2009 Vienna - European Society of Human Genetics

Concurrent Sessions
partial gene deletion (n66c4 x 2, n85a3 -) dn, and c.1349T mat. Patients
with SHANK3 mutation (Group A) were compared with a total of
7 patients (group B) with a true 22q13 deletion, varying in size from 1.4
to 7 Mb. Briefly, patients in group A and B shared accelerated growth,
absent/severely retarded speech, facial coarseness and hypotonia. All
the patients in group A had familiarity for behaviour disorders and additional
CNVs. On the contrary, patients in group B were all sporadic
with respect to behaviour disorders, and no additional CNVs were detected.
Interestingly, the mother with c.1349T mutation presented with
behaviour abnormalities but with normal intelligence and without additional
clinical manifestations of the 22q13 deletion syndrome. Different
CNVs outside 22q13.3 were present in the remaining parents with
behaviour abnormalities but with normal SHANK3. We suggest that
the 22q13 deletion syndrome is unlikely to be a single gene disorder.
Although SHANK3 can be considered the major pathogenic gene, additional
gene mutations are requested for the full phenotype.
c16.6
An international standardized cytogenomic Array (iscA)
consortium approach to the design, implementation and
reporting of constitutional oligo array-cGH
S. Huang 1 , D. H. Ledbetter 2 , C. L. Martin 2 , S. Aradhya 3 , S. J. L. Knight 4 , K.
Smith 5 , K. Kok 6 , J. R. Vermeesch 7 , J. A. Crolla 1 ;
1 National Genetics Reference Laboratory (Wessex), Salisbury, United Kingdom,
2 Emory University, Atlanta, GA, United States, 3 GeneDx, Gaithersburg,
MD, United States, 4 Oxford Partnership Comprehensive Biomedical Research
Centre, Oxford, United Kingdom, 5 Oxford Regional Cytogenetics Laboratory,
Oxford, United Kingdom, 6 University Medical Center Groningen, Groningen,
The Netherlands, 7 University of Leuven, Leuven, Belgium.
Experience to date in ~1,000 reported cases from the National Genetics
Reference Laboratory (Wessex) in the UK has shown that use of a customized
4x44k oligo array in karyotypically normal patients ascertained
for developmental delay or mental retardation with or without congenital
abnormalities, results in the detection of ~25% significant copy number
changes (CNCs) ~15% of which are de novo. The NGRL (Wessex)
is also part of the ISCA Consortium which is a collaboration comprising
~70 laboratories in the USA, Canada, South America and Europe.
Two ISCA workshops held in 2008 led to agreement in two main areas
firstly the design, testing and implementation of oligo arrayCGH utilising
multiple formats including 8x60k, 2x105k and 4x180k. The consensus
design is based on extensive experience derived principally from
five laboratories each of which independently custom designed constitutional
cytogenetic arrays (4x44k or 2x105k) using Agilent’s eArray
software. The ISCA oligo array combines targeting for ~500 genomic
regions of known or suspected pathogenicity together with an “even
backbone” coverage of one oligo probe every ~25 kb. The second ISCA
objective is to set up genome browser-based data sharing between
Consortium Laboratories to help develop data sets which will help to
differentiate between benign and pathogenic copy number changes.
The NGRL (Wessex) is about to initiate testing of the ISCA 4x180k array
and preliminary results on 40 patients together with a summary of
our results to date with the 4x44k array will be presented.
c17.1
Genome-wide analysis in Parkinson‘s disease
J. Simón-Sánchez1,2 , C. Paisán-Ruiz3 , J. Bras2 , S. Scholz2 , R. Gibbs2 , PD
Genetics Consortium, T. Gasser4 , A. B. Singleton2 ;
1 2 Vrije Universiteit Medical center, Amsterdam, The Netherlands, National
Institute on Aging, National Institutes of Health, Bethesda, MD, United States,
3Department of Molecular Neuroscience and Reta Lila Weston Laboratories,
Institute of Neurology, University College London, London, United Kingdom,
4Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain
Research, University of Tübingen, Tübingen, Germany.
