2008 Barcelona - European Society of Human Genetics

Concurrent Symposia
s10.2
Non-invasive prenatal diagnosis of Down syndrome: a
challenging puzzle in circulating fetal nucleic acid research
R. Chiu;
Li Ka Shing Institute of Health Sciences and Department of Chemical Pathology,
The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin,
New Territories, Hong Kong.
In 1997, our group discovered the existence of cell-free fetal DNA and
subsequently fetal RNA in the plasma of pregnant women . Such circulating
fetal nucleic acids represent a convenient source of genetic
material from the unborn child that could be sampled non-invasively
and simply through the collection of a maternal blood sample . This
approach is thus a safe alternative to conventional methods which rely
on fetal cell sampling through invasive procedures such as amniocentesis
. We showed that the detection of circulating fetal nucleic acids
could potentially be applied to the non-invasive assessment of fetal
blood group status, sex-linked genetic diseases and beta-thalassaemia
as well as the monitoring of pregnancy-related complications, such
as preeclampsia . Among these applications, the non-invasive assessment
of fetal rhesus D status has been adopted as a routine clinical
test in a number of centres in Europe . However, Down syndrome is the
main reason for couples opting for prenatal diagnosis . Due to the cellfree
nature of fetal DNA/RNA in maternal plasma, development of noninvasive
definitive diagnostic methods for Down syndrome had been
a challenge . After tackling this puzzle for a decade, we have recently
developed strategies to directly assess the dosage of chromosome
21 from maternal plasma allowing for direct non-invasive detection of
fetal Down syndrome . One method, termed the RNA-SNP approach,
is based on determining the ratio between polymorphic alleles of a
placental expressed mRNA derived from chromosome 21 in maternal
plasma . Another method, termed the relative chromosome dosage approach,
is based on the detection of an excess of chromosome 21
DNA sequences with respect to a reference chromosome in maternal
plasma . These approaches have brought us closer to realising the
goal of non-invasive prenatal diagnosis of fetal Down syndrome .
s10.3
the regulation of prenatal and preimplantation genetic diagnosis
in the UK
E. Jackson;
Law Department, London School of Economics, London, United Kingdom.
This paper will explain how the Human Fertilisation and Embryology
Authority (HFEA) regulates preimplantation genetic diagnosis (PGD)
in the UK . Prenatal genetic diagnosis is not separately regulated in the
UK, although abortion law provides a special ground for abortion on
the grounds of abnormality, and this initially was used as a model for
the regulation of PGD .
PGD is not specifically mentioned in the UK’s legislation - the Human
Fertilisation and Embryology Act 1990 . Instead the HFEA has laid
down the circumstances in which PGD may be used through its Code
of Practice, currently in its 7 th edition. In short, there has to be a significant
risk of a serious condition being present in the embryo, and the
Code fleshes out what this means.
Every centre that wants to carry out PGD needs a variation to its licence
for each genetic condition it wishes to test for . There is a list of
previously-approved conditions which can be authorized fairly speedily
if an experienced centre wishes to add them to its licence . For new
centres, and for late-onset or lower-penetrance conditions, each application
must be separately approved by a licence committee .
The HFEA has also permitted preimplantation HLA-typing, provided
certain criteria are met .
This paper will explore how the HFEA has made policy decisions about
legitimate uses of PGD, and how, in practice, it regulates PGD . It will
also consider whether the law which is currently before parliament will
make any substantive changes to the regulatory framework in the UK .
s11.1
Peroxisomal disorders: biochemistry, molecular biology and
genetics
H. R. Waterham;
Academic Medical Center, Laboratory Genetic Metabolic Diseases, Amsterdam,
Netherlands.
Peroxisomes are ubiquitous organelles that play an essential role in
cellular metabolism as underscored by the recognition of a large number
of often severe genetic disorders in which one or more peroxisomal
functions are defective. These peroxisomal disorders can be classified
into two main groups, including the Peroxisome Biogenesis Disorders
(PBDs) and the single peroxisomal enzyme deficiencies.
The group of single peroxisomal enzyme deficiencies currently comprises
10 different defects, 5 of which involve enzymes involved in peroxisomal
fatty acid beta-oxidation, including the most common peroxisomal
disorder X-linked adrenoleukodystrophy (X-ALD) . The distinction
between the different disorders can be readily made on the basis
of specific metabolite patterns in combination with selective enzyme
diagnostics and followed by diagnostic DNA testing .
The PBDs comprise a group of severe, often lethal multi-systemic
autosomal recessive disorders displaying considerable clinical, biochemical
and genetic heterogeneity . Based on clinical and biochemical
parameters, originally 3 different presentations had been defined,
including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy
(NALD) and infantile Refsum disease (IRD), with decreasing clinical
and biochemical severity . Recently, however, they have been assigned
to the Zellweger Spectrum continuum based on the recognition that
the different presentations can be caused by mutations in different
genes, different mutations within the same gene and the fact that they
show considerable clinical and biochemical overlap . A fourth entity assigned
to the group of PBDs is Rhizomelic Chondrodysplasia Punctata
(RCDP) type 1, the clinical presentation of which clearly differs from
those observed in the Zellweger Spectrum disorders .
PBDs can be caused by mutations in any of at least 13 different PEX
genes, which encode proteins (peroxins) involved in different stages
of peroxisomal protein import and organelle biogenesis . To establish
the overall mutational spectrum of PBDs with respect to the affected
PEX gene as well as mutations therein and to allow rapid identification
of the defective PEX gene for diagnostic purposes, we developed
genetic complementation assays based on peroxisome restoration
assessment following PEG-mediated fusion of patient cell lines with
tester cell lines or transfection of patient cell lines with either of the
known PEX cDNAs. Using these assays we have assigned skin fibroblasts
from over 500 patients diagnosed with a PBD, to different
genetic complementation groups representing defects in the various
PEX genes . For all the genes we implemented diagnostic DNA testing
involving gene sequencing .
1 . Wanders RJ & Waterham HR . 2006 . Biochemistry of mammalian
peroxisomes revisited . Annu Rev Biochem 75:295-332 .
2 . Wanders RJ, Waterham HR . 2006 . Peroxisomal disorders: the single
peroxisomal enzyme deficiencies. Biochim Biophys Acta 1763:1707-
1720 .
3 . Waterham HR, Koster J, van Roermund CW, Mooyer PA, Wanders
RJ, Leonard JV . 2007 . A lethal defect of mitochondrial and peroxisomal
fission. N Engl J Med 356:1736-1741 .
s11.2
Diagnostic tools in mitochondrial respiratory chain defects
O. Elpeleg;
Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Congenital disorders of the mitochondrial respiratory chain are common
inborn errors of metabolism with an incidence of 1:5,000-8,000
live births . The respiratory chain consists of 85 subunits which are assembled
into five enzymatic complexes. Thirteen of the 85 subunits
are encoded by the mitochondrial DNA (mtDNA) and a large number of
proteins are required for the replication of the mtDNA molecule, its expression
and for the assembly of each of the complexes . Most patients
present with neurological symptoms accompanied by lactate elevation
and the enzymatic diagnosis is established in muscle tissue . However,
translation of the results of the enzymatic analysis into genetic counseling
is hampered by the fact that the same defect is not present in
fibroblasts and that many of the genes encoding the non-structural
factors are presently unknown .