May 31 - June 3, 2014
Milan, Italy
Abstracts
European Human Genetics
Conference 2014
Volume 22 Supplement 1 May 2014 www.nature.com/ejhg
ABSTRACTS
ESHG 2014 | MILAN, ITALY | WWW.ESHG.ORG
European Human Genetics Conference
in conjunction with the
European Meeting on Psychosocial aspects of Genetics
May 31 - June 3, 2014
Milan, Italy
Abstracts
EMPAG
EUROPEAN MEETING ON PSYCHOSOCIAL ASPECTS OF GENETICSABSTRACTS
ESHG 2014 | MILAN, ITALY | WWW.ESHG.ORG
European Society of Human Genetics
ESHG Office
European Society
of Human Genetics
Karin Knob
Andrea Robinson
c/o Vienna Medical Academy
Alser Strasse 4
1090 Vienna
Austria
T: 0043 1 405 13 83 20 or 35
F: 0043 1 407 82 74
E: office@eshg.org
www.eshg.org
Executive Board 2013-2014
President
Han Brunner, NL
Vice-President
Stanislas Lyonnet, FR
President-Elect
Helena Kääriäinen, FI
Secretary-General
Gunnar Houge, NO
Deputy-Secretary-General
Karin Writzl, SI
Treasurer
Andrew Read, UK
Executive Officer
Jerome del Picchia, AT
Scientific Programme Committee
Chair
Brunhilde Wirth, DE
Members
Antonio Amoroso, Local Host, Turin, IT
Jeffrey Barrett, Cambridge, UK
Alexis Brice, Paris, FR
Paul de Bakker, Utrecht, NL
Martina Cornel, Amsterdam, NL
Helene Dollfus, Strasbourg, FR
David Fitzpatrick, Edinburgh, UK
Francesca Forzano, Genova, IT
Maurizio Genuardi, Florence, IT
Daniel Grinberg, Barcelona, ES
Gunnar Houge, Bergen, NO
Erik Iwarsson, Stockholm, SE
Xavier Jeunemaitre, Paris, FR
Lidia Larizza, Milan, IT
Jose C. Machado, Porto, PT
Giovanni Neri, Rome, IT
William Newman, Manchester, UK
Minna Nyström, Helsinki, FI
Francesc Palau, Valencia, ES
Anita Rauch, Zurich, CH
Samuli Ripatti, Helsinki, FI
Peter N. Robinson, Berlin, DE
Marco Seri, Bologna, IT
Joris Veltman, Nijmegen, NL
Joris Vermeesch, Leuven, BE
Karin Writzl, Ljubljana, SI
Board Members
Liaison Members
Yasemin Alanay, TR
Martijn Breuning, NL
Pascal Borry, BE
Nina Canki-Klain, CR
Ana Carrió, ES
Domenico Coviello, IT
Koen Devriendt, BE
Munis Dundar, TR
Peter Kroisel, AT
Dorit Lev, IL
Milan Macek Jr., CZ
Julie McGaughran, AU
Bela Melegh, HU
Will Newman, UK
Markus Nöthen, DE
Markus Perola, FI
Borut Peterlin, SI
Trine E Prescott, NO
Hans Scheffer, NL
Jörg Schmidtke, DE
Heather Skirton, UK
Martina Cornel, NL
Ros Hastings, UK
Thomas Liehr, DE
Milan Macek Jr., CZ
Tayfun Ozcelik, TR
Heather Skirton, UK
GertJan B. van Ommen, NL
Brunhilde Wirth, DE
Further information on structure and organisation can be found on the website
www.eshg.org
Future European Human Genetics Conferences
European Human Genetics Conference 2015
Glasgow, United Kingdom
June 6 – 9, 2015
European Human Genetics Conference 2016
Barcelona, Spain
May 21 – 24, 2016
ABSTRACTS
ESHG 2014 | MILAN, ITALY | WWW.ESHG.ORG
Spoken Presentations
4
Plenary Lectures...PL1.1 – PL5.1 ... 4
Concurrent Symposia ...S01.1 – S19.3 ... 7
Educational Sessions ...ES1.1 – ES8.2 ... 15
Concurrent Sessions ...C01.1 – C22.6 ... 19
EMPAG Educational Sessions ... EES1.1 – EES2.1... 349
EMPAG Plenary Lectures ...EP1.1 – EPL9.6 ... 349
Posters
51
P01. Reproductive Genetics/Prenatal Genetics ...P01.002-128 ... 51
P02. Sensory disorders (eye, ear, pain) ...P02.01-49 ... 76
P03. Internal organs & endocrinology (lung, kidney, liver, gastrointestinal) ...P03.01-49 ... 86
P04. Skeletal, connective tissue, ectodermal and skin disorders ...P04.01-73 ... 96
P05. Cardiovascular disorders ...P05.01-67 ... 112
P06. Metabolic and mitochondrial disorders...P06.01-61 ... 127
P07. Immunology and hematopoietic system ...P07.01-43 ... 140
P08. Intellectual Disability...P08.01-81 ... 148
P09. Neurogenetic disorders ...P09.001-154 ... 165
P10. Neuromuscular disorders ...P10.01-42 ... 197
P11. Multiple Malformation/anomalies syndromes ...P11.001-154 ... 205
P12. Cancer genetics ...P12.001-143 ... 237
P13. Basic mechanisms in molecular and cytogenetics ...P13.01-49 ... 266
P14. New diagnostic approaches, technical aspects & quality control ...P14.01-97 ... 276
P15. Personalized/Predictive Medicine and Pharmacogenomics ...P15.01-39 ... 296
P16. Omics/Bioinformatics/Epigenetics ...P16.01-78 ... 304
P17. Genetic epidemiology/Population genetics/Statistical methodology
and evolutionary genetics ...P17.01-95 ... 320
P18. Genetic counselling/Education/public services ...P18.01-48 ... 338
EP. EMPAG Posters ...EP01-52 ... 360
Published Abstracts J01.01 - J19.31
370
Indices
517
Keyword Index ... 517
Author Index ... 534
Click on the topics in the table of content to jump to the according page.
Abstracts with a presentation number highlighted in
grey
are talks of Young investigator Candidates.
Abstracts with a presentation number highlighted in
blue
are ESHG Poster Award Candidates.
ABSTRACTS
PLENARY LECTURES
ESHG 2014 | MILAN, ITALY | WWW.ESHG.ORG
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PLENARY LECTURES
PL1.1
RASopathies. The other face of RAS signalling dysregulation
M. Tartaglia;
Istituto Superiore di Sanità, Rome, Italy.
