2008 Barcelona - European Society of Human Genetics

Concurrent Sessions
identified 215 carriers for one of the diseases and 14 carrier couples.
Carrier frequency for MRT3, SMA, SMARD and cystic fibrosis was
1:11, 1:13 and 1:10 and 1:21, respectively . Among carrier couples, 15
pregnancies were recorded and 2 pregnancies of affected fetuses terminated
. More than 50% of carrier couples accepted prenatal testing .
While the women in the village were willing to collaborate, an increase
in the willingness to collaborate among men was observed gradually .
The availability of genetic counseling locally and education of the population
are essential for the success of the prevention program . Ethical
aspects of preventative programs based on genetic screening of
premarital, pre-conceptual couples or couples during pregnancy will
be discussed .
c14.4
Differences and similarities in breast cancer risk assessment
models in clinical practice: which model to choose?
C. J. Van Asperen 1 , G. H. De Bock 2 , B. Siegerink 1,3 , C. E. Jacobi 3 ;
1 Center for Human and Clinical Genetics, Leiden, The Netherlands, 2 Dept. Epidemiology,
University Medical Center Groningen, Groningen, The Netherlands,
3 Dept. Medical Decision Making, Leiden, The Netherlands.
Background: Models regarding breast cancer risk assessment focus
on family history and some use personal risk factors additionally . Aim
of this study is to show differences and similarities between the different
models in risk estimates for breast cancer in healthy women from
BRCA1/2-negative or untested families .
methods: After a systematic literature search seven models were selected:
Gail-2, Claus Model, Claus Tables, BOADICEA, Jonker Model,
Claus-Extended Formula, and Tyrer-Cuzick . Life-time risks (LTRs) for
developing breast cancer were estimated for two healthy counsellees
with variety in family histories and personal risk factors . The estimated
LTRs and the threshold for individual mammographic screening based
on guidelines were compared .
Results: Without a clinically significant family history LTRs varied from
6 .7% (Gail-2 model) to 12 .8% (Tyrer-Cuzick Model) . For counsellees
with low and moderate risk, the models mostly agreed. Difficulties in
screening decisions were encountered in some moderate and high risk
individuals, and when including personal risk factors into the estimations
.
conclusion: Older models (i .e . Gail-2 and Claus) are likely to underestimate
the LTR for developing breast cancer as their baseline risk
for women without a significant history of breast cancer is too low.
Current guidelines have been formulated on breast cancer risks based
on family history alone . When models include personal risk factors,
surveillance thresholds have to be reformulated as other factors are
applied . For current clinical practice, the Tyrer-Cuzick Model and the
BOADICEA Model seem good choices .
c14.5
treatable and untreatable diseases in the neonatal-screening
programme: the opinion of future parents in the Netherlands
A. C. Plass1,2 , L. Krijgsman1,2 , L. Gieling1,2 , C. G. van El1,2 , T. Pieters1 , M. C.
Cornel1,2 ;
1 2 VU University medical center, Amsterdam, The Netherlands, EMGO-institute,
Amsterdam, The Netherlands.
In the Netherlands, in 2007, the neonatal screening program was expanded
from 3 to 17 disorders for which screening met the Wilson and
Jungner criteria, especially regarding treatability . The desicion whether
or not to add diseases to the newborn screening programme has often
been made by expert groups, whereas the opinion of those whom
it concerns: the parents-to-be remains unknown . In our research we
investigated the opinion of future parents concerning screening newborns
also for incurable, but to some extent treatable or even untreatable
disorders .
A structured questionnaire consisting of 3 parts in which similar questions
were posed about treatable, incurable, but treatable, and untreatable
childhood onset disorder was posted on the website of a national
pregnancy fair. 1631 prospective parents filled out the questionnaire.
259 were excluded because they did not meet our inclusion criteria .
In contrast to current policy, overall they showed a positive attitude
towards inclusion of incurable, but treatable [88%] or non-treatable
disorders [73%] within the national newborns screening programme .
