2009 Vienna - European Society of Human Genetics

Reproductive genetics
NF-κB pathway deregulation may be related to oocyte competence.
In male gamete development, NF-κB is activated in pachitene stage
and in the following germinal differentiation steps triggering specialized
genes expression.
We analysed IκBα transcript levels in meiotic arrested bovine oocytes
at different stages of maturation (diplotene of prophase I and metaphase
II) and in early embryogenesis. We included three expressed
oocyte genes: BMP15, GDF9, SPIN1. We examined ZAR1, specific
oocyte maturation marker, whose transcript generally underwent degradation
during meiosis. We observed a significant reduction of the
IκBα mRNA during meiotic maturation. On the contrary, we observed
that the amount of IκBα protein increased during the transition from
immature to mature oocytes, while it was significantly decreased in
embryos. Further analysis will be performed to establish how IκBα is
regulated during developmental competence and if it is involved in human
diseases such as premature aging and infertility.
P04.15
Bench to Bedside: translating genetic eye research into
different reproductive options.
L. S. Kearns1,2 , A. C. Cohn2 , E. C. Osborne3 , V. Kralevski3 , C. Beyer3 , S. Staffieri4
, A. W. Hewitt4,2 , J. B. Ruddle4,2 , J. E. Craig5 , A. L. Vincent6 , D. A. Mackey4,2 ;
1 2 Centre for Eye Research Australia,, East Melbourne, Australia, Royal Victorian
Eye and Ear Hospital, East Melbourne, Australia, 3Monash IVF, Clayton,
Australia, 4Centre for Eye Research Australia, East Melbourne, Australia,
5Flinders Medical Centre, Department of Ophthalmology, Adelaide, Australia,
6Department of Ophthalmology, Faculty of Medical and Health Sciences, University
of Auckland, Auckland, New Zealand.
Purpose: To demonstrate the translation of genetic eye research into
the IVF (In Vitro Fertilisation) and preimplantation genetic diagnosis
(PGD) setting for a family with Autosomal Dominant Optic Atrophy
(ADOA).
Methods: Genetics is rapidly impacting on clinical care. It helps confirm
the clinical diagnosis, as well as identify carrier status and mutations
in non-symptomatic patients who have known familial mutations.
This helps to facilitate early diagnosis and subsequent interventions.
The clinical need and cost effective benefits of genetic testing in ophthalmology
has already been well documented in retinoblastoma RB1
testing. While many genes have been identified as causing inherited
ocular disease, genetic testing has primarily been performed on a research
basis. However this knowledge from the laboratory is translating
into clinical care and providing couples with reproductive options
in the form of prenatal diagnosis (PND) and pre-implantation genetic
diagnosis (PGD). We present a family identified with a known OPA1
mutation as part of the Autosomal Dominant Optic Atrophy research
study who have chosen to utilise In Vitro Fertilisation coupled with preimplantation
genetic diagnosis to avoid passing this condition on to
their child.
Results: This couple elected to undergo two IVF/PGD cycles at Monash
IVF. They achieved a successful singleton pregnancy in their second
cycle and have subsequently given birth to a healthy baby girl.
Conclusions: From research studies we are often able to provide individuals
with information on their specific genetic mutation and some
couples choose to use this knowledge to broaden their reproductive
options.
P04.16
Vascular Endothelial Growth Factor Gene Polymorphism and
Ovarian hyperstimulation syndrome
N. Ghasemi, R. Firouazabadi, S. Ahmadi, H. Oskouian;
Yazd Research and Clinical Center For Infertility, Yazd, Islamic Republic of Iran.
Purpose : Ovarian hyperstimulation syndrome (OHSS) is one of the
most important complication of assisted reproduction treatment . The
pathophysiology of OHSS remains to be full elucidated. Many substances
and more recently, vascular endothelial growth factor (VEGF)
have been suggested to be involved in the pathogenesis of OHSS .
VEGF is a member of a family of heparin - binding proteins that act
directly on endothelial cells to induce proliferation and angiogenesis .
In vivo , VEGF is a powerful mediator of vessel permeability, Increased
vascular permeability mediated by VEGF has been implicated in the
sudden increase in capillary permeability , then it is logical to examine
the relationship between the VEGF polymorphism and OHSS. In this
paper, we conducted a case - control study to evaluate potential as-
sociation between OHSS and VEGF gene 460 polymorphism.