RAS proteins are small monomeric GTPases that function as molecular swit-ches controlling a major intracellular signaling network that, depending on the cellular context, guides diverse biological functions, including proliferation, cell fate determination, survival, migration, differentiation, and senescence. RAS signaling is switched on upon stimulation by numerous cytokines, hormones, and growth factors, and mediates the appropriate cell response to external sti-muli through the regulation of transcription, cytoskeletal rearrangement, and metabolism. Within this network, signal flow through the RAF-MEK-ERK pa-thway, the first identified mitogen-associated protein kinase (MAPK) cascade, mediates early and late developmental processes, including determination of morphology, organogenesis, synaptic plasticity, and growth.
Signaling through the RAS-MAPK cascade is tightly controlled, and its enhanced activation has been known for decades to represent a major event in oncoge-nesis. Activating somatic RAS gene mutations occur in approximately 30% of human cancers, and upregulation of this signaling pathway can also result from enhanced function of upstream signal transducers or RAS effectors, and inef-ficient function of feedback mechanisms.
Unexpectedly, discoveries derived from a massive disease gene hunting effort have recently established a novel scenario in which the upregulation of this signaling cascade underlies a group of clinically related developmental disor-ders, the RASopathies, characterized by facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and muscu-loskeletal anomalies, and increased risk for certain malignancies. These dis-orders are caused by mutations in genes encoding RAS proteins, regulators of RAS function, modulators of RAS interaction with effectors or downstream signal transducers. Based on the relatively high prevalence of some of these disorders (i.e., Noonan syndrome and neurofibromatosis type 1), the dysregu-lation of this signaling pathway represents one of the most common events af-fecting developmental processes. These discoveries have also provided us with unpredicted molecular mechanisms converging toward the dysregulation of this signaling network.
PL1.2
Evolution of the HD gene
E. Cattaneo;
Department of Bioscience, University of Milan, Milan, Italy.
The Hdh gene arose with no CAGs in Dictyostelium discoideum (Dd), around 800 million-year ago before the protostome-deuterostome divergence (Zuccato, Physiol Rev 2010). The CAG then has appeared in and is unique to the deute-rostome branch. Two CAGs are found in Hdh in sea urchin (Strongylocentrotus
purpuratus, Sp), the first specie to carry a primitive nervous system, and two
CAGs are present in amphioxus (Branchiostoma floridae, Bf), the first specie to exhibit a rudimental hollow nerve tube and cephalization. Four CAG are found in Hdh from the more evolved fishes, amphibians, and birds. The CAG further expands in mammals and reaches its maximum length in human. A study of 278 normal subjects revealed an increase in grey matter with increasing length of the CAG repeat (Muhlau, PlosOne 2012), indicating that CAG size could influ-ence normal brain structure. Our hypothesis is that the progressive increase in CAG length in the Hdh gene observed during evolution may be implicated in the evolutionary changes that have occurred in the developing and adult ner-vous system throughout vertebrate phylogeny, with a possible role for the CAG in newly emerging cognitive functions in the mammalian brain. We have now collected the Hdh gene from new species both in the protostome and deutero-stome branch. In addition to further analyze the CAG tract during mammalian evolution we have collected genomic DNA and amplified the CAG tract from non-anthropomorphic and anthropomorphic primates. Our reconstruction of htt phylogeny supports further that the CAG tract expands during deuterosto-me evolution and seems to correlate with the appearance and/or evolution of progressively more complex nervous systems.
PL1.3
Genetic engineering of hematopoietic stem cells for the treatment of inherited diseases
L. Naldini;
Milan, Italy.
No abstract received at production date. Check the online database at www.eshg.org/astracts2014.0.html for possible updates.
PL2.1
Early-Onset Stroke and Vasculopathy Associated with Mutations in ADA2
I. Aksentijevich1, Q. Zhou1, A. K. Ombrello1, D. Yang2, A. V. Zavialov3, R. Sood1, M. Boehm2, D.
L. Kastner1;
1NHGRI/NIH, Bethesda, MD, United States, 2NHLBI/NIH, Bethesda, MD, United States, 3University of Turku, Turku, Finland.
We initially observed 3 unrelated patients with fevers, livedo reticularis, vas-culopathy, and early-onset recurrent ischemic strokes. We performed exome sequencing on affected patients and their unaffected parents that pointed to recessively inherited predicted-deleterious mutations in CECR1, encoding adenosine deaminase 2 (ADA2). All mutations are either novel or present at low frequency (<0.001) in several large databases, consistent with the reces-sive inheritance. Candidate gene screening was done in additional 6 patients. Nine patients shared 4/9 missense mutations in CECR1 along with conserved haplotypes. Computer modeling based on the crystal structure of the human ADA2 suggests that CECR1 mutations either disrupt protein stability or impair enzyme activity. All patients had at least a 10-fold reduction in serum and plas-ma concentrations of ADA2, and reduced ADA2-specific adenosine deaminase activity. ADA2 is expressed predominantly in myeloid cells and is a secreted protein. Animal models suggest that ADA2 is the prototype for a family of grow-th factors (ADGFs). Algrow-though grow-there is no murine homolog of CECR1, grow-there are 2 zebrafish homologs, Cecr1a and Cecr1b. Knockdown of a zebrafish ADA2 homolog caused intracranial hemorrhages and neutropenia, phenotypes that were rescued by wild type but not mutant human CECR1. Skin, liver, and brain biopsies from patients demonstrated vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflam-mation although ADA2 is not expressed in the endothelial cells. Our data sug-gest that loss-of-function mutations in CECR1 are associated with a spectrum of vascular and inflammatory phenotypes ranging from early-onset recurrent stroke to systemic vasculopathy and/or vasculitis.
PL2.2
Disrupted auto-regulation of SNRPB causes cerebro-costo-mandibular syndrome
D. C. Lynch1, T. Revil2, J. Schwartzentruber3, E. J. Bhoj4, A. M. Innes1, R. E. Lamont1, E. G.
Lemire5, B. N. Chodirker6, J. P. Taylor7, E. H. Zackai4, D. R. McLeod1, E. P. Kirk8, J. Hoover-Fong9,
L. Fleming10, R. Savarirayan11, .. Care4Rare Canada12, J. Majewski13, A. Jerome-Majewska14, J.
S. Parboosingh1, F. P. Bernier1;
1Department of Medical Genetics, University of Calgary, Calgary, AB, Canada, 2Department
of Human Genetics, McGill University, Montréal, QC, Canada, 3McGill University and Génome
Québec Innovation Centre, Montréal, QC, Canada, 4Department of Genetics, The Children‘s
Hospital of Philadelphia, Philadelphia, PA, United States, 5Division of Medical Genetics,
Department of Pediatrics, University of Saskatchewan, Saskatoon, SK, Canada, 6Department
of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada, 7Genetic
Health Service, Auckland, New Zealand, 8Sydney Children‘s Hospital, Randwick, Australia, 9Greenberg Center for Skeletal Dysplasias,McKusick-Nathans Institute of Genetic Medicine,
Johns Hopkins University, Baltimore, MD, United States, 10McKusick-Nathans Institute of
Genetic Medicine, Johns Hopkins University, Baltimore, MD, United States, 1112Victorian
Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, Australia,
12Children‘s Hospital of Eastern Ontario, Ottawa, ON, Canada, 13Department of Human
Genetics, McGill University, Montreal, QC, Canada, 14Department of Pediatrics, McGill
University, Montréal, QC, Canada.
The discovery of highly conserved non-coding elements has unleashed a race to elucidate their functional significance. A class of intragenic highly conserved non-coding elements has previously been associated with regulating levels of core spliceosomal components, which affects the alternative splicing of down-stream genes. These regulatory exons contain a premature termination codon, and trigger nonsense-mediated mRNA decay (NMD) when included in the as-sociated transcript. In this study we identify mutations in one such exon in SN-RPB as the cause of cerebro-costo-mandibular syndrome (CCMS). CCMS, one of the last unsolved classical Mendelian disorders, is a multiple malformation syndrome characterized by posterior rib gaps and micrognathia. The identi-fied mutations fall within exonic splicing silencer sequences. We show by both qRT-PCR and a minigene reporter assay that these mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. This decrease is predicted to influence the splicing of a diverse but limited number of downstream target genes. Our data provide the first evidence for the functional importance of this class of conserved elements in the regulation of human development. We suggest that this exon, which is highly conserved across placental mammals but not other vertebrates, accords a subtle regulato-ry role to SNRPB which may have contributed to the complexity of mammalian development.
PL2.3
The First 100 patients diagnosed by whole-exome sequencing through FORGE Canada: Insights for Clinical Translation
S. L. Sawyer1, C. L. Beaulieu1, T. Hartley1, D. Bulman1, J. Majewski2, FORGE Canada
Consortium, K. M. Boycott1;
ABSTRACTS
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2Department of Human Genetics, McGill University, Montréal, QC, Canada.
An accurate genetic diagnosis is fundamental for pediatric patients with rare genetic disorders to improve disease management, access to resources, and recurrence risk counseling. A diagnosis also provides psychosocial benefits to families. The Finding of Rare Disease GEnes (FORGE) Canada project, which sought to identify novel rare disease genes by whole-exome sequencing (WES), shows that 36% of the solved disorders were secondary to mutations in known genes; 95 known disease genes were identified out of 264 total disorders stu-died. All patients had undergone standard of care genetic testing in Canada and no diagnosis was forthcoming. Thus, for 104 families, WES provided a clinical diagnosis; 24 of these were dominant (most de novo), 68 were autosomal reces-sive, four were X-linked mutations and one family had two disorders. Although many of the 104 families who received a clinical diagnosis were ascertained because of familial recurrence or consanguineous parents, 91 single affected patients without a family history were also included for WES. This latter subset of the above 264 disorders are representative of what geneticists often see in the clinic and had a diagnostic rate of 43%. Thus, WES would seem to be an ef-ficient and cost-effective means of clinical diagnosis for many patients who are currently undiagnosed. Our findings suggest that patients with genetically he-terogeneous disorders or sibling recurrence are the most likely to be diagnosed by WES. Canada is building on the success of these 104 diagnosed families to develop a national framework for clinical exome sequencing.
PL2.4
Transcriptomes of individual cells
C. Borel, P. G. Ferreira, M. Garieri, F. A. Santoni, O. Delaneau, E. Falconnet, P. Ribaux, P.
Makrythanasis, M. Guipponi, E. T. Dermitzakis, S. E. Antonarakis; University of Geneva Medical School, Geneva, Switzerland.
We sequenced hundreds of single-cell transcriptomes to decipher the cell-to-cell transcriptional variation. Starting from a homogeneous cell-to-cell population of human female primary fibroblasts from one individual, we used the C1 Single-Cell-Auto-Prep-System to capture individual cells and to generate pre-amplified cDNA for next-generation sequencing. On average, 9322 genes per single-cell (RPKM >0.3) were detected, representing ~50% of the total genes detected by the bulk sample containing millions of cells. We noted a wide spectrum of tran-scriptional heterogeneity. Correlation analysis between single-cells showed an average coefficient of 62% (0.3-0.9). A large number of detected genes are cell-specific with gene mRNA levels variable between single-cells. Moreover, we identified cell-specific novel exons, multitude of alternative spliced isoforms and 3’UTR isoforms due to alternative polyadenylation. Hence, 1% of exons showed difference for exon inclusion between single-cells and 10% of 3’UTR contained alternative transcript termination sites.
To further assess the differential allelic expression at the single-cell level, WGS has been performed on this sample. Our data revealed that both alleles are ac-tively transcribed for most of the detected genes. Interestingly, we observed a skewed monoallelic distribution in single-cells in a given snapshot of time. In-deed, for most of the genes, we detected one transcribed allele at the time in an individual cell. For a specific gene, rare are the individual cells expressing both alleles simultaneously. The results were validated in fibroblasts from a second individual. We will also provide a comprehensive survey of imprinted genes, X inactivation and escape.
S.E.A and E.T.D. laboratories contributed equally. PL2.5
Chromosome X-wide association analysis discovers new loci for complex traits including a height locus not dosage compensated between men and women
T. Tukiainen1,2,3, M. Pirinen3, A. Sarin3,4, C. Ladenvall5, J. Kettunen3,4, T. Lehtimäki6, M.
Lokki7, M. Perola3,4,8, J. Sinisalo9, E. Vlachopoulou7, J. G. Eriksson4,10,9, L. Groop11,3, A. Jula12, M.
Järvelin13,14, O. T. Raitakari15, V. Salomaa4, S. Ripatti3,16,17;
1Massachusetts General Hospital, Boston, MA, United States, 2Broad Institute of Harvard
and MIT, Cambridge, MA, United States, 3Institute for Molecular Medicine Finland (FIMM),
University of Helsinki, Helsinki, Finland, 4National Institute for Health and Welfare, Helsinki,
Finland, 5Lund University and Lund University Diabetes Centre, CRC at Skåne University
Hospital, Malmö, Sweden, 6University of Tampere School of Medicine, Tampere, Finland, 7Haartman Institute, University of Helsinki, Helsinki, Finland, 8Estonian Genome Center,
University of Tartu, Taru, Estonia, 9Helsinki University Central Hospital, Helsinki, Finland, 10Department of General Practice and Primary Healthcare, University of Helsinki, Finland, 11Lund University and Lund University Diabetes Centre, CRC at Skåne University Hospital,
Malmö, Finland, 12National Institute for Health and Welfare, Turku, Finland, 13School of
Public Health, Imperial College London, London, United Kingdom, 14Institute of Health
Sciences and Biocenter Oulu, University of Oulu, Finland, 15University of Turku and Turku
University Hospital, Turku, Finland, 16Wellcome Trust Sanger Institute, Hinxton, Cambridge,
United Kingdom, 17Hjelt Institute, University of Helsinki, Helsinki, Finland.
