Mapping of a new locus for congenital anomalies of the kidney and urinary tract on chromosome 8q24

Background. Congenital anomalies of the kidney and urinary tract (CAKUT) account for the majority of end-stage renal disease in children (50%). Previous studies have mapped autosomal dominant loci for CAKUT. We here report a genome-wide search for linkage in a large pedigree of Somalian descent containing eight affected individuals with a non-syndromic form of CAKUT. Methods. Clinical data and blood samples were obtained from a Somalian family with eight individuals with CAKUT including high-grade vesicoureteral reflux and unilateral renal agenesis. Total genome search for linkage was performed using a 50K SNP Affymetric DNA microarray. As neither parent is affected, the results of the SNP array were analysed under recessive models of inheritance, with and without the assumption of consanguinity. Results. Using the non-consanguineous recessive model, a new gene locus (CAKUT1) for CAKUT was mapped to chromosome 8q24 with a significant maximum parametric Logarithm of the ODDs (LOD) score (LODmax) of 4.2. Recombinations were observed in two patients defining a critical genetic interval of 2.5 Mb physical distance flanked by markers SNP_A-1740062 and SNP_A-1653225. Conclusion. We have thus identified a new non-syndromic recessive gene locus for CAKUT (CAKUT1) on chromosome 8q24. The identification of the disease-causing gene will provide further insights into the pathogenesis of urinary tract malformations and mechanisms of renal developmen

Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

A. Palotie on työryhmän jäsen.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 pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p. T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10(-4); OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.Peer reviewe

Beam test performance of a prototype module with Short Strip ASICs for the CMS HL-LHC tracker upgrade

The Short Strip ASIC (SSA) is one of the four front-end chips designed for the upgrade of the CMS Outer Tracker for the High Luminosity LHC. Together with the Macro-Pixel ASIC (MPA) it will instrument modules containing a strip and a macro-pixel sensor stacked on top of each other. The SSA provides both full readout of the strip hit information when triggered, and, together with the MPA, correlated clusters called stubs from the two sensors for use by the CMS Level-1 (L1) trigger system. Results from the first prototype module consisting of a sensor and two SSA chips are presented. The prototype module has been characterized at the Fermilab Test Beam Facility using a 120 GeV proton beam

Aeltere Arbeitnehmer und betriebliche Sichtweisen Erste Ergebnisse einer empirisch-explorativen Studie im Arbeitsamtsbezirk Schweinfurt

Die Autoren untersuchen m. H. einer Betriebsbefragung, wie die Betriebe auf das Phaenomen eines alternden Erwerbspersonenpotentials reagieren. Im Ergebnis der Befragung wird deutlich, dass 'freimotivierte betriebliche Strategien zur Eingliederung Aelterer in den Arbeitsmarkt unter dem derzeitigen Problemdruck und den moeglichen Alternativen bei den befragten Betrieben im Arbeitsamtsbezirk Schweinfurt eher nicht zu erwarten sind. Dennoch zeigen sich im Detail einige Beschaeftigungspotentiale fuer Aeltere. Durch den Abbau von Vorurteilen, durch Qualifikation und staatliche (finanzielle) Unterstuetzung koennen diese Kapazitaeten ausgebaut werden.' (IAB2)SIGLEAvailable from IAB / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Beam test studies with silicon sensor module prototypes for the CMS Phase-2 Outer Tracker

The Large Hadron Collider (LHC) at CERN will be upgraded to the High-Luminosity LHC (HL-LHC) by 2029. In order to fully exploit the physics potential of the high luminosity era the experiments must undergo major upgrades. In the context of the upgrade of the Compact Muon Solenoid (CMS) experiment the silicon tracker will be fully replaced. The outer part of the new tracker (Outer Tracker) will be equipped with about 13,000 double-layer silicon sensor modules with two different flavors: PS modules consisting of a macro-pixel and a strip sensor and 2S modules using two strip sensors. These modules can discriminate between trajectories of charged particles with low and high transverse momentum. The different curvature of the trajectories in the CMS magnetic field leads to different hit signatures in the two sensor layers. By reading out both sensors, matching hits in the seed and correlation layer “stubs” are identified. This stub information is generated at the LHC bunch crossing frequency of 40 MHz and serves as input for the first stage of the CMS trigger. In order to quantify the hit and stub detection efficiency, beam tests have been performed. This article comprises selected studies from measurements gathered during two beam tests at the DESY test beam facility with 2S prototype modules assembled in 2021, featuring the Low Power Gigabit Transceiver (lpGBT). In order to compare the module performance at the beginning and end of the CMS runtime, a module with irradiated components has been built and intensively tested

