Abstracts Topics Symposia Symposia S_1 Structural variation S 1 Structural variation S 2 Low risk cancer genes S1_01 S 3 Transgeneration effects and Molecular Mechanisms and Clinical Consequences of Genomic Disor- epigenetic programming ders. Implementation of array CGH in Genetic Diagnostics. The Baylor S 4 Ciliopathies Experience S 5 Systems biology Pawel Stankiewicz S 6 Molecular processes in meiosis Dept. of Molecular & Human Genetics, Baylor College of Medicine, Hous- ton, TX, USA Genomic disorders are a group of human genetic diseases caused by Selected Presentations DNA rearrangements, ranging in size from an average exon (~100 bp) to megabases and affecting dosage sensitive genes. Three major mo- lecular mechanisms: non-allelic homologous recombination (NAHR), Workshops non-homologous end joining (NHEJ), and the fork stalling and tem- W 1 Clinical genetics plate switching (FoSTeS)/microhomology-mediated breakage-induced W 2 Molecular basis of disease I repair (MMBIR) have been described as causative for the vast majority W 3 Cancer genetics of genomic disorders. Recurrent rearrangements are typically mediated W 4 Molecular basis of disease II by NAHR between low-copy repeats that are usually >10 kb in size with >97% DNA sequence identity. Nonrecurrent CNVs have been found to W 5 Imprinting be formed by NAHR between highly homologous repetitive elements W 6 Genomics technology / bioinformatics (e.g. Alu, LINE) and more often by NHEJ and FoSTeS/MMBIR stimu- W 7 Complex diseases lated, but not mediated, by genomic architectural features. Further- W 8 Cytogenetics / prenatal genetics more, simple repeating DNA sequences that have a potential of adopt- ing non-B DNA conformations (e.g. triplexes, cruciforms, left-handed Z-DNA, and tetraplexes) have been shown to lead to gross genomic Educational Sessions rearrangements associated with some genomic disorders. Complex re- EDU 1 Imprinting Update arrangements (e.g. duplication/triplication) can be explained by FoS- EDU 2 Risikoscreening für Aneuploidien TeS/MMBIR. EDU 3 Copy number abnormalities In 2003, a BAC clone-based targeted array CGH called Chromosome (CNAs) in der Tumorgenetik Microarray Analysis (CMA) for high-resolution human genome anal- ysis was designed, developed, validated, and implemented at BCM. EDU 4 Ionenkanal-Krankheiten BCM has strategically positioned coverage on its array to detect the known genomic disorders. Targeted arrays of 356 (V4), 853 (V5) and Poster 1475 (V6) BAC clones have yielded detection rates of 6.5%, 9%, and P001–P068 Clinical genetics 12.6%, respectively. In March 2006, utilizing the knowledge of our ge- P069–P104 Cytogenetics nome architecture, CMA has been transitioned to genome-wide BAC- emulated oligonucleotide arrays V6 (44 K) and V7 (105 K). The results P105–P153 Cancer genetics of CMA in 20,000 patients will be presented. P154-P255 Molecular and biochemical basis of disease, developmental genetics, neurogenetics S1_03 P256–P294 Genetic analysis, linkage and Genome Architecture in Autism Spectrum and Related Neuropsychi- atric Disorders association, complex genetics/ Pr. Stephen W. Scherer, PhD FRSC diseases The Centre for Applied Genomics, The Hospital for Sick Children and P295–P298 Normal variation, population University of Toronto genetics, genetic epidemiology, evolutionary genetics Autism spectrum disorders (ASDs) are common, heritable neurodevel- opmental conditions characterized by impairments in social commu- P299–P305 Genomics, technology nication and by a preference for repetitive activities. ASD is observed and bioinformatics in ~1 in every 150 newborns with over 30,000 new diagnoses in North P306–P316 Prenatal diagnosis, reproductive America each year. Twin and family data suggest ASD is mainly a ge- medicine netic condition of complex etiology. A multidisciplinary pan-Canadian P317–P327 Genetic counselling, education, group has come together (funded by Genome Canada and partners) with international collaborators in 15 other countries (coordinated genetic services, public policy by Autism Speaks), to study autism genetics. This ‘Autism Genome P328–P333 Therapy for genetic diseases Project’ team has now completed linkage, genome-wide association, and copy number variation (CNV) scans of DNA from thousands of families and the resulting data is beginning to reveal the genetic con- tributors (or genome architecture) underlying ASD. Our group is also investigating other neuropsychiatric disorders related to- or overlap- ping- with the clinical presentation of ASD. We find that ~10% of ASD Medizinische Genetik 1 · 2009 | 57 Abstracts arises secondary to other disorders, some 10% is due to chromosome S2_02 abnormalities and CNVs, and another ~2% appears monogenic (aris- Low penetrance predisposition genes for