2008 Barcelona - European Society of Human Genetics

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Plenary Lectures meta-analysis of three T2D GWA scans (DGI, FUSION, WTCCC) encompassing 10,128 European-descent individuals (4549 cases and 5579 controls) and ~2 .2 million SNPs (directly genotyped and imputed) . Even after excluding known type 2 diabetes loci, we saw a strong enrichment of highly associated variants (426 with p
Plenary Lectures 6 Medical Genetics Dept., St. Elizabeth Cancer Institute, Bratislava, Slovakia, 7 Azienda Ospedaliera San Giovanni Battista, Torino, Italy, 8 Dept. of Pathology, „OIRM-S.Anna“ Hospital, Torino, Italy, 9 Consultant Histopathologist, King Abdul Aziz Specialist Hospital, Taif, Saudi Arabia, 10 Institute of Human Genetics, University of Duisburg-Essen, Essen, Germany, 11 Centre for Human Genetics, University hospital, Regensburg, Germany, 12 Prenatal Medicine, Department of Gynecology and Obstetrics, University Hospital, Cologne, Germany, 13 Medical Centre of Rheumatology, Berlin-Buch, Germany, 14 Department of Paediatric Radiology, University Hospital, Cologne, Germany, 15 Department of Neuropediatrics, Vestische Kinder- und Jugendklinik, University of Witten/Herdecke, Datteln, Germany. Impaired fetal movement causes growth retardation, fetal hydrops, polyhydramnios, pulmonary hypoplasia, multiple joint contractures with or without webbing (pterygia), and other features, summarized under the term fetal akinesia deformation sequence (FADS) . We sequenced 75 patients with severe FADS and found mutations in the γ, α1and δ subunit of the AChR as well as in the receptor associated protein of the synapse, rapsyn . Our major conclusions are that - FADS is a frequent genetic condition . - Doctors in pre- and neonatal care are often confronted with FADS but are not as aware of possible involvement of AChR pathway mutations as a neurologist would be . - More awareness of the potential involvement of the AChR pathway will save the lives of some newborns . Our findings are important to the understanding of cellular biology, genetics and clinical relevance of AChR mutations especially in pre- and neonatal care . Early neonatal diagnosis in one of our families helped to start effective treatment for the second affected child, whereas the first affected - undiagnosed - died in infancy . One major conclusion is that the inclusion of clinical and molecular data from prenatally deceased siblings is crucial to elucidate severe phenotypes of AChR pathway mutations . We suggest that the AChR pathway contributes to a broad spectrum of intrauterine phenotypes and should be examined functionally and genetically in patients with recurrent spontaneous abortions, fetal akinesia, hydrops, pterygia, or inborn contractures . PL2.7 Plastin 3 protects against spinal muscular atrophy (smA) - the first report of a fully protective modifier of a Mendelian disease Brunhilde Wirth 1,2,3 , Sandra Kröber 1,2 , Michelle L. McWhorter 4 , Wilfried Rossoll 5 , Stefan Müller 3 , Michael Krawczak 6 , Gary J. Bassell 5 , Christine E. Beattie 4 , and Gabriela E. Oprea 1,2,3 ; 1 Institute of Human Genetics, University Hospital, Cologne, Germany, 2 Institute of Genetics and 3 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany, 4 Centre for Molecular Neurobiology, The Ohio State University, Columbus, OH, USA, 5 Emory University School of Medicine, Department of Cell Biology, Atlanta, GA, USA, 6 Institute of Medical Informatics and Statistics, Christian-Albrechts University of Kiel, Kiel, Germany. Homozygous deletion of SMN1 leads to spinal muscular atrophy (SMA), the most frequent genetic cause of early childhood lethality . In rare instances, however, individuals carrying the same SMN1 mutations as their affected siblings are found to be fully asymptomatic, thereby suggesting the action of modifier genes. By comparing the transcriptoms of lymphoblastoid cell lines from unaffected and affected SMN1-deleted siblings, we identified plastin 3 (PLS3, localized on Xq23) to be abundant in unaffected, but not affected counterparts . We showed that PLS3 expression in blood is rare, occurring in only 5% of controls . Interestingly all eight unaffected SMN1-deleted individuals were female . Despite extensive research, the molecular cause for this gender-specific protective effect still remains unknown. We found that PLS3 is highly expressed in spinal cord, associates with SMN, and that both proteins are part of a large multi-protein complex in spinal cord . Both PLS3 and SMN are present at similar subcellular locations in primary motor neurons and increase in expression during neuronal differentiation. As an actin bundling protein, PLS3 influences the Factin level known to be important