Respondents who already had children at the time of filling out the
questionnaire were even more in favour of uptake of childhood dis-
orders, especially untreatable diseases . The most important reason
mentioned was: to prevent a long diagnostic quest . Obtaining information
to enable reproductive choices in future pregnancies was hardly
mentioned .
Since a relevant part of the Dutch population seems interested in considering
screening newborns for untreatable disorders we argue that
further debate is needed between policy, public and health care professionals
to discuss pros and cons .
c14.6
Promoting clinically relevant genetics education for medical
trainees: the importance of educational outcomes and resources
for each stage of medical training
M. Martyn 1 , S. Burke 2 , C. Bennett 1 , A. Stone 3 , E. Harvey 1 , R. Newton 1 , P. Farndon
1 ;
1 NHS National Genetics Education and Development Centre, Birmingham,
United Kingdom, 2 Centre for Research in Medical and Dental Education,
Birmingham, United Kingdom, 3 Thornley Street Practice, 40 Thornley Street,
Wolverhampton, United Kingdom.
It is widely acknowledged that the genetics education of healthcare
staff across the world has not kept pace with advances in genetics .
The NHS National Genetics Education and Development Centre is
working to address this situation in the UK by promoting clinically relevant
genetics education for healthcare professionals across all stages
of education and training . To achieve this, it is important to develop
clinically relevant educational outcomes and to identify and develop
resources to support these across all stages of training . This will be
illustrated by results from the UK .
The first step in promoting clinically relevant genetics education was to
develop educational outcomes linked to clinical practice at each stage
of training . Outcomes have been developed for medical students and
general practice and specialty trainees by working with health professionals
to define genetics relevant to practice for these stages of
training . To promote incorporation of these outcomes into curricula,
the Centre worked with education bodies to raise awareness of the
importance of clinically relevant genetics education .
Now the outcomes have been incorporated into medical training curricula,
the Centre is focusing on supporting teachers and learners
through the development and evaluation of learning and teaching resources
and professional development for educators . Resources covering
core genetics concepts for medical students and resources to
support general practice training are currently being developed .
The educational outcomes and many of the resources will be made
freely available online at www .geneticseducation .nhs .uk and may be
of use to those involved in genetics education across Europe .
c15.1
systemic antisense-mediated exon skipping studies in mouse
models for Duchenne muscular dystrophy
A. Aartsma-Rus1 , H. A. Heemskerk1 , C. L. de Winter1 , M. van Putten1 , A. A. M.
Janson2 , S. de Kimpe2 , J. C. T. van Deutekom2 , G. B. van Ommen1 ;
1 2 Leiden University Medical Center, Leiden, The Netherlands, Prosensa BV,
Leiden, The Netherlands.
Duchenne muscular dystrophy (DMD) is a severe, progressive neuromuscular
disorder leading to loss of muscle function and generally premature
death before the age of 30 . The disease is caused by mutations
in the DMD gene that disrupt the open reading frame and lead to complete
abolishment of functional dystrophin . Our group has pioneered
antisense-based exon skipping to restore the reading frame . Here,
antisense oligoribonucleotides (AONs) induce specific exon skipping
during pre-mRNA splicing . They have been successful in repairing the
disrupted open reading frame and the generation of internally deleted,
partially functional Becker-like dystrophins . Proof of concept has been
achieved in cultured muscle cells from patients and the mdx mouse
model . Recently, exon 51 skipping and dystrophin restoration was
confirmed after a single intramuscular dose of AON in a local-administration
clinical trial in 4 patients . Our current research focuses on optimizing
systemic delivery of 2’-O-methyl phosphorothioate AONs and
comparison of different routes of administration and dosing regimes .
We show that after systemic injection, AONs are preferentially taken
up by dystrophic muscle compared to healthy fibers. Furthermore, we
were able to induce exon skipping and dystrophin restoration in all
muscles, including the heart after short term treatment with high AON