European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Normal variation, population genetics, genetic epidemiology
P1181. Disease frequency of Inborn Errors of Metabolism in the
Irish Traveller Community
A. Murphy 1,2 , S. Lynch 1 , A. Monavari 2 , P. Mayne 2 , E. P. Treacy 2 ;
1 National centre for Medical Genetics, Our Lady’s Hospital for Sick children,
Crumlin Dublin 12, Dublin, Ireland, 2 National Centre for Inherited Metabolic
Disorders, Dublin, Ireland.
The frequency of Inherited Metabolic Disorders (IEMs) varies between
ethnic groups, reflecting founder effect, genetic isolation, and the potential
effects of consanguinity. These disorders are a major cause of
morbidity and mortality in “Irish Travellers“, an endogamous group of
nomads.
We aimed to compare the birth prevalence of IEMs in Traveller with
non-Traveller children attending a tertiary level metabolic centre and to
examine possible genetic factors contributing to observed differences.
A retrospective review of diagnoses in Travellers was performed for 5
years (2002-2006). Mean birth prevalence was calculated and compared
with overall figures for IEMs in the total population.
Travellers constitute 9% of the total patient group, but only 0.6% of the
Irish population. 15 IEMs were noted, Galactosaemia, MPS 1, Mitochondrial
cytopathies, Glutaric Aciduria Type 1(GA1),GSD Type 111a,
Mucolipidosis Type 11, Hyperprolinemia Type 11 being the commonest.
The birth prevalence of IEMs in the Traveller group for this period
was estimated to be 1/80,Whereas that for the total population for
2006 approximates 1/500. Carrier frequency for the common galactosaemia
mutation (Q188R) is 1/11. The W402X homozygous mutation
explains all cases of MPS 1. All GA1 patients are homozygous for the
E365K mutation. Hyperprolinemia Type 11 is caused by one mutation
(G521fs(+1)) in an extended pedigree.
We propose that the high incidence of IEMs in Irish Travellers may
reflect initial founder effects and the increased rate of consanguinity.
P1182. Mosaic imprinting aberrations at H19, SNRPN and
KvDMR1 are not common after in vitro fertilisation.
V. F. Oliver1 , W. S. Cutfield2 , H. L. Miles2 , P. L. Hofman2 , I. M. Morison1 ;
1 2 University of Otago, Dunedin, New Zealand, Liggins Institute, University of
Auckland, Auckland, New Zealand.
In vitro fertilisation (IVF) potentially provides a profoundly abnormal
environment for an embryo. Studies with mice, sheep and cattle have
indicated that the culture environment of the embryo can affect the
imprinting of genes and the phenotype of the animal. Recent studies
have suggested that IVF causes a small but increased risk of imprinting
aberrations such as Angelman syndrome and Beckwith-Wiedemann
syndrome. Given that mosaicism for the imprinting defect has
been observed in Angelman syndrome and Beckwith-Wiedemann syndrome,
we hypothesised that low-level, mosaic imprinting defects may
be present in phenotypically normal individuals conceived using IVF.
DNA samples from peripheral blood were obtained from 70 IVF-conceived
pre-pubertal children and 70 matched controls. DNA methylation
of CpG sites within the H19, SNRPN and KvDMR1 loci was accurately
quantified using methylation-sensitive restriction digest followed
by real-time quantitative PCR (MSQ-PCR). Global DNA methylation
was also examined by using MSQ-PCR on the Satellite 2 repeat region.
No differences in the percentage of methylation between the IVFconceived
and control children were observed at the examined CpG
sites.
We concluded that low-level imprinting errors are not a common occurrence
in children conceived using IVF. Our data provides reassurance
that IVF-associated imprinting errors are sporadic and rare.
P1183. A novel variant E43K found in KCNE1 gene
N. Correia 1 , H. Caria 1,2 , G. Fialho 1 ;
1 Center of Genetics and Molecular Biology, Faculty of Sciences, University
of Lisbon, Lisbon, Portugal, 2 College of Health Care, Polytechnic Institute of
Setúbal, Setúbal, Portugal.
KCNE1 gene encodes a K + channel ß-subunit (mink or KCNE1) that
modulates voltage-gated potassium channels in various organs,
namely heart and cochlea. A functional K + channel requires coexpression
of this transmembrane protein and a α-subunit, usually KCNQ1,
coded by gene KCNQ1. In the inner ear, the KCNE1/KCNQ1 channels
play a key role in ensuring K + homeostasis. Loss of functional channels
leads to a reduction of endolymph potencial, which can originate hearing
loss. Mutations in KCNE1 are also responsible for the prolongation
of the action potential in the heart, which leads to a prolonged QT
interval and to a cardiac disease known as long QT syndrome (LQTS),
associated or not to severe congenital bilateral hearing loss.
In the present study we report a novel heterozygous 127G>A mutation
in KCNE1 gene. This variant was detected in a healthy individual
of our control population by direct sequencing in both directions. The
mutation results in an acid to basic amino acid substitution in the extra
cellular domain of the protein at codon 43 (E43K), a position highly
conserved among MinK proteins of different vertebrates.
Recent findings suggest that common variants located in the KCNQ1,
KCNE1, KCNH2 and SCN5A genes might influence the QT interval in
healthy individuals and might also represent risk factors for arrhythmias
or cardiac sudden death. We have thus investigated whether
variant E43K could influence, by itself or in association with other variants,
the channel function and, as a consequence, the length of the QT
interval, leading to LQTS expression.
P1184. Genetic susceptibility to legionnaires‘ disease
V. Romano-Spica1 , F. Impagnatiello1 , G. Gianfranceschi1 , A. Bargellini2 , L.
Cauteruccio2 , P. Borella2 ;
1 2 University of Rome - IUSM, Rome, Italy, University of Modena and Reggio,
Modena, Italy.
Legionnaires’ disease is a bacterial pneumonia due to Legionella
pneumophyla. Given the reported wide exposure to this pathogen,
behavioural, microbial and environmental risk factors might not fully
explain the limited known number of pathological cases thus suggesting
the involvement of differences in host susceptibility.
With the aim of addressing the potential role of genetic polymorphisms,
a case-control study was recently realised within the nationwide research
network. Candidate genes included interleukins and respective
receptors.
Herein we report on the analysis of genetic polymorphisms at CCR
and TLR. Specifically, patients (n=96), exposed subjects (n=106) and
controls (n=320) were recruited based on stringent inclusion criteria.
Genomic DNA was isolated from peripheral blood cells and mutation
detection by polymerase chain reaction. We report a significant (