for axonal outgrowth and guidance . PLS3 knock-down in neuronal differentiated PC12 cells severely affects axonal growth whereas PLS3 over-expression induces axonal growth . Most importantly, over-expression of PLS3 rescues the axonal growth defect caused by reduced SMN levels in neuronal differentiated PC12 cells, in primary motor neurons of SMA mouse embryos and in an in vivo zebrafish SMA-model. Our data strongly support the view that the involvement of SMN in axonal outgrowth and pathfinding is the major pathogenic defect in SMA . The discovery of PLS3 as a protector against SMA provides the opportunity to identify novel regulatory mechanisms that may act specifically in motor neurons, and which may be useful for understanding the molecular pathogenesis of other motor neuron diseases as well . The results may also help to identify novel targets for SMA therapy. Our discovery signifies a major breakthrough in medical genetics and represents the first report ever of a fully protective modifier for a Mendelian disorder in humans. PL3.1 systematic resequencing of the coding exons of the X chromosome in X-linked mental Retardation M. Stratton; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. Mental retardation (MR) affects 1-3% live births and has both genetic and non-genetic causes . A proportion of cases with genetic abnormalities are attributable to mutations of genes on the X chromosome . Although several X-linked MR (XLMR) genes have been reported, identification of more by conventional approaches is problematic because mutations of many genes cause MR and their associated phenotypes are similar . Here, we have implemented a new strategy in which the coding exons of X chromosome genes (~1Mb DNA per sample) have been systematically resequenced for disease-causing variants in individuals from more than 200 XLMR families . The strategy has yielded several new XLMR genes . However, many families remain to be explained . The study also indicates that loss of function of ~1% of X-genes is compatible with apparently normal existence . To our knowledge, this is the largest resequencing study to identify human disease genes thus far conducted . The results highlight issues that will be faced in the future by whole genome screens for rare diseasecausing variants . PL3.2 cap-Analysis Gene Expression (cAGE) analysis of transcriptional complexity and regulation P. Carninci, Y. Hayashizaki; Functional Genomics Technology Team, Omics Science Center, Omics Science Center, Yokohama, Kanagawa, Japan. The genome sequence is an invaluable resource, yet it is still hard to identify all its encoded RNAs and regulatory regions . Despite there are about 20,000 protein coding genes, 63% to 93% of the mammalian genomes is expressed, mainly producing non-coding RNAs, starting from more than 230,000 core promoters. These are identified with CAGE (can-analysis gene expression), resulting in a finely redefinition of the promoter structure . The development of novel generation of sequencing instruments allows addressing the RNA complexity at a much higher definition. We are using multiple platforms (454 Life Science, Illumina/Solexa and ABI-SOLiD sequencers) to produce hundreds of millions of functional sequencing tags, with particular focus on CAGE and short RNA libraries . Sequencing of deep-CAGE libraries, which contain 1 to more than 10 millions tags, produces much detailed and sensitive data than microarrays at a progressively decreasing cost . We are broadening the CAGE applications to the ENCODE project and have also miniaturized the protocol, to work with RNA extracted from less than 1000 cells (neurons) . CAGE analysis allows correlating promoter elements to transcriptional control, as demonstrated by reconstructing the transcriptional network of differentiation of THP-1, a human myeloid leukemia cell in the Fantom 4 project in an integrated approach. We provide the first description of the dynamics and architecture of a human transcriptional network undergoing transition from a proliferating to a differentiated state PL3.2 High-throughput sNP genotyping and ultra-high-throughput sequencing for genome-wide association studies I. G. Gut; CEA - Institut de Genomique, Centre National de Genotypage, Evry, France. In the course of the last 2 years the Centre National de Génotypage (CNG) has run numerous genome-wide association (GWA) studies us-
Page 1 and 2: Volume 16 Supplement 2 May 2008 www
Page 3 and 4: Committees - Board - Organisation E
Page 5: Plenary Lectures ESHG PLENARY LECTU
Page 9 and 10: Concurrent Symposia ESHG CONCURRENT
Page 11 and 12: Concurrent Symposia s04.1 microRNA
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Page 41 and 42: Clinical genetics ESHG POSTERS P01.