The X chromosome (chrX) has often been overlooked in genetic association studies, thus representing one potential source for the “missing heritability” for complex phenotypes. Additionally, as up to 15% chrX genes escape from X inactivation (XCI), chrX may be enriched in sexually dimorphic associations,
further highlighting that chrX warrants attention.
We investigated the contribution of >400,000 chrX SNPs to the levels of twelve common quantitative phenotypes in almost 25,000 individuals from Finland and Sweden. ChrX-wide association analysis pinpointed three new loci: two for height (FGF16/ATRX/MAGT1, P-value=2.71×10-9; ITM2A, P-value=3.03×10-10) and one for fasting insulin (Xq23, P-value=5.18×10-9), the first X-chromo-somal ones for these traits in Europeans. Interestingly, the genetic effects for height near ITM2A, a gene implicated in chondrogenesis and know to escape from XCI, showed sex-heterogeneity in a manner consistent with no dosage compensation between men and women, observation further supported by statistical model comparison and female-bias in ITM2A expression. Given the converging evidence, this height locus likely represents the first link between an XCI-escaping gene and phenotypic variation in a population sample, and we estimate it explains approximately 1.5% of the height difference between men and women.
Together our findings underline the value of including chrX in large-scale gene-tic studies of complex diseases and traits. Our estimate that chrX accounts on average 2.6% of complex trait heritability, suggests there are tens of associated chrX loci to be discovered, with the intriguing possibility that some of the loci can also contribute to sexual dimorphisms.
Ref. Tukiainen et al. PLoS Genet. 2014 PL2.6
Genome sequencing identifies major causes of severe intellectual disability
C. Gilissen1, J. Y. Hehir-Kwa1, D. T. Thung1, M. Van de Vorst1, B. W. M. van Bon1, M. H.
Willemsen1, M. Kwint1, I. Janssen1, A. Hoischen1, R. Leach2, R. Klein2, R. Tearle2, T. Bo3, R.
Pfundt1, H. G. Yntema1, B. B. A. De Vries1, T. Kleefstra1, H. G. Brunner1,4, L. E. L. M. Vissers1, J. A.
Veltman1,4;
1Radboud university medical center, Nijmegen, Netherlands, 2Complete Genomics Inc,
Mountain View, CA, United States, 3State Key Laboratory of Medical Genetics, Central
South University, Changsha, China, 4Maastricht University Medical Centre, Maastricht,
Netherlands.
Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin. The extensive genetic heterogeneity of the dis-order requires a genome wide detection of all types of genetic variation. Mi-croarray studies and more recently exome sequencing have demonstrated the importance of de novo copy number variations (CNVs) and single nucleotide variations (SNVs) in ID, but the majority of cases remains undiagnosed. Here we applied whole genome sequencing (WGS) to 50 patients with severe ID and their unaffected parents. All patients were negative after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, de novo SNVs affecting the coding region provided a conclusive genetic cause in 13 patients and a possible cause for ano-ther 8 patients. In addition, we identified 7 clinically relevant de novo CNVs as well as one recessively inherited compound heterozygous CNV. These CNVs included single exon and intraexonic deletions of known ID genes as well as in-terchromosomal duplications. Local realignment of sequence reads allowed the mapping of most of these CNVs at single nucleotide resolution level and provi-ded positional information for duplicated sequences. These results show that de novo mutations and CNVs affecting the coding region are the major cause of severe ID. Genome sequencing can be applied as a single genetic test to reliab-ly identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID. PL3.1 - Summary
Incidental findings in clinical exome and genome sequencing
Diagnostic exome and genome sequencing data can be interrogated for clini-cally relevant variants other than those relevant for a diagnostic request. There are different opinions on the way to deal with these „incidental findings“ in the clinic, on the potential benefits and risks to patients, on patient autonomy and on the obligation of laboratories to report these findings. These will be debated with representatives from both sides of the Atlantic.
PL3.1
Incidental findings in clinical exome and genome sequencing
R. Green;
Boston, MA, United States.
In 2013, the American College of Medical Genetics and Genomics (ACMG) is-sued Recommendations for incidental findings in clinical exome and genome sequencing. The Recommendations were written by a Working Group of 14 me-dical geneticists, laboratory geneticists, genetic counselors and ethicists who met regularly for 14 months to draft them. The draft Recommendations were presented for commentary in a public forum at the 2012 Annual Meeting of the ACMG, reviewed by 15 additional experts, and reviewed several times by the Board of the ACMG before being issued in March, 2013. The Recommendations
ABSTRACTS
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were recently amended in March, 2014.
The Recommendations were consensus-based, as empirical data on populati-on penetrance and medical outcomes of identifying incidental variants are not available. The Recommendations called for molecular laboratories performing clinical sequencing for any indication on patients of any age to examine 56 ge-nes associated with 24 actionable conditions for pathogenic variants. The Re-commendations now suggest that patients be offered an option to decline these tests as a group at the time they are ordered.
Several clinical sequencing laboratories in the US have adopted the Recom-mendations and over 1000 reports of incidental findings have been issued. The incidence of the ACMG variants in unselected populations appears to be 2-4%. Additional data from our experimental laboratory of translational genomics on the issue of incidental findings will be presented.
PL3.3
Debate: Active search for clearly pathogenic variants that require direct clinical intervention; When related to late onset disorders, adults only.
M. Kriek;
Clinical Geneticist, Department of Clinical Genetics, Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
In 2013 the ‘American College of Medical Genetics and Genomics’ (ACMG) pu-blished a list of 56 genes that are proposed specific targets of a search for pa-thogenic variants in both children and adults (Green et al.). These genes are as-sociated with diseases with an indication for immediate medical intervention of the patient or of a family member. The publication asserts that, in principle, the necessary patient data are available following a NGS procedure and therefore cannot be ignored. For purposes of clarity, the vast majority of these variants are removed during the various filtering stages of the normal trio analysis pro-cess and that identification of these variants will require additional actions. During the American Society of Human Genetics meeting 2013, it was argued that consensus on a basic list of clearly pathogenic variants in the relevant ge-nes is essential if this form of diagnosis is to be implemented in genetic diagno-stics. A disadvantage of the approach as proposed by the ACMG (analysis of the entire gene, rather than focusing on known pathogenic gene variants) is that variants will be detected that have not been previously reported and/or are of undefined pathogenicity. This could result in considerable distress for the patient and family. To avoid this, only selected variants in the genes nominated by the ACMG will be analysed.
