and familial segregation analysis were performed by quantitative polymerase chain reaction (qPCR). KEY FINDINGS: We detected five exon-disrupting RBFOX1 deletions in the IGE patients, whereas none was observed in the controls (p&nbsp;=&nbsp;0.008, Fisher&#39;s exact test). The size of the exonic deletions ranged from 68 to 896&nbsp;kb and affected the untranslated 5&#39;-terminal RBFOX1 exons. Segregation analysis in four families indicated that the deletions were inherited, display incomplete penetrance, and heterogeneous cosegregation patterns with IGE. SIGNIFICANCE: Rare deletions affecting the untranslated 5&#39;-terminal RBFOX1 exons increase risk of common IGE syndromes. Variable expressivity, incomplete penetrance, and heterogeneous cosegregation patterns suggest that RBFOX1 deletions act as susceptibility factor in a genetically complex etiology, where heterogeneous combinations of genetic factors determine the disease phenotype

Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy

Gephyrin is a postsynaptic scaffolding protein, essential for the clustering of glycine and gamma-aminobutyric acid type-A receptors (GABA(A)Rs) at inhibitory synapses. An impairment of GABAergic synaptic inhibition represents a key pathway of epileptogenesis. Recently, exonic microdeletions in the gephyrin (GPHN) gene have been associated with neurodevelopmental disorders including autism spectrum disorder, schizophrenia and epileptic seizures. Here we report the identification of novel exonic GPHN microdeletions in two patients with idiopathic generalized epilepsy (ICE), representing the most common group of genetically determined epilepsies. The identified GPHN microdeletions involve exons 5-9 (Delta 5-9) and 2-3 (Delta 2-3), both affecting the gephyrin G-domain. Molecular characterization of the GPHN Delta 5-9 variant demonstrated that it perturbs the clustering of regular gephyrin at inhibitory synapses in cultured mouse hippocampal neurons in a dominant-negative manner, resulting in a significant loss of gamma(2)-subunit containing GABAARs. GPHN Delta 2-3 causes a frameshift resulting in a premature stop codon (p.V22Gfs*7) leading to haplo-insufficiency of the gene. Our results demonstrate that structural exonic microdeletions affecting the GPHN gene constitute a rare genetic risk factor for IGE and other neuropsychiatric disorders by an impairment of the GABAergic inhibitory synaptic transmission. (C) 2014 Published by Elsevier Inc