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

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Plenary Lectures Plenary Lectures PL01. Establishment and hereditary transmission of epigenetic modifications and pathological developments: the mouse model F. Cuzin; Unité 636 de l’Institut de la Santé et, de la Recherche Médicale, Nice, France. No abstract available as per date of printing. Please check www.eshg. org for updates in the online database. PL02. DNA Repair, genome maintenance and human disease M. Radman; Faculté de Médecine, Necker, Université Paris 5, Paris, France. No abstract available as per date of printing. Please check www.eshg. org for updates in the online database. PL03. Human neuroimaging - contributions to neurogenetics R. Frackowiak; Wellcome Department of Imaging Neuroscience, Institute of Neurology, UCL, London, United Kingdom. Voxel based morphometry (VBM) is a new way of analysing structural MR images. VBM can characterise differences in structural MRI scans of diseases influenced by genetic variation. In X-linked Kallmann’s syndrome there is selective hypertrophy of the pyramidal tract in patients with mirror movements compared to those without. In a dominantly inherited, dyspraxic, language-impaired family, gene penetrance is full and associated with abnormal structure and function of the caudate nucleus and other areas. Atrophy of the caudate in affected family members is associated with task-related hyperactivity, suggesting functional compensation. Presently unaffected individuals from families of Huntington’s patients show caudate atrophy that correlates with genetic status. Caudate atrophy correlates with clinical score and CAG codon repeats on chromosome 4. Studies with Turner’s and partial Turner’s patients have identified focal structural brain abnormalities. Candidate regions on the X-chromosome have been found that influence amygdala and orbital frontal cortex development. A structural amygdala abnormality in patients predicts failure to recognise fear in photographs of faces; a prediction that is now confirmed. These studies suggest that imaging is an efficient way of associating candidate genes with quantitative measures of brain structure and function and that informative intermediate phenotypes can be described that predict future disease in asymptomatic at-risk individuals. PL04. Neurodegeneration in lysosomal storage diseases is associated with impairment of autophagy A. Fraldi 1 , C. Settembre 1 , C. Spampanato 1 , R. de Pablo 1 , D. L. Medina 1 , L. Jahreiss 2 , A. Lombardi 1 , C. Venturi 3 , C. Tacchetti 3 , D. C. Rubinsztein 2 , A. Ballabio 1,4 ; 1 Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy, 2 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom, 3 Department of Experimental Medicine and §MicroSCoBiO Research Center and IFOM Center of Cell Oncology and Ultrastructure, University of Genoa, Genoa, Italy, 4 Medical Genetics, Department of Pediatrics, Federico II University, Naples, Italy. Autophagy is the mechanism responsible for the turn-over of intracellular organelles and digestion of protein aggregates which are sequestered by autophagosomes and degraded upon the fusion of the autophagosome with the lysosome. Several neurodegenerative disorders, such as Alzheimer, Parkinson and Huntington diseases are associated with an impairment of autophagy. We have analyzed the autophagic pathway in two different murine models of lysosomal storage disorders (LSDs), Multiple Sulfatase Deficiency (MSD) and Mucopolysaccharidosis type IIIA (MPS-IIIA). Western blotting, immunofluorescence and immunohistochemical analyses using anti-LC3 antibodies demonstrated a significant intracellular accumulation of autophagic (LC3-positive) vacuoles in MEFs as well as in several brain regions of both MSD and MPS-IIIA mice. Accumulation of autophagosomes was also confirmed by ultrastructural analysis. Co-staining of MEFs using both anti-LC3 and anti-LAMP2 antibodies demonstrated that autophagosomes do not co-localize with lysosomes, suggesting the presence of a fusion defect. As a consequence of an impairment of autophagy, a massive intracellular accumulation of ubiquitin-positive aggregates and an increased number of mitochondria with altered membrane potential were detected in the brain of both MSD and MPS-IIIA mice. Interestingly, the build-up of polyubiquitinated proteins and dysfunctional mitochondria has been associated with neuronal cell death in neurodegenerative diseases. Taken together our data indicate that accumulation of storage material, due to the lysosomal enzyme deficiency, causes a lysosomal dysfunction which affects the autophagic pathway, and more specifically the formation of autophagolysosomes. We postulate that neurodegeneration in LSDs is caused by secondary storage of toxic protein aggregates due to an impairment of