Another point of discussion is whether conditions that manifest later in life should be investigated in children. While the ACMG is in favour, Ploem et al. are of a different opinion: „When it comes to the unsolicited findings of NGS diagno-stics in a young child, the interests of the child prevail over any wishes of the parents (not) to receive certain information.“ (NTVG 2014;158:A6757). This is consistent with ESHG recommendations (EJHG 2013;21:580-4)).
‘In case of testing minors, guidelines need to be established as to what unsolicited information should be disclosed in order to balance the autonomy and interests of the child and the parental rights and needs (not) to receive information that may be in the interest of their (future) family’
A solution to these conflicting interests is as follows: where the index patient is a minor, a genetic predisposition for ‘late onset’ diseases for which immedi-ate medical treatment is indicimmedi-ated will only be sought in parents. This is made possible by the setup of trio analysis in which variant lists are available for each parent.
Genetic variants that result in clinical manifestations that in require direct in-tervention during childhood will be analysed in the index patient, even when a minor.
PL3.4
Debate: Whole-genome sequencing in health care: proceed with caution and avoid incidental findings
M. C. Cornel;
VU University Medical Center, Amsterdam, Netherlands.
Whole-genome sequencing (WGS) of the human genome has a great potential to identify the genetic component of health problems, and probably, in the near future, at a lower cost than that of the current techniques. Proof of principle regarding the clinical utility of WGS followed by whole genome analysis (WGA) has been reported, especially for rare diseases. The Public and Professional Policy Committee of ESHG developed recommendations on whole genome se-quencing for health care (EJHG 2013;21:580-4).
As a first element of the discussion, we have to consider all stakeholders invol-ved: patients looking for a diagnosis, primary care physicians referring patients and following them for many years after the diagnosis, laboratory experts and clinical geneticists, legal and ethical experts. If a new technology is being im-plemented, a mutual learning process starts. Structures are needed for sharing experiences and establish testing guidelines at local, national and international levels.
When in the clinical setting either targeted sequencing or analysis of genome data is possible, it is preferable to use a targeted approach first in order to avoid unsolicited findings or findings that cannot be interpreted. The ACMG advoca-tes (Genet Med 2013;15:565-74) that there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The ESHG position is that whenever possible, such testing should be targeted to genome regions linked to the indication. Wider testing requires a justification in terms of necessity and proportionality. Adding screening targets to a diagnostic test violates the necessity criterion. Imposing this extra testing upon patients who need an answer to their clinical problem is at odds with respect for autonomy (Science 2013;341:958-9). Guidelines for the informed consent procedure in WGA must be developed (Hum Mutat. 2013;34:1322-8).
Also in a targeted analysis it is possible to detect an unsolicited genetic variant, indicative of serious health problems (either in the person tested or his or her close relatives) that allow for treatment or prevention. In principle, a health-care professional should report such genetic variants (EJHG 2013;21:580-4). To prepare the health care professionals for WGS in health care, a sustained effort at genetic education is required at various levels: in primary care to in-form and refer people appropriately, and in specialized care to counsel or refer patients, and to discuss and interpret genetic test results adequately. Genetic experts should engage in discussing new developments in genetics, and explain the pros and cons of genetic testing and screening in clinical and commercial settings to inform the public and raise public awareness. Enhancing genetic li-teracy in patients and the lay public will help to involve wider society in this debate.
PL4.1
Gene Targeting into the 21st Century: Mouse Models of Human Diseases
from Cancer to Neuropsychiatric Disorders
M. Capecchi;
Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT, United States.
Gene targeting provides the means for modifying any gene in any desired man-ner in an intact, living animal, the mouse. This technology permits the evalua-tion of the funcevalua-tion of genes in mammals. Because nearly all biological phe-nomena are mediated or influenced by the activity of genes, this methodology permits the analysis of the most complex biological processes such as develop-ment, learning, normal and aberrant behavior, cancer, immunology and a mul-titude of congenital human diseases. In the past, gene targeting has been used primarily to generate ‚knockout‘ mice, that is mice in which the chosen gene has been disrupted in the germline, such that every cell in the mouse carries the mutations. This methodology permits evaluation of the function of that gene in the intact mouse. However, many, if not most, genes have multiple functions. If one of those functions is critical to the survival of the mouse, then subsequent functions of that gene in the mouse cannot be evaluated by the above means. This problem can be circumvented by generating conditional mutations, that restrict the effects of the mutation temporally, spatially (to defined sets of cells or tissue), or both. In mice, conditional mutagenesis is achieved by combining gene targeting, which is achieved through homologous recombination, with a site-specific recombination system, such as Cre/loxP or Flp/FRT. Cre and Flp are recombinases that mediate recombination between specific, short DNA se-quences, loxP and FRT, respectively. Gene targeting is used to flank your chosen gene with either loxP or FRT sites in the mouse germline. By restricting the production of the Cre or Flp recombinase to either a specific set of cells, a cho-sen temporal period, or both, within the developing or adult mouse, the gene is only excised from the genome of the mouse, in those selected cells, during that chosen temporal period, or both. I will describe a number of applications of gene targeting and conditional mutagenesis derived in our laboratory that address interesting biological questions from modeling human cancer to neu-ropsychiatric disorder in the mouse.
PL5.1
Signatures of Mutational Processes in Human Cancer
M. Stratton;
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
All cancers are caused by somatic mutations. However, the processes under-lying the genesis of somatic mutations in human cancer are remarkably poorly understood. Recent large-scale cancer genome sequencing initiatives have pro-vided us with new insights into these mutational processes through the muta-tional signatures they leave on the cancer genome. In this talk I will review the mutational signatures found across cancer and consider the underlying muta-tional processes that have been operative.
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S01.1
From rare disease to management of common disorders
M. Summar;
Washington, DC, United States.
No abstract received at production date. Check the online database at www.eshg.org/astracts2014.0.html for possible updates.
S01.2
Breast cancer genes: beyond BRCA1 and BRCA2
P. Pharoah;
Dept of Oncology, Cambridge, United Kingdom.
No abstract received at production date. Check the online database at www.eshg.org/astracts2014.0.html for possible updates.
S01.3
Age-related Macular Degeneration
C. Klaver;
Rotterdam, Netherlands.
No abstract received at production date. Check the online database at www.eshg.org/astracts2014.0.html for possible updates.
S02.1
Variation and genetic control of chromatin in humans
B. Deplancke;
Lausanne, Switzerland.
Understanding how a genome gives rise to complex phenotypes is one of the key unresolved questions in biology. In this talk, I will present results from our study aiming to examine the mechanistic relationship between genomic and molecular phenotypic variation. Specifically, we profiled three histone modifications (H3K4me1, H3K4me3, H3K27ac), two DNA binding factors (PU.1, RNA polymerase II), and gene expression in lymphoblastoid cell lines from 50 European individuals, reasoning that an integrated analysis of in-termediate molecular phenotypes coupled with personal genome informati-on might enable an in-depth characterizatiinformati-on of ninformati-on-coding variatiinformati-on. I will discuss how the resulting data allowed us to measure inter-individual va-riation in chromatin states, to predict sex-biased regulatory regions, and to map the regulatory architecture behind gene expression variation. As such, I will argue that we were able to provide a comprehensive view of chroma-tin state variation in a human population and to generate novel molecular insights into the propagation of genetic signals along the complex chain of molecular, regulatory events.
S02.2
Control of gene expression in disease
M. Georges;
Liège, Belgium.
No abstract received at production date. Check the online database at www.eshg.org/astracts2014.0.html for possible updates.
S02.3
Computational challenges in single-cell transcriptomics
J. Marioni;
EMBL-EBI, Hinxton, United Kingdom.
Recent technical developments have enabled the transcriptomes of hundreds of cells to be assayed in an unbiased manner. These approaches have enabled heterogeneity in gene expression levels across populations of cells to be characterized as well as facilitating the identification of new, and potentially physiologically relevant, sub-populations of cells.
However, to fully exploit such data and to answer these questions, it is ne-cessary to develop robust computational methods that take account of both technical noise and underlying, potentially confounding, variables such as the cell cycle.
In this presentation I will begin by briefly describing how we used spike-ins to quantify technical noise in single-cell RNA-seq data, thus facilitating iden-tification of genes with more variation in expression levels across cells than expected by chance. Subsequently, I will discuss a computational approach that uses latent variable models to account for potentially confounding fac-tors such as the cell cycle before applying it to study the differentiation of Th2 cells. I will show that accounting for cell-to-cell correlations due to the cell cycle allows identification of otherwise obscured sub-populations of cells that correspond to different stages along the path to fully differentiated Th2 cells.
To conclude, I will briefly discuss further applications of single-cell RNA-seq
in the context of studying neuronal cell types, including olfactory neurons. S03.1
Pontocerebellar hypoplasia
K. Kutsche;
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Pontocerebellar hypoplasias (PCH) constitute a group of autosomal reces-sively inherited neurodegenerative disorders with prenatal onset. Classi-fication based on clinical, neuroradiological and neuropathological charac-teristics divided PCH into eight subtypes; the underlying genetic cause has been identified in six PCH types (PCH1, PCH2, and PCH4-6 and 8). PCH2 represents the most frequent form of PCHs and typical clinical features are respiratory and feeding difficulties at birth, dyskinesia and chorea, severe impairment of cognitive and motor development, progressive microcepha-ly, and frequent death in late infancy or early childhood. MRI imaging in PCH2 shows brainstem and cerebellar hypoplasia, with the cerebellar he-mispheres more affected than the vermis. In patients with PCH2, 4 and 5, biallelic mutations in genes encoding three subunits of the heterotetrameric transfer RNA (tRNA) splicing endonuclease complex, TSEN54, TSEN2, and
TSEN34 have been identified. PCH shows significant overlapping features
with microcephaly with pontine and cerebellar hypoplasia (MICPCH), gene-rally associated with loss-of-function CASK mutations. The classical MICPCH phenotype can be found in females who typically have moderate to severe intellectual disability and progressive microcephaly with pontine and cere-bellar hypoplasia. Possible findings are ophthalmologic anomalies and sen-sorineural hearing loss. Males with a CASK mutation have also been iden-tified. The phenotypic spectrum ranges from severe intellectual disability and MICPCH, or early-infantile epileptic encephalopathy to mild X-linked intellectual disability (XLID) with or without nystagmus. I will present an overview on clinical and genetic data of patients with PCH and MICPCH and how to discriminate the two conditions. My focus will be on the different
CASK mutations in females and males and their associated phenotypes to
help understanding genotype-phenotype relationships. S03.2
The neurobiology of lissencephal
A. Wynshaw-Boris;
Cleveland, OH, United States.
No abstract received at production date. Check the online database at www.eshg.org/astracts2014.0.html for possible updates.
S03.3
Neuronal migration defects associated with mutations in tubulins and MT‐related proteins
L. Broix, K. Poirier, Y. Saillour, N. Bahi-Buisson, J. Chelly;
Cochin Institute, INSERM Unit 1016, CNRS –UMR 8104, Paris‐Descartes University,
Paris, France.
Neuronal migration disorders such as malformations of cortical develop-ment are frequent causes of epilepsy and intellectual disability. Disrupted biological and cellular processes such as neuronal progenitors proliferation, neuronal migration, and cortical organization, are traditionally used as a basis for the classification of MCD. Etiologies of these disorders are hetero-geneous and genetic studies in humans and mice have identified a spectrum of mutations in genes involved in an array of crucial processes that often disrupt the development of the cerebral cortex. Aside from genes such as ARX, GPR56 and WDR62, the importance of genes encoding cytoskeletal proteins has become evident. For example, mutations in DCX and LIS1, both of which encode proteins involved in MT homeostasis, are associated with a large spectrum of neuronal migration disorders. Moreover, MCD associated with mutations in α- or β-tubulin-encoding genes such as TUBA1A, TUBB2B, TUBB3 and TUBB5, have been also described. These tubulin-related corti-cal dysgenesis are thought to involve a combination of abnormal neuronal proliferation, migration and differentiation. More recently, we reported the association between mutations in TUBG1, DYNC1H1, KIF2A and KIF5C, and diverse forms of malformations of cortical development with or without microcephaly. We further showed that the mutations in these MTs-related proteins: KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive pro-tein folding and microtubule binding, respectively. In addition, we showed by in utero electroporation that in vivo downexpression by shRNA of mouse, Tubb3 and Tubg1, as well as expression of Kif2a mutants, interferes with proper neuronal polarization and migration, morphogenesis and intermedi-ate progenitor proliferation.
Altogether, these findings together with literature data support the hypo-thesis that proliferation and migration are genetically and functionally in-terdependent. Finally, they reinforce the importance of centrosomal and
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related proteins in cortical development and strongly suggest that MT-dependent mitotic and post-mitotic processes are major contributors to the pathogenesis of MCD.
S04.1
Disease, networks and epistasis
C. Webber;
Neurological Disease Genomics, MRC Functional Genomics Unit, Department of Physiology, Anatomy & Genetics, Oxford University, Oxford, United Kingdom.
I will give an overview of our recent work in identifying the pathways and processes underlying complex disorders, illustrating how different functio-nal genomics resources can each provide novel biological insights into the same phenotype-influencing gene network. The topologies of the identified networks can identify pathway loading (both additive and epistatic) along with the direction in which the pathway is perturbed, thereby inviting drug repurposing. I will also illustrate some of the novel integrative approaches that we’ve been applying in GWA/exome studies and used to determine the significance of a functionally-clustered genome.
