European Human Genetics Conference 2007 June 16 – 19, 2007 ...

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Genetic analysis, linkage, and association France, 4 Département de neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France, 5 Laboratoire de biochimie et génétique moléculaire, CHU Hôpital Cochin, Paris, France, 6 Laboratoire de génétique médicale, EA3949, Faculté de Médecine, Hôpitaux Universitaires de Strasbourg, Strasbourg, France, 7 Laboratoire de cytogénétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. Molecular diagnosis of rare autosomal recessive diseases with genetic heterogeneity represents a real challenge because clinical data do not always suggest a particular defective gene. Consanguinity is frequent in such families. Genome-wide SNP array is a recent tool that allows, by searching for homozygous regions in such patients, to select few candidate genes in which to search for mutations. We report the case of a 51 years old woman who presents a moderate limb-girdle muscular dystrophy, diagnosed at the age of 37 years. We identified six homozygous regions by SNP array analysis (Affymetrix). One of the regions, on chromosome 9, contained the TRIM32 gene. This gene was previously found mutated in families with limb-girdle muscular dystrophy type 2H (LGMD2H), a mild autosomal recessive myopathy described in the Manitoba Hutterite population and in two non-Hutterite brothers from Germany with sarcotubular myopathy. A single mutation was found in these patients, D487N, located in a conserved domain of the C-terminal part of the protein. Haplotype analysis showed that Hutterite and German patients shared common ancestry. TRIM32 was also implicated in Bardet-Biedl syndrome (BBS11), again based on a single missense mutation (P130S, in the N-terminal part) found in a consanguineous Bedouin family, rising the possibility that either the LGMD or the BBS nucleotide change could be associated with disease by linkage disequilibrium rather than being disease causing. Sequencing of TRIM32 in our patient revealed a frameshift mutation, c.1753_1766dup14 (p.L589fs) in the C-terminal part. This second mutation firmly establishes the role of TRIM32 in LGMD. P1112. Tumor Necrosis Factor polymorphisms and asthma in two international population-based cohorts (ECRHS and SAPALDIA studies) F. Castro-Giner 1 , R. F. de Cid 2 , M. Mächler 3 , M. Imboden 3 , M. Wjst 4 , D. Jarvis 5 , M. Kogevinas 1 , N. M. Probst-Hensch 2 ; 1 Centre for Research in Environmental Epidemiology, Barcelona, Spain, 2 Center for Genomic Regulation (CRG), Barcelona, Spain, 3 University of Zurich, Zurich, Switzerland, 4 GSF-National Research Center for Environmental Health, Munich, Germany, 5 Imperial College, London, United Kingdom. Genetic association studies have associated the Tumor Necrosis Factor (TNF) 308G/A polymorphism with an increased asthma risk but, overall, results are inconsistent. We assessed the prevalence of atopy and asthma in adults with two single nucleotide polymorphisms (SNPs) of the TNF and lymphotoxin α (LTA) genes. The <strong>European</strong> Community Respiratory Health Survey (ECRHS) and the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA) are two population based cohorts that have used comparable protocols including the questionnaires for respiratory symptoms and exposures as well as lung function and atopy tests. DNA samples from 10,736 participants from both cohorts were genotyped for TNF-308 and LTA+252. The prevalence of asthma symptoms was 6%. The TNF-308 polymorphism was associated with an increased asthma prevalence. The adjusted odds ratio (OR) for A allele was 1.30 (95%CI 1.1-1.53) for combined sample, 1.49 (95%CI 1.22-1.81) for ECRHS and 0.94 (95%CI 0.69-1.29) for SAPALDIA study. Association pattern shows slight differences between countries. Similar risks were observed in groups stratified by sex, smoking and atopy. The LTA+252 SNP was not associated with the prevalence of asthma symptoms or atopy. Haplotype analysis of both SNPs didn’t show a combined effect, with an OR for LTA+252 and TNF-308 rare alleles, 1.29 (95%CI 1.09-1.52). CONCLUSIONS: Our data suggest that genetic variation in TNF may contribute to a small extent to asthma risk but that this risk may differ between countries. Funding: MaratoTV3, Catalonia, Spain; Genoma España; Swiss National Science Foundation, Switzerland; Lung League Zürich, Switzerland 2 0 P1113. Glucose tolerance test in the Turner syndrome families L. Salomskienė, A. Sinkus, I. Andriuskeviciute, L. Jurkėnienė; Kaunas University of Medicine, Kaunas, Lithuania. The chromosome diseases are polymorphic because a chromosome imbalance lowers the threshold of appearance in family pathology. The decreased homeostatic buffering in developmental pathways leads to stronger phenotypical expression of multifactorially inherited traits. For our investigation were chosen the families with Turner syndrome (TS) patients since they show many extragenital pathology. Peroral glucose tolerance test (GTT) was made for them because glucose intolerance is typically multifactorial trait. GTT was performed for 37 TS patients, 42 their siblings (21 brother and 21 sister) and 52 parents (32 mothers and 20 fathers). The average age of TS patients was 20.8 yrs (ranking from 5 to 46 