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Clinical genetics leles- is in acco
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Clinical genetics Sapienza” Unive
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Clinical genetics P01.090 Fragile X
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Clinical genetics P01.099 Deletion
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Clinical genetics other CNPs, the 1
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Clinical genetics FRAXA is the most
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Clinical genetics and PT 19 cm. Nec
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Clinical genetics P01.133 White mat
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Clinical genetics curved radii, uln
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Clinical genetics ered at the 33 rd
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Clinical genetics P01.160 character
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Clinical genetics P01.169 A variant
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Clinical genetics matological anoma
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Clinical genetics sition was identi
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Clinical genetics women ranges by p
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Clinical genetics MD2I or MDC1C sho
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Clinical genetics P01.215 the ctG r
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Clinical genetics pansion . Longer
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Clinical genetics frequency of this
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Clinical genetics mana, CUCS, Unive
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Clinical genetics P01.253 The first
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Clinical genetics consistent findin
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Clinical genetics P01.270 Genetic s
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Clinical genetics P01.279 Dilated c
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Clinical genetics objectives of our
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Clinical genetics P01.298 Hyperphos
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Clinical genetics P01.307 maternal
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Clinical genetics CM in monozygotic
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Clinical genetics P01.325 mowat-Wil
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Clinical genetics P01.334 Identific
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Clinical genetics birth defects is
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Clinical genetics The cause of this
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Clinical genetics were assumed to b
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Cytogenetics P01.369 three novel mu
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Cytogenetics P02.008 Reconfirmation
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Cytogenetics mosomal rearrangement
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Cytogenetics otide-based array plat
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Cytogenetics rangements ranged betw
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Cytogenetics 593 kb microdeletion a
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Cytogenetics We herewith report two
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Cytogenetics cise etiological diagn
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Cytogenetics deleted region contain
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Cytogenetics P02.078 mental Retarda
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Cytogenetics present on the right s
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Cytogenetics P02.096 Delineation of
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Cytogenetics P02.106 Aneuploidy of
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Cytogenetics biologic (cytogenetic)
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Cytogenetics - 60 .0) per 100 cells
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Cytogenetics netic map of deleted r
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Cytogenetics phic at delivery . Min
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Cytogenetics (according to question
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Cytogenetics P02.160 characterizati
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Cytogenetics DISCUSSION: In this st
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Cytogenetics from peripheral blood
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Cytogenetics did not influence upon
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Cytogenetics sented with ambiguous
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Cytogenetics normalities, cytogenet
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Cytogenetics P02.215 cytogenetic an
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Cytogenetics matozoa from carriers
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Cytogenetics of spermatogenesis in
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Prenental diagnostics Genotype Infe
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Prenental diagnostics T21 samples s
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Prenental diagnostics be withdrawn
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Prenental diagnostics The Consortiu
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Prenental diagnostics Here we descr
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Prenental diagnostics service deliv
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Prenental diagnostics cal Universit
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Prenental diagnostics nuchal transl
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Prenental diagnostics etal anomalie
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Cancer genetics forms . The typical
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Cancer genetics P04.012 A novel PtE
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Cancer genetics P04.021 comparative
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Cancer genetics P04.029 characteris
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Cancer genetics mutations detected
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Cancer genetics deleterious mutatio
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Cancer genetics Research Centre, Mo
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Cancer genetics P04.064 Dissection
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Cancer genetics P04.072 Acute promy
