2009 Vienna - European Society of Human Genetics

Prenatal and perinatal genetics
No difference was observed between both conception groups in the
intake of medication and alcohol, cigarette smoking habits and complications
during pregnancy. The prevalences of major as well as minor
congenital anomalies, hospital admissions and surgical interventions
were similar.
Conclusion: Children born after embryo biopsy applied in PGD/PGS
present similar growth and physical health in the first two years of life
as compared to ICSI children. These reassuring findings should be
further confirmed in a larger cohort study.
P05.45
Assessing microsatellite instability in human preimplantation
embryos
L. Xanthopoulou, J. D. Delhanty, T. Mamas, J. C. Harper, S. SenGupta;
UCL, London, United Kingdom.
Introduction: Mutations or silencing of genes involved in DNA mismatch
repair pathways can result in microsatellite instability (MSI),
a situation whereby repetitive DNA sequences are unstable during
DNA replication. MSI is a common feature of many human tumours,
whereas microsatellite mutations have also been reported in human
spontaneously aborted fetuses. Couples undergoing Preimplantation
Genetic Screening (PGS) are at high risk of meiotic and mitotic chromosome
abnormalities. This study aims to investigate the level of MSI
in this group of patients.
Materials/Methods: Fifty four blastomeres from 23 untransferred embryos
from 5 PGS couples were subjected to whole genome amplification
by Multiple Displacement Amplification (MDA). Genomic DNA
and single lymphocytes from both parents were subjected to MDA and
analysed using microsatellite markers in order to ensure that MDA did
not introduce any artefacts. Embryonic and parental samples were analysed
using the BAT26 and D5S346 markers and the embryonic haplotypes
were compared to the corresponding parental patterns. The
generation of any novel microsatellite alleles in the embryonic samples
was interpreted as MSI.
Results: Out of the 54 cells isolated, 44 generated an MDA product.
The BAT26 and D5S346 PCR results of these MDA products identified
2/23 embryos in which a novel allele was detected.
Discussion/Conclusion: This preliminary data suggests that MSI may
be present in embryos from PGS cycles and further analysis is warranted.
Comparison with MSI levels in embryos from PGD cases without
fertility problems would elucidate whether embryos at high risk of
aneuploidy are at increased risk of MSI.
P05.46
is nuclear transfer morally acceptable as a means to prevent
mtDNA disorders if it cannot avoid residual health risks?
A. L. Bredenoord1,2 , W. J. Dondorp1 , G. de Wert1 ;
1 2 Maastricht University, Maastricht, The Netherlands, University Medical Center
Utrecht, Utrecht, The Netherlands.
Since the 1990s, different variants of nuclear transfer (NT) techniques
have been proposed as possible strategies for preventing the transmission
of a mitochondrial DNA (mtDNA) mutation from mother to
child. The aim is to provide prospective parents with genetically related
offspring without the mtDNA mutation. In a clinical application of NT,
it seems difficult if not impossible to avoid small amounts of affected
mtDNA to come along with the oocyte, pronuclei or nucleus from the
recipient woman. This potential carryover may result in the co-existence
of two populations of mtDNA, also called mtDNA heteroplasmy.
As long as it is not possible to carry out the procedure without the
accompaniment of small amounts of affected mtDNA, the resulting
embryo will always have a certain amount of mtDNA heteroplasmy.
Although in many cases this will be far below the threshold to disease
expression, the occurrence of mitochondrial disease symptoms cannot
be ruled out completely, especially not in the resulting child’s offspring:
due to the existence of a genetic bottleneck, the mutant load may rise
again in the third generation - the couple’s grandchildren.
We will firstly discuss whether NT is morally acceptable as a means
to prevent mtDNA disease if it cannot avoid residual health risks. Secondly,
we discuss the proportionality of the procedure and compare
NT with alternative reproductive options. Thirdly, as mitochondria are
transferred maternally, male offspring will not pass on the mtDNA mutation.
We examine whether this provides a reason to only create or
transfer male embryos.
P05.47
Nuclear and mitochondrial genetic analysis in men opting for art
R. Dada 1 , S. Venkatesh 1 , M. B. Shamsi 1 , M. Tanwar 1 , R. Kumar 2 , N. P. Gupta 2 ,
R. K. Sharma 3 , P. Talwar 3 ;
1 Laboratory for Molecular Reproduction and Genetics,,, New Delhi, India, 2 Department
of Urology, AIIMS, New Delhi, India, 3 ART centre, R&R Hospital, New
Delhi, India.
Azoospermia factor (AZF) microdeletions, cytogenetic abnormalities
and mtDNA mutations are the major genetic suspects of idiopathic
male infertility. Therefore the aim of the study was to study genetic
alterations (cytogenetic, Yq microdeletions, and mtDNA mutations) in
infertile men with idiopathic infertility. Mt mutations were only asses in
men with idiopathic asthenozoopsermia. DNA from semen was isolated
from both patients and controlsfor AZF microdeletion analysis
and mitochondrial genome was sequenced by standard PCR-DNA
sequencing protocol. Of 1500 cases of infertility analysed 17% harboured
cytogenetic abnormalties, 9.8% harboured AZF microdeletions
which were found in idiopathic and non idiopathic cases Mt mutations
were analysed in 40 athenozoopsermic men.72.5% (29/40) of the infertile
patients showed significant nucleotide changes in their sperm
mtDNA compared to the controls. Out of 70 infertile and 40 control
samples analyzed, 80% infertile men were found to have significantly
(p9 and indeed suited for PGD. Though,
6 patients (5.6%) scored under the threshold value. This analysis was
found to be congruent with the majority of our clinical decisions and
reflected our policy.
Scoring system
Onset severity Penetrance
Risk for
affected
offspring
infertility
requiring
iVF
PGD performed
for other
condition
Objection
to t.O.P
Scoring
value
Childhood/
congenital
Lethal 75-100% - - - -
Teen Severe 50-75% >25% Yes Yes -
Early adulthood Debilitating 25-50% 10-25% - - Yes
Late adulthood Mild