yrs), siblings 20.0 yrs (ranking interval 6-56 yrs), and in parents 48.1 yrs (ranking between 27 and 76 yrs). Glucose tolerance was found being disturbed in 7 (<strong>19</strong>.0%) probands, in 4 (9.5%) siblings and in 9 (17.3%) parents while in the control Lithuanian population these disturbances were found only in 1.7% of people at the age of 24-35 yrs and in 5.0% of those who are older than 35 yrs old. Therefore, the GTT shows glucose intolerance level being much more higher for TS patients and their relatives than in general population. These results allow us to affirm that damages of homeostasis usually present in families with chromosome diseases. The frequency of GTT disturbances in TS patients are twice more often than in their siblings. P1114. Mutations of PEO1 gene encoding Twinkle helicase causes mitochondrial DNA depletion E. Sarzi 1 , S. Goffart 2 , D. Chretien 1 , V. Serre 1 , A. Slama 3 , A. Munnich 1 , J. Spelbrink 2 , A. Rötig 4 ; 1 INSERM U781, Paris, France, 2 Institute of Medical Technology and Tampere University Hospital, Tampere, Finland, 3 Hôpital du Kremlin Bicêtre, Paris, France, 4 INSERM U781, PARIS, France. Twinkle is a mitochondrial 5’-3’ DNA helicase is important for mitochondrial DNA (mtDNA) maintenance. Twinkle dominant mutations have been reported in progressive external ophthalmoplegia with multiple mtDNA deletions (adPEO) whereas Twinkle recessive mutations are associated with infantile onset spinocerebellar ataxia (IOSCA). It has been previously shown that Twinkle control mtDNA copy number renders Twinkle gene (PEO1) a candidate gene for mtDNA depletion. We selected a series of 10 patients born to consanguineous parents and presenting a severe mtDNA depletion of yet unknown origin. We then studied the segregation of microsatellite markers flanking PEO1 in these patients. Homozygosity of the microsatellite markers was found for two patients of the same family. They presented neonatal lactic acidosis, trunk hypotonia, seizures, cytolysis and cholestasis. A combined defect of complexes I, III and IV of the mitochondrial respiratory chain was found in liver of both patients as well as severe mtDNA depletion (8% of the normal mtDNA content). This prompted us to sequence PEO1 and to identify a homozygous mutation at a conserved position of the protein (T457I). The similarity of Twinkle and GP4D helicase from phage T7 prompted us to model the structure of this human helicase using the X-ray coordinates of the homohexameric GP4D protein as a tertiary template. Interestingly, the point mutation is located in the interface between two monomers of the hexameric enzyme, and can probably induce a local conformational change. This work reports the first description of a PEO1 mutation responsible for mtDNA depletion in human. P1115. HLA B39 affects the type 1 diabetes predisposing effect of DRB1*0404-DQB1*0302 haplotypes in the Finnish population K. Lipponen 1 , Z. Gombos 1 , A. P. Laine 1 , O. Simell 2 , M. Knip 3,4 , R. Hermann 1,5 , J. Ilonen 1,6 ; 1 University of Turku, Immunogenetics Laboratory, Turku, Finland, 2 University of Turku, Department of Paediatrics, Turku, Finland, 3 Tampere University Hospital, Department of Paediatrics, Tampere, Finland, 4 University of Helsinki, Hospital for Children and Adolescents, Helsinki, Finland, 5 Semmelweis University, Budapest, Hungary, 6 University of Kuopio, Department of Clinical Microbiology, Kuopio, Finland. An autoimmune attack against the insulin-producing β-cells of the pancreas precedes the manifestation of clinical type 1 diabetes (T1D). The genetic factors regulating this process are poorly characterised. The main factors are DQB1-, DRB1- and DQA1-genes in human leuko-
Genetic analysis, linkage, and association cyte antigen (HLA) Class II area. However, several studies support the modifying role of HLA Class I variants. We aimed to characterize Class I modifiers of the DRB1*0404-DQB1*0302 haplotypes in relation to T1D risk and to emergence of humoral beta-cell autoimmunity. We analysed 303 ICA-positive children who were identified in a population-based genetic screening. All individuals carried the DQB1*02/*0302 or *0302/x (x≠*02, *0301, *0602) risk genotypes. Mean follow-up time was 5.46 years. Study subjects were further tested for insulin, IA2 and GAD autoantibodies and genotyped for HLA DRB1-DQA1-DQB1, HLA-B and for the insulin gene HphI promoter polymorphism. The DRB1*0404-DQB1*0302-HLA-B*39 and DRB1*0404-DQB1*0302non-HLA-B*39 haplotypes conferred significantly different T1D risks, the haplotype carrying HLA-B*39 being more predisposing (HR 7,08; p
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Volume 15 Supplement 1 June 2007 ww
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Table of Contents Spoken Presentati
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Plenary Lectures Plenary Lectures P
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Plenary Lectures labile iron can be
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Concurrent Symposia S07. Vertebrate
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Concurrent Symposia S17. Towards a
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Concurrent Symposia 11 at E13.5 sim
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Concurrent Symposia 1 phomagenesis.