Mapping of a new locus for congenital anomalies of the kidney and urinary tract on chromosome 8q24

Background. Congenital anomalies of the kidney and urinary tract (CAKUT) account for the majority of end-stage renal disease in children (50%). Previous studies have mapped autosomal dominant loci for CAKUT. We here report a genome-wide search for linkage in a large pedigree of Somalian descent containing eight affected individuals with a non-syndromic form of CAKUT

Identification of a Ninein (NIN) mutation in a family with spondyloepimetaphyseal dysplasia with joint laxity (leptodactylic type)-like phenotype

Spondyloepimetaphyseal dysplasia with joint laxity-leptodactylic type (SEMDJL2) is an autosomal dominant skeletal dysplasia which is characterized by midface hypoplasia, short stature, joint laxity with dislocations, genua valga, progressive scoliosis, and slender fingers. Recently, heterozygous missense mutations in KIF22, a gene which encodes a member of the kinesin-like protein family, have been identified in sporadic as well as familial cases of SEMDJL2. In the present study homozygosity mapping and whole-exome sequencing were combined to analyze a consanguineous family with a phenotype resembling SEMDJL2. We identified homozygous missense mutations in the two nearby genes NIN (Ninein) and POLE2 (DNA polymerase epsilon subunit B) which segregate with the disease in the family and were not present in 500 healthy control individuals and in the 1094 control individuals contained within the 1000-genomes database. We present several lines of evidence that mutant Ninein is most likely causative for the SEMDJL2-like phenotype. The centrosomal protein NIN shows a functional relationship with KIF22 and other proteins associated with chromosome congression/movement, centrosomal function, and ciliogenesis, which have been associated with skeletal dysplasias. Moreover, compound heterozygous missense mutations at more N-terminal positions of Ninein have very recently been identified in a family with microcephalic primordial dwarfism. Together with the present report this strongly supports a fundamental role of Ninein in skeletal development. (C) 2013 Elsevier B.V. All rights reserved

Linkage and Association Analysis Identifies TRAF1 Influencing Common Carotid Intima-Media Thickness

Background and Purpose-Carotid intima-media thickness is a marker for subclinical atherosclerosis that predicts subsequent clinical cardiovascular events. The aim of this study was to identify chromosomal loci with linkage or association to common carotid intima-media thickness. Methods-Nuclear families were recruited using the single parental proband sib-pair design. Genotype data were available for 546 individuals from 132 nuclear families of the Bonn IMT Family Study using the Affymetrix GeneChip Human Mapping 250K Sty chip. Multipoint logarithm of the odds (LOD) scores were determined with the quantitative trait locus statistic implemented in multipoint engine for rapid likelihood. Linkage analysis and family-based association tests were conducted. Data from 2471 German participants from the HNR (Heinz Nixdorf Recall) Study were used for subsequent replication. Results-Two new genomic regions with suggestive linkage (LOD>2) were identified on chromosome 4 (LOD=2.26) and on chromosome 17 (LOD=2.01). Previously reported linkage findings were replicated on chromosomes 13 and 14. Fifteen single nucleotide polymorhisms, located on chromosomes 4, 6, and 9, revealed P<10(-4) in the family-based association analyses. One of these signals was replicated in HNR (rs2416804, 1-sided P=1.60x10(-3), located in the gene TRAF1). Conclusions-This study presents the first genome-wide linkage and association study of common carotid intima-media thickness in the German population. Alleles of rs2416804 in TRAF1 were identified as being linked and associated with carotid intima-media thickness. Further studies are needed to evaluate the contribution of this locus to the development of atherosclerosis