Parkinson’s disease (PD) is a progressive, age-associated neurodegenerative
disorder characterized by loss of dopaminergic neurons,
resting tremor, bradykinesia, rigidity, and postural instability. PD, which
is estimated to be the second most common neurodegenerative disease,
will become an increasing social and economic burden as the
world population continues to live longer. In an attempt to further understand
the genetic basis of PD and thus gain insight into the etiology
of this disorder we performed a genome wide association study
in cohorts of Caucasian (n = 5,691) and Asian (n = 3,500) PD cases
and controls. Replication of the most significant loci was performed in
a total of 7,745 Caucasian and ~ 4,000 Asian cases and controls. The
strongest consistent association across all populations was observed
within the gene encoding alpha-synuclein (Asian, rs11931074, odds
ratio (OR) = 1.2, p =6.17 x 10 -13 ; Caucasian, rs2736990, OR = 1.27, p
=5.69 x 10 -9 ), providing unequivocal evidence that common variation at
this locus is a risk factor for typical PD. A Caucasian-specific association
was identified across the MAPT locus (rs415430, OR = 1.34 ; p =
4.5x10 -8 ), not only indicating that variation at this locus, implicated in
several neurodegenerative disorders, is a risk factor for PD but also
that the well-known population specific heterogeneity across this genomic
region impacts risk for disease.
Besides, our analysis suggests that a 0.17Mb region in chromosome
1q32 containing 7 genes and predicted transcripts might confer risk for
the development of PD in both the Asian and the Caucasian cohorts.
c17.2
A regional high risk isolate for schizophrenia reveals an
enrichment of three large copy number variations overlapping
developmental genes
O. P. H. Pietiläinen 1,2 , T. Paunio 2 , A. Tuulio-Henriksson 3,4 , J. Suvisaari 3 , J.
Haukka 3 , T. Varilo 2 , K. Rehnström 2 , E. Jakkula 2 , J. Wedenoja 2 , A. Loukola 2 , J.
Suokas 3 , L. Häkkinen 4 , S. Ripatti 2 , S. Ala-Mello 5 , M. Jussila 2 , J. Lönnqvist 3 , H.
Stefansson 6 , L. Peltonen 1,2,7 ;
1 The Wellcome Trust Sanger Institute, Cambridge, United Kingdom, 2 Institute
for Molecular Medicine, FIMM, Helsinki, Finland, 3 National Institute for Health
and Welfare, Department of Mental Health and Alcohol Research, Helsinki,
Finland, 4 University of Helsinki, Department of Psychology, Helsinki, Finland,
5 Helsinki University Central Hospital, Department of Clinical Genetics, Helsinki,
Finland, 6 deCODE genetics, Reykjavik, Iceland, 7 The Broad Institute of MIT and
Harvard University, Cambridge, MA, United States.
Copy number variations (CNVs) have consistently been reported to occur
more frequently in patients with schizophrenia compared to healthy
individuals. Already several rare CNVs, suggestive of high risk for the
disease, have been identified. We analyzed a special Finnish study
sample of 196 schizophrenia cases and 199 controls emerging from
a high risk isolate for schizophrenia with a specific interest to identify
potential moderate to high risk CNV alleles that thanks to recent
population bottle necks would have become enriched in this founder
population. We discovered three large (> 50 kb) CNV alleles on chromosomes
9p24.3, 17p13.3, and 22q11.22 significantly enriched to isolate
schizophrenia cases (p < 0.05). After analyzing additional 4,431
Finnish population controls, as well as 2,614 schizophrenia cases and
42,276 controls of European origin, the three CNVs were found to be
significantly enriched in the Finnish sub-isolate (p < 1.5*10 -6 ) and within
the isolate associating to schizophrenia (p