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cover cryptic mutations in Drosophi
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Concurrent Sessions first excluded
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Concurrent Sessions of 210 ancestry
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Concurrent Sessions C23. Literature
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Concurrent Sessions a boy with a ty
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Concurrent Sessions C40. Mutation o
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Concurrent Sessions C48. CHROMSCAN:
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Concurrent Sessions C57. RNAi-based
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Concurrent Sessions been replicated
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Concurrent Sessions involved in an
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Concurrent Sessions tion considers
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Clinical genetics lateral neurosens
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Clinical genetics apparently sporad
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Clinical genetics itar syndrome, wh
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Clinical genetics diseases, Foundat
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Clinical genetics P0041. The first
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Clinical genetics EFNB1 was found t
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Clinical genetics of the CSB gene.
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Clinical genetics growth retardatio
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Clinical genetics PCR with a modifi
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Clinical genetics pound heterozygou
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Clinical genetics plicated: two cou
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Clinical genetics P0105. APC gene m
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Clinical genetics an indication of
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Clinical genetics great importance
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Clinical genetics P0133. Hidrotic e
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Clinical genetics eight patients as
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Clinical genetics P0152. Kabuki syn
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Clinical genetics P0161. Intrafamil
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Clinical genetics matter and normal
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Clinical genetics type at 550 bands
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Clinical genetics will be confirmed
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Clinical genetics nosed. Accurate r
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Clinical genetics which has not bee
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Clinical genetics P0217. Partial mo
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Clinical genetics fested progeroid
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Clinical genetics A 29 years old ma
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Clinical genetics ing loss (HHL). I
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Clinical genetics dació Son Llatze
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Clinical genetics These preliminary
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Clinical genetics P0272. Williams S
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Cytogenetics Po02. Cytogenetics P02
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Cytogenetics to reports from Saudi
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Cytogenetics P0298. Female-specific
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Cytogenetics P0306. Lipoatrophic pa
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Cytogenetics 22 leading to the form
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Cytogenetics somal sperm and that o
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Cytogenetics University of Belgrade
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Cytogenetics Within the same metaph
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Cytogenetics Less than 10 cases of
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Cytogenetics lar markers taken from
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Cytogenetics Brain Unaffected Schiz
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Cytogenetics ability with no speech
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Cytogenetics P0389. An age based cy
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Cytogenetics P0399. Molecular Chara
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Cytogenetics ing of complex examina
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Cytogenetics letion in 5q33 in all
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Cytogenetics and his son carried th
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Prenatal diagnosis tion about famil
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Prenatal diagnosis P0443. The risk
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Prenatal diagnosis in house PCR pro
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Prenatal diagnosis P0462. Increased
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Prenatal diagnosis P0471. Preimplan
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Prenatal diagnosis agreement with w
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Prenatal diagnosis of Turner Syndro
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Cancer genetics ously defined for d
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Cancer genetics Their frequencies w
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Cancer genetics tion Clinic-Portugu
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Cancer genetics tric carcinogenesis
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Cancer genetics P0532. Secondary ch
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Cancer genetics P0542. Differential
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Cancer genetics gastric cancer risk
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Cancer genetics ania, 3 The Institu
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Cancer genetics low: 8% (8/98 sampl
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Cancer genetics P0578. Somatic mito
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Cancer genetics P0587. Differential
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Cancer genetics cinoma (ESCC), whic
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Cancer genetics method to measure t
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Cancer genetics pression (compared
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Cancer genetics to available biolog
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Molecular and biochemical basis of
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Page 231 and 232: Molecular and biochemical basis of
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Page 235 and 236: Genetic analysis, linkage, and asso
Page 281: Genetic analysis, linkage, and asso
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Genetic counselling, education, gen
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Therapy for genetic disease Po10. T
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Therapy for genetic disease P1405.
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Therapy for genetic disease exon 7
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Author Index 1 Arslan-Krichner, M.:
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Author Index Borkowska, A.: P1089 B
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Author Index Coviello, D.: P0078, P
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Author Index Estivill, X.: P1216, P
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Author Index Graf, S. A.: P0021 Gra
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Author Index 1 Josifiova, D.: PL07
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Author Index Laurier, V.: C03 Lauri
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Author Index Melo, D. G.: P0260, P0
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Author Index Osorio, P.: P0218 Osta
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Author Index Reese, T.: C06 Regal,
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Author Index 1 Shaposhnikov, S.: P0
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Author Index Touitou, I.: P0733 Tou
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Author Index Xiao, C.: P1241 Xie, G
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Keyword Index ARMR: P0907 array CGH
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Keyword Index Consanguineous marria
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Keyword Index 1 Fronto-temporal dem
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Keyword Index IRF5: P1086 IRF6: P07
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Keyword Index NBS1 gene: P0567 NBS-
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Keyword Index P1085 Rep1: P1104 rep
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Keyword Index vision: P0632 Vitamin
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Notes 1
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A natural choice in Fabry Disease P
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European Human Genetics Conference 2007 June 16 – 19, 2007 ...

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