2009 Vienna - European Society of Human Genetics

Concurrent Symposia
Monogenic diabetes accounts for 1-2% of diabetes with an estimated
prevalence of up to 1/1000 in Europe. For some patients, defining the
genetic aetiology of their diabetes may lead to improved treatment.
Mild fasting hyperglycaemia resulting from heterozygous inactivating
GCK mutations does not usually require pharmacological treatment
and children misdiagnosed as having type 1 diabetes have been able
to stop insulin injections without a deterioration in glycaemic control.
Those patients with HNF1A or HNF4A mutations are sensitive to low
dose oral sulphonylureas but may later progress to insulin.
Heterozygous activating mutations in the KCNJ11 and ABCC8 genes
encoding the Kir6.2 and SUR1 subunits of the beta-cell ATP sensitive
potassium (K ATP ) channel account for around 50% of patients with permanent
neonatal diabetes (PNDM) diagnosed in the first 6 months of
life. This discovery of the underlying genetic aetiology has dramatically
improved treatment since most patients achieve improved glycaemic
control upon transfer from insulin to high dose oral sulphonylureas.
The challenge now is to educate health care professionals to recognise
monogenic subtypes of diabetes in order to maximise the benefits
of a pharmacogenetic approach to treating diabetes.
s04.3
microRNAs: Functions in metabolism and therapeutic
opportunities
M. Stoffel;
Institute of Molecular Systems Biology, Swiss Federal Institute of Technology,
ETH Zurich, Zürich, Switzerland.
No abstract received as per date of printing. Please see www.eshg.
org/eshg2009 for updates.
s05.1
structural genomic variation
C. Lee;
Department of Pathology, Brigham and Women’s Hospital, EBRC 404A, Boston,
MA, United States.
No abstract received as per date of printing. Please see www.eshg.
org/eshg2009 for updates.
s05.2
Array-cGH in clinical practice: Fascination and frustration.
K. Devriendt;
Center for Human Genetics, University of Leuven, Leuven, Belgium.
Array-CGH gradually is being integrated into the routine clinical practice
to detect submicroscopic chromosomal imbalances. The first experience
is one of fascination. In about 15% of cases with a “chromosomal”
phenotype, an etiological diagnosis can now be reached.
Mosaicism can be detected more easily, and chromosomal aberrations
are characterized precisely. Improved genotype-phenotype correlations
not only facilitates counselling and guidance, but also has lead to
the elucidation of the genetic cause of several clinical disorder such as
CHARGE and Pitt-Hopkins syndromes. More surprisingly, the field of
reverse phenotyping has emerged, where phenotyping of individuals
sharing a similar imbalance has resulted in the delineation of novel
recognisable entities.
Now that the major technical issues of array-CGH have been solved,
its application in clinical practice faces several challenges. In an attempt
to decipher the large number of remaining unexplained cases,
higher resolution arrays were applied, but met with limited success.
It appears that many smaller imbalances cause a monogenic disorder,
which had not been recognized clinically. The high number of rare
variants poses major difficulties in the interpretation of found imbalances.
Traditional cytogenetic criteria of pathogenicity such as size or
de novo occurrence do not longer apply. Also, the distinction between
pathogenic and polymorphic becomes blurred even further since many
CNV’s act as susceptibility loci and in addition, the associated phenotypes
vary in an unexplained way. Also, as a result of genome wide
screening, the clinician will be confronted with unexpected results that
may have important implications for the person and his family. These
issues will have to be considered before one can apply array-CGH in
prenatal diagnosis.
s05.3
mitotic recombination in leukaemia
B. D. Young, M. Raghavan, M. Gupta;
Cancer Research UK , Barts and Royal London School of Medicine, Medical
Oncology Unit, Cancer Genomics Group, London, United Kingdom.
The introduction of array-based analysis of single nucleotide polymorphisms
(SNPs) allows the rapid determination of many thousands of
allelotypes in a human DNA sample. This technology is particularly
suited to the study of changes that take place during the development
of cancer. For example, regions of tumour-associated loss of heterozygosity
(LOH) can be detected as by comparison with germline DNA
from the same individual. Since this approach also yields copy number
information it is possible to determine the probable source of LOH.
The application of SNP genotype arrays to acute myeloid leukaemia
(AML) unexpectedly uncovered large regions of acquired homozygosity
which were not associated with copy number gain or loss and which
cannot be detected by conventional cytogenetics. This phenomenon,
which often continues to the telomere, has been termed acquired uniparental
disomy (aUPD) and is the consequence of a mitotic recombination
event occurring during the evolution of the cancer. In a large
study we have demonstrated that there is a distinct pattern of aUPD
in approximately 17% of AML with certain regions being preferentially
affected. Furthermore we have shown that certain gene mutations are
being rendered homozygous by the mitotic recombination event, including
FLT3, WT1and CEBPA. These data strongly suggest that the
mutation precedes mitotic recombination [1].
A relatively large proportion of AML patients will relapse with resistant
disease. Recently we have applied SNP array analysis to serial
leukaemia samples including both presentation and relapse material
in order to determine whether mitotic recombination could have a role
in disease evolution. It was observed that up to 40% of AML at relapse
should evidence of aUPD frequently affecting chromosome 13q and
involving mutations to FLT3. This suggests that mitotic recombination
events could have an important role in the evolution of AML [2]
References
1. Gupta, M., Raghavan, M., Gale, R.E., Chelala, C., Allen, C., Molloy,
G., Chaplin, T., Linch, D.C., Cazier, J.B., and Young, B.D., Novel
regions of acquired uniparental disomy discovered in acute myeloid
leukemia. Genes Chromosomes Cancer, 2008. 47(9): p. 729-39.
2. Raghavan, M., Smith, L.L., Lillington, D.M., Chaplin, T., Kakkas,
I., Molloy, G., Chelala, C., Cazier, J.B., Cavenagh, J.D., Fitzgibbon,
J., Lister, T.A., and Young, B.D., Segmental uniparental disomy is a
commonly acquired genetic event in relapsed acute myeloid leukemia.
Blood, 2008. 112(3): p. 814-21.
s06.1
Genetics of human autoimmune disease
D. Hafler;
Brigham and Women’s Hospital and Harvard Medical School, Division of
Molecular Immunology,Center for Neurologic Diseases, Boston, MA, United
States.
No abstract received as per date of printing. Please see www.eshg.
org/eshg2009 for updates.
s06.2
Genome-wide association studies of obesity and height: What
have we learned?
J. Hirschhorn1,2 , for the GIANT Consortium;
1Department of Genetics, Children’s Hospital/Harvard Medical School, Boston,
MA, United States, 2Broad Institute, Cambridge, MA, United States.
Genome-wide association (GWA) studies have been used to map loci
at which common genetic variants are associated with polygenic traits
and diseases. However, the modest effects of these common variants
has meant that mapping and validating associated loci requires large
numbers of samples and collaborations. We have taken a collaborative
approach and are using GWA studies representing over 100,000
individuals to identify common variants associated with anthropometric
traits, including height and measures of obesity. Earlier iterations of
these efforts, involving studies of up to 30,000 samples, successfully
identified 10 loci for body mass index and over 40 loci for height. These
results have implicated both expected and novel biological pathways,
and have highlighted the role of central nervous system in regulating
body weight as well as several distinct pathways in the regulation of