colorectal and other ing due to single gene alterations). For the remaining ~80% of cases we cancers are still seeking answers, but there is significant progress. For example, Ian Tomlinson many large rare-CNVs are being observed in ASD families. Some of the Molecular and Population Genetics, Wellcome Trust Centre for Human ASD genes now identified such as SHANK3 and neuroligin 4, encode Genetics, Oxford, UK proteins functioning at the synaptic complex in neurons, providing new targets for development of therapeutics. Functional experiments Recent large-scale screens have shown that the common disease- including therapeutic- and mutation mechanism- testing will be con- common variant genetic model is correct for the major cancers. Sev- ducted using induced pluripotent stem (iPS) cell lines from patients eral SNPs have now been associated with a differential risk of breast, with known mutations, as well as animal models. Finally, for some fam- colorectal and prostate carcinomas, and evidence for similar predis- ilies the CNV and gene discoveries are starting to have clinical utility position to other tumour types is accumulating. There appear to be allowing early identification and refined diagnosis of ASD. These tests several different mechanisms of raising cancer risk, but some prime are now being transferred to hospital-based diagnostic labs in Canada. candidate genes, such as those involved in DNA repair, are strikingly Together our genomic discoveries are redefining our understanding of absent to date. The relative risks associated with cancer susceptibility autism and we are working closely with families and their supporters SNPs are modest (typically up to 1.3-fold) and the variants detected to to best realize the benefits. date can account for a small proportioin of the familial clustering of cancer. The remaining risk may be explained by other types of genetic variant, including copy number polymorphisms and rare (or “private”) S_2 Low risk cancer genes alleles with modest effects on disease risk. S2_03 S2_01 Moleculargenetics of Paraganglial Tumors: Selection of Susceptibility Low risk cancer���������������������������������������������������� genes – current knowledge and possible implications Genes for genetic counselling in familial breast cancer Hartmut P.H. Neumann Alfons Meindl on behalf of the German Consortium for Hereditary Breast University Medical Center, Department of Nephrology and General Medici- and Ovarian Cancer ne, Albert-Ludwigs-University, Freiburg i.B., Germany Klinikum rechts der Isar an der Technischen Universit�ä������������������������������������������t, Frauenklinik, Abt. Gyn�ä��������������������������������������������������������������������������������kologische Tumorgenetik, Munich, Germany Pheochromocytomas and paragangliomas form the group of para- ganglial tumors which can occur in any paraganglion from the skull Except for the high breast cancer risk in BRCA1 and BRCA2 mutati- base to the pelvic floor. The terminology is inconstant. The WHO uses on carriers, familial clustering of breast cancer remains largely unex- pheochromocytoma exclusively for adrenal tumors. In contrast many plained. While candidate gene approaches demonstrated moderately clinicians and we use pheochromocytoma also for extraadrenal ab- increased breast cancer risks for rare mutations in genes involved in dominal and thoracic tumors, since by tradition pheochromocytoma is DNA repair (ATM, CHEK2, BRIP1, PALB2, and RAD50), genome- a vasoactive tumor. In contrast, head and neck paraganglioma is mostly wide association-studies (GWAS) identified several single nucleo- only a space occupying mass. tide polymorphisms as low penetrance breast cancer susceptibility One third of the patients with pheochromocytomas and paraganglio- polymorphisms within genes as well as in chromosomal loci with no mas are carriers of germline mutations in one of 6 genes and have thus known genes (FGFR2, TNRC9, LSP1, MAP3K1, TGFB1, 2q35, 6q22). hereditary disorders. Moreover, some of these low penetrance breast cancer susceptibility The first is neurofibromatosis type 1 (NF 1). About 1% of NF 1 patients polymorphisms additionally act as modifier genes in BRCA1/ BRCA2 have pheochromocytomas. The susceptibility gene NF1 is located on mutation carriers (Antoniou et al., Am J Hum Genet 82:937–48, 2008). chromosome 17 (#17q11.2) and consists of 59 exons. Germline muta- All of these low risk variants have reached statistical significance only tion screening in patients with NF 1 and pheochromocytoma revealed through the analysis of several thousands of sporadic cases and most a random distribution over the gene. All pheochromocytoma patients of them are associated with rather low risks (Easton et al., Nature with NF 1 show also cutaneous