Methods : 75 OHSS patients and 85 normoresponse patients were
enrolled in this study. Polymerase chain reaction- restriction fragment
length polymorphism analysis was used to resolve the VEGF 460 genotype
of OHSS patients and normoresponder controls.
Results : The frequency of homozygosity of the VEGF 460 gene was
significantly higher among women with OHSS.
Conclusion : Homozigosity of the VEGF 460 gene may serve as a
susceptibility factor affecting for OHSS.
P04.17
Prevalence of epimutations in imprinted PLAGL (LOT /ZAC )
locus in first-trimester miscarriages
E. A. Sazhenova, I. N. Lebedev;
Institute of Medical Genetics, Tomsk, Russian Federation.
Genomic imprinting plays a critical role in regulation of fetal development.
Previously we have reported a tissue-specific loss of methylation
in KCNQ1OT1 (11p15) in 9.5% of spontaneous abortions, but normal
epigenetic status of H19, CDKN1C and SNRPN genes. The aim
of the present research was investigation of differential methylation of
maternal imprinted gene PLAGL1 (6q24-25), which is involved in control
of cell proliferation. Methylation-specific PCR of PLAGL1 promoter
was performed using DNA from extraembryoniñ mesoderm (EM) and
cytotrophoblast (CT) of 87 first-trimester missed abortions. Thirty induced
abortions were studied as a control group. Nine miscarriages
(10.3%) have revealed a loss of methylation of PLAGL1 on maternal
chromosome. Loss of imprinting (LOI) was confined by EM or CT in
6 and 2 miscarriages, respectively. For one embryo with epimutation
only cytotrophoblast was available. Two conceptions have revealed
LOI in both PLAGL1 and KCNQ1OT1 genes confined by EM. Tissuespecificity
of epimutations allows suggesting independent sporadic
epigenetic events in different embryonic germ layers after its divergence.
Importantly, significant prevalence of recurrent pregnancy loss
was found in women having a miscarriage with PLAGL1 epimutation
in compare with women having a conception with normal imprinting
(33.3% vs 7.7%, respectively, P=0.05). At the same time, no significant
differences in the maternal age were found between these groups. Our
results provide evidence that errors of imprinting maintaining mechanisms
on maternal chromosomes during embryo development may be
among molecular processes responsible for dysfunction of imprinted
loci and recurrent pregnancy loss.
This study was supported by RFBR (N 08-04-01344).
P04.18
common variants on chromosome 9p21 are associated with
preeclampsia in the Finnish population
H. Peterson 1 , K. Kivinen 2 , L. Hiltunen 3 , E. Salmela 4,5 , T. Lappalainen 5 , V. Rasi 3 ,
A. Sayed 6 , L. Poston 7 , L. Morgan 6 , J. Kere 1 , H. Laivuori 4,8 ;
1 Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm,
Sweden, 2 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus,
Hinxton, Cambridge, United Kingdom, 3 Finnish Red Cross Blood Service,
Helsinki, Finland, 4 Department of Medical Genetics, University of Helsinki,
Finland, 5 Finnish Genome Center, Institute for Molecular Medicine Finland,
University of Helsinki, Finland, 6 Department of Clinical Chemistry, Institute of
Genetics, University of Nottingham, United Kingdom, 7 Division of Reproduction
and Endocrinology, King’s College London, United Kingdom, 8 Department of
Clinical Genetics, Helsinki University Central Hospital, Finland.
Preeclampsia is a pregnancy specific disorder, characterized by hypertension
and proteinuria. Its etiology and pathophysiology remain poorly
understood, but it has clearly a familial component, suggesting that genetic
factors play a role in the susceptibility. We have previously reported
linkage to preeclampsia on chromosome 9p13. Interestingly, several
genome-wide association (GWA) studies have identified a region
on chromosome 9p21 that is associated with coronary artery disease
(CAD) and type 2 diabetes (T2D). As preeclampsia has been linked
to increased risk for both T2D and CAD later in life, and our linkage
region is closely located to the GWA signals, we decided to genotype
previously reported associated SNPs in15 preeclampsia families and
a nation-wide case-control preeclampsia cohort (340 cases and 357
matched controls). In total, 23 markers were successfully genotyped.
Single-marker and haplotype associations were calculated and four
SNPs showed nominal association (P