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Cancer genetics P04.081 Discordance
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Cancer genetics ity of the malignan
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Cancer genetics Method: mRNA level
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Cancer genetics preparations were o
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Cancer genetics ries.The identifica
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Cancer genetics P04.127 FGFR3 mutat
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Cancer genetics Our experience show
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Cancer genetics way consists of thr
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Cancer genetics and/or prognostic m
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Cancer genetics P04.162 HER-2/neu A
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Cancer genetics controls, by hetero
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Cancer genetics P04.179 molecular g
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Cancer genetics there are no change
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Cancer genetics P04.197 mutation in
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Molecular and biochemical basis of
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Genetic analysis, linkage, and asso
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Normal variation, population geneti
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Genomics, technology, bioinformatic
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Genetic counselling, education, gen
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Therapy for genetic disease 0 proce
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Therapy for genetic disease The die
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Therapy for genetic disease Science
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Therapy for genetic disease P10.26
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EMPAG Plenary Lectures and perceive
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EMPAG Plenary Lectures 0 mutation i
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EMPAG Plenary Lectures EPL5.2 the m
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EMPAG Workshops Methods The matrix
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EMPAG Posters their own home . It e
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EMPAG Posters with resultant specia
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EMPAG Posters 0 the family, relativ
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EMPAG Posters ties raised by IBMPFD
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EMPAG Posters ics, Nicosia, Cyprus,
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EMPAG Posters In collaboration with
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EMPAG Posters most patients’ psyc
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EMPAG Posters 0 EP13.2 Decision mak
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EMPAG Posters Objective . GeneBanC
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EMPAG Posters EP14.12 the role of t
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EMPAG Posters patient (35% vs . 26%
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Author Index Al-Owain, M.: P06.160
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Author Index 0 Baka, M.: P04.082 Ba
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Author Index Berwouts, S.: P09.20,
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Author Index P07.117 Buil, A.: P06.
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Author Index Cho, J.: P04.192, P08.
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Author Index Damy, T.: P01.057 Damy
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Author Index 0 Dror, A.: P05.074 Dr
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Author Index Fernandez-Real, J.: P0
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Author Index P06.310 Gavriliuc, A.
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Author Index Grinberg, Y. I.: P01.0
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Author Index Hood, L.: PL4.1 Hoogeb
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Author Index 0 P02.240, P09.63 Kala
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Author Index Kongstad, O.: P09.39 K
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Author Index Lee, C.: C13.3 Lee, D.
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Author Index Mahjoubi, F.: P02.045,
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Author Index P04.196 Meindl, A.: c0
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Author Index 00 Mottaghi, L.: P01.0
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Author Index 0 Oh, T. Y.: P01.084 O
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Author Index 0 Peñaloza, R.: P05.2
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Author Index 0 Proverbio, M.: P05.0
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Author Index 0 Rogers, M.: EP14.18
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Author Index 0 Scarcella, M.: P05.0
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Author Index P06.179 Sobrino, B.: P
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Author Index Taschner, P. E. M.: P0
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Author Index Urreizti, R.: P01.050,
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Author Index Voegele, C.: P04.121 V
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Author Index 0 P04.095, P04.106 Zem
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Keyword Index AMACR gene: P04.182 a
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Keyword Index cardiac: S04.1 Cardio
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Keyword Index Crohn: P07.022 Crohn
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Keyword Index evolution: P02.112, P
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Keyword Index 0 haemoglobinopathies
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Keyword Index KCNJ11: P05.026 KCNQ1
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Keyword Index MLH1: P04.010, P04.02
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Keyword Index osteochondrodysplasia
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Keyword Index PXE-like syndrome: P0
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Keyword Index 0 sperm: P02.205 sper
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Keyword Index venous thrombosis: P0
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2008 Barcelona - European Society of Human Genetics

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