S04.2
Understanding molecular mechanisms of human disease mutations and coding variants through 3D protein networks
H. Yu;
Ithaca, NY, United States.
To better understand the molecular mechanisms and genetic basis of hu-man disease, we combined the massive scale of network systems biology with the supreme resolution of traditional structural biology to generate the first comprehensive atomic-resolution 3D interactome-network com-prising 3,398 interactions between 2,890 proteins with structurally-defined interface residues for each interaction. We found that disease mutations are significantly enriched both among interface residues and other non-inter-face ones within the same domains, contradicting the previous assumption that only a few interface residues are mutation hot spots for disease. We further classified 94,476 disease-associated mutations according to their in-heritance modes and found that the widely-accepted “guilt-by-association” principle does not apply to dominant mutations. Furthermore, recessive truncating mutations on the same interface are much more likely to cause the same disease, even if they are close to the N-terminus of the protein, indicating that a significant fraction of truncating mutations can generate functional protein products.
S04.3
From protein networks to disease mechanisms
R. Sharan;
Tel Aviv University, Department of Computer Science, Tel Aviv, Israel.
In recent years, there is a tremendous growth in large scale data on human proteins, their interactions, and their relations to diseases. These allow for the first time a systems-level analysis of the molecular basis of disease. In my talk I will describe several recent works in this direction, aiming to unco-ver novel disease proteins and their underlying pathways with implications to diagnosis and therapy.
S05.1
Dynamic blastomere behaviour
R. Pera;
Stanford, CA, United States.
No abstract received at production date. Check the online database at www.eshg.org/astracts2014.0.html for possible updates.
S05.2
24 chromosome copy number analysis for preimplantation genetic screening
A. H. Handyside;
Illumina, Cambridge, United Kingdom.
Chromosome aneuploidy in human gametes and embryos is a major cause of IVF failure and miscarriage and can result in affected live births. To avoid these outcomes and improve implantation and live birth rates, preimplanta-tion genetic screening (PGS) aims to identify any euploid embryos prior to transfer but has been restricted to analysis of a limited number of chromoso-mes. Over the last 15 years, various technologies have been developed which allow copy number analysis of all 23 pairs of chromosomes, 22 autosomes and the sex chromosomes, or ‘24 chromosome’ copy number analysis in sin-gle or small numbers of cells. The pros and cons of these technologies will be reviewed and evaluated for their potential as screening or diagnostic tests when used in combination with oocyte or embryo biopsy at different stages.
S05.3
Preimplantation genetic diagnosis
T. Voet;
Leuven, Belgium.
No abstract received at production date. Check the online database at www.eshg.org/astracts2014.0.html for possible updates.
S06.1
Risk is More Than a Number: About Risks and Probabilities and People’s Perceptions of Genetic Risks
D. R. M. Timmermans1,2;
1Department of Public and Occupational Health, EMGO Institute, VU University
Medical Center, Amsterdam, Netherlands, 2National Institute for Public Health and the
Environment, Bilthoven, Netherlands.
Risk communication is an essential component of genetic counseling . Ge-netic testing and providing information about geGe-netic predisposition may enable early disease detection, targeted surveillance, and may lead to effec-tive prevention strategies and behavioral change. However, the impact of ge-netic information on people’s perceptions may be limited. Most people are unfamiliar with probabilistic thinking and find it hard to understand risks. Moreover, risks are experienced differently depending on the characteristics of the risk. A risk is more than a number. It is not only the probability, the quantification of the uncertainty, but also the nature of the risk, the severity of the consequences and the degree of control what matters. People process and evaluate information about potential risks in two different ways: analy-tical-rational if possible, but always intuitive-affective. The characteristics of the risks as well as the way risk information is processed impact people’s understanding and perception of risks. This perception may be in discor-dance with the way experts’ perceive genetic risks. In order to enable people to make informed decisions, information about (genetic) risks should not only be adequate but should also be in line with people’s perceptions or mental model. Discrepancies with people’s mental model of genetic risks as well the abstractness of the risk information may hamper people’s informed decision making. In this presentation I will discuss the factors affecting the perception of health risks and genetic risks in particular, the way people understand the risks communicated to them and what this means for risk communication
S06.2
Risk perception: what could be at stake in multiple genetic testing?
C. M. Julian-Reynier;
Institut Paoli-Calmettes, UMR912 Inserm, Marseille, France.
First the concept of risk perception will be introduced, highlighting its inter-est for clinical practice or various research fields. We will focus on associated factors and in particular on the potential role of emotions in risk perception. Then the evidence for the relevance of previous findings will be reviewed in the context of genetic risk assessment and genetic test result disclosure such as investigated in clinical genetics/genetic counseling. Different application fields such as cancer genetics will be selected as illustrations of different situational contexts. Finally the way these previous experiences and body of knowledge could help to anticipate the potential consequences of multiple risk information disclosure and to document specific recommendations in the context of the process of multiple genetic testing or next generation se-quencing will be discussed.
S06.3
Risk Communication Methods for Helping Patients Understand the Risks and Benefits of Genetic Testing
A. Fagerlin;
University of Michigan, Ann Arbor VA Center for Clinical Management Research, Ann Arbor, MI, United States.
Making decisions about whether to undergo genetic testing or how to use information from genetic tests is exceedingly complex. The complexity is due, in part, to the numeracy demands required of patients to understand the information being presented. In this talk, I will discuss methods for im-proving patients understanding of risk and benefit information. Furthermo-re, I will discuss how different risk communication methods can influence risk perceptions. Finally, I will discuss the role of family history and how that affects patients’ (hypothetical) perception of risk and how patients weigh information about their family history and their risks to make screening de-cisions.
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S07.1
Gene therapy of human genetic diseases with AAV vectors
A. Auricchio;
Telethon Institute of Genetics and Medicine (TIGEM), Napoli, Italy.
No abstract received at production date. Check the online database at www.eshg.org/astracts2014.0.html for possible updates.
S07.2
Epithelial stem cell in cell and gene therapy
M. De Luca;
Dipartimento di Scienze della Vita sede ex-Scienze Biomediche, Modena, Italy.
