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

Clinical genetics
P0231. Renin-angiotensin system gene polymorphisms and
arterial hypertension in children.
S. V. Kuzmina 1 , M. A. Bogdanova 2 , A. N. Voitovich 2 , O. A. Mutafyan 1 , V. I. Larionova
2 ;
1 St.Petersburg State Medical Academy of Postgraduate Studies, Saint-Petersburg,
Russian Federation, 2 St.Petersburg State Pediatric Medical Academy,
Saint-Petersburg, Russian Federation.
The I/D polymorphism of the angiotensin converting enzyme gene
(ACE), the M235T polymorphism of the angiotensinogen gene(AGT),
and the A1166C polymorphism of the angiotensin II type 1 receptor
gene (AGTR1) were identified in 85 children with arterial hypertension
(aged 7-17), 146 controls (aged 7-17).
Arterial hypertension was defined as systolic/diastolic blood pressure
measurements higher than 95 age-gender-height percentile of the adopted
reference values.
DNA was extracted from blood samples according to standard protocols
and analyzed by the PCR technique.
Table 1 shows the genotype distribution and allele frequency in two
groups. The distribution of ACE genotypes and allele frequency did
not differ significantly between patients with arterial hypertension and
control subjects. The frequency of the AGT TT genotype and T allele
were significantly higher in hypertensive patients than in controls.
There were significant increase in the CC genotype frequency and C
allele of AGTR1 in children with arterial hypertension compared with
control subjects.
These results suggest an association of the M235T polymorphism
AGT and A1166C polymorphism AGTR1 with essential hypertension
in children.
Table1. The allelic and genotypic frequencies of the renin-angiotensin
system polymorphisms in hypertensive and control subjects.
ACE Hypertensive (n=85) Control (n=146) p
II 24 (28,2%) 44 (30,2%)
ID 41 (48,2%) 72 (49,3%) 0,861
DD 20 (23,6%) 30 (20,5%)
I 89 (52,3%) 160 (54,8%)
D 81 (47,7%) 132 (45,2%) 0,681
AGT Hypertensive (n=85) Control (n=96)
MM 16 (18,8%) 52 (54,2%)
TM 41 (48,2%) 37 (38,5%) 0,001
TT 28 (33%) 7 (7,3%)
M 73 (42%) 141 (73,4%)
T 97 (58%) 51 (26,6%) 0,001
AGTR1 Hypertensive (n=85) Control (n=56)
AA 21 (24,7%) 31 (55,4%)
AC 39 (45,9%) 19 (33,9%) 0,001
CC 25 (29,4%) 6 (10,7%)
A
C
81 (47,6%)
89 (52,4%)
81 (72,3%)
31 (27,7%)
0,001
P0232. Molecular genetic analysis of Rb1 gene - differentiation
of hereditary and non-hereditary forms of retinoblastoma
R. Gaillyová, A. Kratochvílová, I. Valášková, T. Kepák, J. Štěrba, R. Autrata;
University Hospital Brno, Brno, Czech Republic.
Retinoblastoma is an uncommon malignant tumour of the eye in children(
1:18,000 - 30,000 in live born). It is a model example of genetic
disposition for tumour disorder. The fundamental part in genesis
of retinoblastoma represents the tumour suppressor gene Rb1. The
presence of at least one functional alela of the gene leads to normal
production of protein pRB. The exact analysis of Rb1 gene in children
with retinoblastoma influences the way of treatment received by the
patients with retinoblastoma and their families. The hereditary form of
retinoblastoma is in about half of the patients and is due to mutations
in Rb1 gene. The differentiation of hereditary and non-hereditary forms
has a fundamental influence on the treatment, prognosis and genetic
counselling in the family. We perform an analysis of Rb1 gene in all
children with retinoblastoma.
With conventional cytogenetics we can detect 8% of changes in Rb1
gene, with FISH 10%, with Southern blot hybridisation 16%, with PCR
and sequence analysis about 75%. At University Hospital Brno we use
a combination of PCR amplification of all 27 exons of Rb1 gene and
subsequent sequence analysis in DNA from peripheral blood. Up to
the present time we have found a mutation in Rb1gene in 6 patients
with hereditary form of retinoblastoma and in one foetus.