autophagy. PL05. Identification of 3 novel genes that cause X-linked mental retardation; AP1S2, CUL4B and ZDHHC9. F. Raymond 1 , P. Tarpey 2 , G. Turner 3 , R. Stevenson 4 , C. Schwartz 4 , J. Gecz 5 , P. Futreal 2 , M. Stratton 2 , on behalf of the GOLD (Genetics of Learning Disability) study; 1 Cambridge Institute for Medical Research, Cambridge, United Kingdom, 2 Sanger Institute, Cambridge, United Kingdom, 3 University of Newcastle, Newcastle, Australia, 4 JC Self Research Institute of Human Genetics, Greenwood, SC, United States, 5 University of Adelaide, Adelaide, Australia. Phenotypic variability, genetic heterogeneity and the high number of disease genes estimated to be involved has made the identification of causative gene abnormalities in X-linked mental retardation complex. To identify further novel disease genes we have used a systematic mutational screen of the X chromosome in 250 families with multiple affected members with mental retardation. We report the identification of 3 novel genes that cause X-linked mental retardation. AP1S2 encodes the sigma 2 subunit of the adaptor protein 1 complex. We have identified 3 truncating mutations associated with mental retardation, hypotonia, delayed walking, absent speech and aggressive behaviour. The AP1 complex is present in endosomes and the trans- Golgi network and binds vesicle cargo proteins destined for transport into different cellular compartments. CUL4B is an ubiquitin E3 ligase subunit involved in targeting of proteins for intracellular degradation. We have identified 8 mutations, 5 truncating and 3 conserved missense mutations. Additional clinical features include macrocephaly, central obesity, hypogonadism, pes cavus and tremor were observed in some of the affected individuals but not all. ZDHHC9 is a palmitoyltransferase that catalyses the post-translational modification of NRAS and HRAS. The phenotype associated with the 2 truncating and 2 conserved missense mutations found were mental retardation and a Marfanoid habitus. This systematic strategy has identified 3 entirely novel disease causing mechanisms which would not have been predicted by a candidate gene approach and illustrates that defects in many different cellular processes may be sufficient to cause a mental retardation phenotype. PL06. Mutations in LRP2, coding for the multi-ligand receptor megalin, cause Donnai-Barrow and Faciooculoacousticorenal (FOAR) syndromes S. Kantarci 1 , L. Al-Gazali 2 , R. Hill 3 , D. Donnai 4 , G. C. M. Black 4 , E. Bieth 5 , N. Chassaing 5,6 , D. Lacombe 6 , K. Devriendt 7 , A. Teebi 8 , M. Loscertales 1 , C. Robson 9 , T. Liu 10 , D. T. MacLaughlin 1 , K. M. Noonan 1 , M. K. Russell 1 , C. A. Walsh 3,9 , P. K. Donahoe 1 , B. R. Pober 1,9 ; 1 Massachusetts General Hospital, Boston, MA, United States, 2 UAE University, Al Ain, United Arab Emirates, 3 Beth Israel Deaconess Medical Center, Boston, MA, United States, 4 University of Manchester and St Mary’s Hospital, Manchester, United Kingdom, 5 Hopital Purpan, Toulouse, France, 6 Hôpital Pelligrin, Bordeaux, France, 7 University of Leuven, Leuven, Belgium, 8 Weill Cornell Medical College in Qatar and Hamad Medical City, Doha, Qatar, 9 Children’s Hospital, Boston, MA, United States, 10 Brigham and Women’s Hospital, Boston, MA, United States. Donnai-Barrow syndrome (DBS) is an autosomal recessive disorder characterized by hypertelorism, myopia, corpus callosum agenesis, deafness, omphalocele, and congenital diaphragmatic hernia. There is phenotypic overlap with Faciooculoacousticorenal syndrome (FOAR). Genetic mapping using Affymetrix 10K SNP arrays on four DBS children from one large consanguineous kindred identified a 17 cM region of homozygosity-by-descent on chromosome 2q23.3-q31.1. This was refined and confirmed by microsatellite marker analysis in three additional multiplex DBS families. Sequencing of candidate genes in six DBS and one FOAR kindreds revealed homozygous or compound heterozygous mutations in the 79 exon LRP2 gene in all cases. LRP2 encodes megalin, a ~600 kDa
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Page 39 and 40: Clinical genetics lateral neurosens
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Page 43 and 44: Clinical genetics itar syndrome, wh
Page 45 and 46: Clinical genetics diseases, Foundat
Page 47 and 48: Clinical genetics P0041. The first
Page 49 and 50: Clinical genetics EFNB1 was found t
Page 51 and 52: Clinical genetics of the CSB gene.
Page 53 and 54: 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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Genetic analysis, linkage, and asso
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Genomics, technology, bioinformatic
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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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