Adult stem cells are cells with a high capacity for self-renewal that can pro-duce terminally differentiated progeny. Stem cells generate an intermediate population of committed progenitors, often referred to as transit amplifying (TA) cells, that terminally differentiate after a limited number of cell divisi-ons. Human keratinocyte stem cells are clonogenic and are known as holo-clones. Human corneal stem cells are segregated in the limbus while limbal-derived TA cells form the corneal epithelium. Self-renewal, proliferation and differentiation of limbal stem cells are regulated by the ΔNp63 (α, β and γ), C/EBPδ and Bmi1 transcription factors. Cultivated limbal stem cells gene-rate sheets of corneal epithelium suitable for clinical application. We report long-term clinical results obtained in an homogeneous group of 154 patients presenting with corneal opacification and visual loss due to chemical and thermal burn-dependent limbal stem cell deficiency. The corneal epitheli-um and the visual acuity of these patients have been restored by grafts of autologous cultured limbal keratinocytes. In post hoc analyses, success was associated with the percentage of p63-bright holoclone-forming stem cells in culture. Graft failure was also associated with the type of initial ocular damage and postoperative complications. Mutations in genes encoding the basement membrane component laminin 5 (LAM5) cause junctional epider-molysis bullosa (JEB), a devastating and often fatal skin adhesion disorder. Epidermal stem cells transduced with a retroviral vector expressing the β3 cDNA can generate genetically corrected cultured epidermal grafts able to permanently restore the skin of patients affected by LAM5-β3-deficient JEB. The implication of these results for the gene therapy of different genetic skin diseases will be discussed.
S07.3
Therapeutic targeting of Phosphatidylinositol-3-kinase/AKT/mTOR signalling in segmental overgrowth disorders
R. Semple;
University of Cambridge, Metabolic Research Laboratories, Addenbrooke‘s Hospital, Cambridge, United Kingdom.
The type 1A phosphatidylinositol-3-kinase (PI3K) enzyme complex serves as a signal transducer for a diverse range of hormone and growth factor re-ceptors, and harbours somatic activating mutations in a large number of can-cers. We and others have recently established that mosaicism for many of the same mutations underlies a spectrum of disorders of segmental overgrowth, ranging from isolated macrodactyly to catastrophic overgrowth affecting lar-ge parts of the body and several tissues, and commonly associated with com-plex vascular anomalies. Identification of the underlying signalling defect in affected tissues has immediately suggested that pharmacological targeting of the PI3K/AKT/mTOR pathway may offer the first rational, effective thera-peutic approach for these disorders. The effect of mTORC or PI3K inhibition in dermal fibroblasts from affected patients will be discussed, as well as the early experience of sirolimus treatment in a severely affected proband. S08.1
Demographic inference from identity by descent
I. Pe’er;
New York, NY, United States.
No abstract received at production date. Check the online database at www.eshg.org/astracts2014.0.html for possible updates.
S08.2
Insights into European genetic history at fine geographic scales using haplotype-based approaches
S. Myers;
Dept of Statistics, Oxford University, United Kingdom
Wellcome Trust Centre for Human Genetics, Oxford University, United Kingdom
Modern genetic datasets are revealing features of our genetic history, and how this has shaped our genomes, in unprecedented detail. Across Europe, multiple invasions and migrations have taken place over the past several millennia, but the possible genetic effects of these and of subsequent re-gional isolation remain uncharacterised, partly due to the extremely
subt-le differences between the groups involved. We apply a set of approaches based on “painting” the genomes of people as haplotypic mosaics and de-scribe insights into the existence and nature of extremely fine-scale diffe-rences among people from different regions of the UK, and Spain, as well as elsewhere in Europe. In the case of the UK, we show how these differences relate directly to specific historical migration events from other European countries, including invasions by Angles, Saxons and Jutes, and the Vikings. The groups involved in, genetic contributions, and dates, of these migrations are characterized based on genetic information alone.
S08.3
The role of population isolates in understanding genetic and complex diseases
P. Gasparini;
Trieste, Italy.
The use of isolated populations to reduce disease heterogeneity of complex disorders has already proven very useful in identifying DNA polymorphis-ms associated with complex diseases and quantitative traits. The study of complex traits in geographically and culturally isolated populations is par-ticularly useful because the entire population can be analyzed, the relative weight of environmental variation can be controlled and genetic factors can be more easily identified. In these genetically and culturally homogeneous populations, a large proportion of individuals presenting a given trait is li-kely to share the same trait-predisposing gene inherited from a common ancestor. Furthermore, inbreeding, typical of small communities, reduces genetic heterogeneity and increases homozygosity, providing greater power for detection of susceptibility genes. We have created the Italian Network of Genetic Isolates (INGI) that collects the samples coming from several villa-ges from 5 different Italian regions for a total of more than 6000 samples. Moreover, additional 1500 samples have been collected along the Silk Road. For all of them a great number of information regarding medical records, hematological parameters and lifestyle has been collected as well as DNA samples which have been genotyped with high density chip arrays. To eva-luate the power to detect association in our cohorts we aimed at replicating several already published results and to verify if any new Italian specific loci were present. For example, GWAS were carried out on several hematological and serum lipids traits, blood glucose levels, blood pressure and anthropo-metric measures leading to the replication of 206 loci and to the discovery of some novel associations for BMI and weight. For 12 of these loci the top associated SNP was different from the one previously published highlighting the importance of having a population specific reference panel for persona-lized medicine. Moreover, specific genes/variants associated to phenotypes such as hearing, smell, taste and food preferences have been identified. More recently, new data have been obtained using whole genome sequencing data that allow refining the results previously obtained and will lead to the dis-covery of even more population specific genetic variants. Our results show that genetic isolates are a powerful resource for studying complex traits and thus to create genetic risk profiles which will be the bases for personalized medicine in Italy. Updated data will be presented and discussed.
S09.1
Twenty-five years of research in sarcomeric cardiomyopathies and therapeutic perspectives
H. Watkins;
University of Oxford, Oxford, United Kingdom.
Hypertrophic cardiomyopathy was one of the first monogenic cardiovascu-lar disorders to be understood at the molecucardiovascu-lar level. Twenty years after the discovery of the first disease gene, HCM is still seen principally to be a disease of the sarcomere. At the biophysical level, the contractile protein mutations that cause HCM are seen to be activating in that they enhance Ca(2+) sensitivity, maximal force production, and ATPase activity. These defects then entrain secondary disturbances of energy deficiency and alte-red Ca(2+) handling that appear to be major common paths leading to the phenotype of hypertrophy and risk of sudden cardiac death. Importantly, these functional consequences of HCM mutations may lend themselves to specifically targeted approaches to disease modifying therapy for HCM, and phase I/II clinical trials have been completed or are underway.
In contrast, dilated cardiomyopathy is caused by mutations in genes enco-ding many different classes of proteins with very diverse roles in cardio-myocyte function, e.g. ranging from the nuclear envelope through to the contractile and force transduction apparatus. This indicates that the DCM phenotype is the end result of disparate pathways that lead to myocyte loss and fibrous replacement, suggesting that finding broadly applicable approa-ches to disease-modifying therapy may be difficult. In the subset of DCM caused by sarcomeric mutations the picture is clearer, and may lead to ap-proaches to therapy, as DCM alleles result in functional changes that are the