In the future we will introduce RNA and subsequent DNA analysis,
MLPA and methylation analysis of the promoter, in cooperation with
other oncological centres a population study to verify the causality of
the found mutations.
P0233. Determination of direction of skewing demonstrates
effect of X chromosome inactivation on phenotype of Rett
syndrome associated with mutation in the X chromosome gene,
MECP2
H. Archer 1 , J. Evans 1 , H. Leonard 2 , L. Colvin 2 , D. Ravine 2 , J. Christodoulou 3 , S.
Williamson 3 , T. Charman 4 , M. Bailey 5 , J. Sampson 1 , N. de Klerk 2 , A. Clarke 1 ;
1 Cardiff University, Cardiff, United Kingdom, 2 University of Western Australia,
Perth, Australia, 3 University of Sydney, Sydney, Australia, 4 University College
London, London, United Kingdom, 5 University of Glasgow, Glasgow, United
Kingdom.
Previous attempts to demonstrate a genotype-phenotype correlation
among patients with Rett syndrome (RTT) have shown some effect of
the type of mutation (e.g. nonsense or frameshift versus missense) on
severity of phenotype. It has been clear that the pattern of X chromosome
inactivation has been important - as with the recognition of some
clinically unaffected mutation carriers with highly skewed XCI - but it
has been difficult to demonstrate the effect of XCI in lymphocytes on
the severity of phenotype among affected individuals because only the
extent of skewing but not its direction was known. This led us to examine
the relationship between XCI in lymphocytes and disease severity
in a group of UK and Australian patients in whom the direction as
well as degree of skewing of XCI could be determined. Although limited
by lack of informativeness for SNPs within the MECP2 gene, we
have been able to show that the clinical severity in RTT patients with
a p.R168X or p.T158M mutation is statistically related to the direction
and degree of skewing of XCI in lymphocytes but that this is not likely
to be helpful in establishing the prognosis in an individual case.
P0234. Novel mutation in the cellular retinaldehyde-binding
protein gene RLBP1 associated with severe juvenile flecked
retinal dystrophy
B. Krabichler 1 , I. Baldissera 2 , E. Schmid 2 , G. Haznedaroğlu 3 , G. Utermann 1 , A.
Janecke 1 ;
1 Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical
University, Innsbruck, Austria, 2 Department of Ophthalmology, Medical University,
Innsbruck, Austria, 3 Eye Department, Ege University, Izmir, Turkey.
Retinitis punctata albescens (RPA) is a rare form of autosomal recessive
(and rarely dominant) retinal dystrophy characterized by earlyonset
severe night blindness, and aggregation of irregular white flecks
throughout the fundus. RPA is progressive and evolves to generalized
atrophy of the retina.
A distantly similar but distinct clinical entity, Fundus albipunctatus (FA)
is also characterized by white dots of the fundus but is apparently a
rare form of stationary night blindness. RPA is caused mostly by mutations
in the cellular retinaldehyde-binding protein (RLBP1), and occasionally
in rhodopsin (RHO), retinal degeneration gene (slow) (RDS),
and retinol dehydrogenase 5 (RDH5). Three patients from a consanguineous
family displaying a flecked retinal dystrophy were examined
for best-corrected visual acuity, and by visual field and color-vision
testing, electroretinography, dilated fundus examination, and fundus
photography. We analyzed RLBP1, RDH5 and RHO by both linkage
analysis and direct sequencing in this family. While an initial clinical
diagnosis of FA was made in these patients, follow-up investigations
revealed a significant progression of the disorder within a few years,
which let to a reclassification of RPA. RDH5 and RHO sequencing
did not reveal any variants, but in RLBP1 we identified a novel homozygous
12-bp in-frame deletion (c.666-677del12). We conclude that
mutation analysis of RLBP1 is suited to help differentiate between FA
and RPA, which is important for counselling of concerned families, and
RLBP1 is a major gene for RPA.
P0235. The first report of two cases of spino cerebellar ataxia
(SCA) in Hamadan province, Iran
E. Ahmad, M. S. Fallah, F. Ostadi, M. Shahghadam;
Kowsar Medical genetics Center, Hmedan, Islamic Republic of Iran.
Two cases with ataxia and gait disturbance with first diagnosis as MS
was referred to our Genetic counseling clinic in Hamadan, Explained
as below:
Case 1: