2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
correlate their complex clinical manifestations with the content of the
deleted chromosomal segment. Detailed examinations showed that
both Czech patients were identical in terms of clinical symptomatology
and they shared the major characteristic clinical features with the originally
reported AMME phenotype, although the two phenotypes were
not completely identical. It thus seems that a very similar contiguous
syndrome associated with a microdeletion in Xq22.3 occurred independently
in two unrelated families. A detailed cytogenetic comparison
of the two microdeletions could contribute to clarification of the minor
clinical differences observed and to the definition of specific candidate
genes. Our knowledge of the phenotype of the 20 year-old uncle
might also be useful for predicting the development of the symptoms
in younger affected patients.
P02.010
Association of variants t2373G, t1808A glucocorticosteroids
gene NR3c1 and c3435t multidrug resistance gene (mDR1) with
severity of bronchial asthma (BA)
Z. A. Mironova, V. I. Trofimov, E. D. Iantchina, M. A. Simakova, M. V. Dubina;
Pavlov State Medical University, St-Petersburg, Russian Federation.
The aim of study was to evaluate the incidence of T1808A (exon 5),
T2373G (exon 9) NR3C1 gene (associated with primary glucocorticosteroidresistance
- PSR) C3435T (exone 26) MDR1 gene and their
association with BA severity.
88 patients with moderate and severe BA and 53 healthy controls were
investigated by PCR-RLFP method.
All patients were homozygous at T allele of NR3C1 gene, so PSR was
not revealed.
Rates of C allele (“aggressive allele”) and T gene MDR1 in BA group
were 0,52 and 0, 48, in controls 0,3 and 0,7. T allele was more frequent
in controls than in BA (x 2 = 12,1; p=0,0005). In patients with moderate
BA T allele of MDR1 gene was more frequent than in severe BA (x 2
= 4,6; p=0,038). Rate of CC genotype of MDR1 gene was more in
patients with severe BA than in controls x 2 =8,15 (p=0,004). Incidence
of TT genotype of MDR1 gene was more in patients with moderate BA
than in severe one (x 2 = 4,6; p=0,038).
In 33 BA patients complications of glucocorticosteroid treatment
(GCST) were observed. TT genotype of MDR1 gene was more frequent
in patients without GCST complications (x 2 =4,19; p=0,0406).
So, association of T2373G, T1808A variants of NR3C1 gene and
MDR1 (C3435T) gene with BA severity degree was shown. In all patients
signs of PSR were absent. Severe BA course with complications
of GCST was revealed in patients with CC genotype of MDR1 gene.
TT genotype of MDR1 gene was associated with moderate course of
BA.
P02.011
A new case of Ataxia type 10 in a mexican female
D. Garcia-Cruz 1 , G. Castañeda-Cisneros 2 , S. A. Gutierrez-Rubio 3 , N. Y. Nuñez-
Reveles 1 , J. Sanchez-Corona 3 , R. C. Rosales 3 , A. Andrade 1 , J. Jimenez-Gil 4 , C.
Moran-Moguel 3 ;
1 Instituto de Genética Humana “Enrique Corona Rivera”, Universidad de
Guadalajara, Guadalajara, Mexico, 2 Servicio Neurocirugía, UMAE Hospital de
Especialidades, Centro Médico de Occidente, IMSS, Guadalajara, Mexico,
3 División de Medicina Molecular, Centro de Investigación Biomédica de Occidente,
Centro Médico de Occidente, IMSS, Guadalajara, Mexico, 4 Servicio
Neurología, UMAE Hospital de Especialidades, Centro Médico de Occidente,
IMSS, Guadalajara, Mexico.
Introduction: The spinocerebellar ataxia type 10 (SCA 10) is an autosomal
dominant disorder with cerebellar dysfunction involving ataxia,
dysmetria, seizures and anticipation. SCA10 is caused by repeat expansion
of pentanucleotide ATTCT in the ataxin 10 gene (ATXN10,
603516.0001), candidate region on chromosome 22q13.3, these repeats
form unpaired DNA structure that works as aberrant DNA replication
origin and contributes to the repeat instability and cell death, but
how produces a neurodegenerative effect is unknown.
The aim of this research is to present the results of the molecular studies
in a female patient affected with SCA10.
Material and Methods: A female aged 20 years old was studied clinically
due to SCA10, laboratorial studies were performed with 5mL of
peripheral blood were used to isolate patient’s DNA by GeneCatcher
Kit (invitrogen). The molecular analysis was made by PCR with previous
described primers to detect normal alleles, the PCR product was
submitted to electrophoresis in 8% polyacrilamide gel. A blank, and
two normal individuals were test simultaneously as quality controls.
Results: We obtained a single band that corresponds to 19 ATTCT
repeted normal allele, thus our patient corresponds to an heterozygous
genotype 19/unknown.
Discussion: SCA10 mutation accounts for almost 15% of autosomal
dominant ataxia in Mexicans population and in Brazilians in 1.8%. This
low incidence can be explained probably by the limited molecular studies
in our country.
P02.012
clinical and genetic study of a large Dutch family with
autosomal dominant restless legs syndrome
A. J. A. Maat-Kievit 1 , A. M. G. Sas 2 , S. L. M. Bakker 3 , A. Di Fonzo 1 , B. Oostra 1 ,
A. J. A. Boon 2 , V. Bonifati 1 ;
1 Dept of Clinical Genetics, Rotterdam, The Netherlands, 2 Department of Neurology,
Erasmus Medical Center, Rotterdam, The Netherlands, 3 Department of
Neurology, St. Franciscus General Hospital, Rotterdam, The Netherlands.
Genetic factors play an important role in the aetiology of restless legs
syndrome (RLS). Familial aggregation has been documented with up
to 90% of the idiopathic cases reporting a positive family history. Several
loci and association with several genes have been described for
Mendelian forms of RLS.
Thirty-one family members out of three generations of a Dutch family
segregating autosomal dominant RLS, were examined. Each family
member underwent a general medical and neurological examination.
An extensive questionnaire was completed, and RLS symptoms were
quantified using the International RLS Rating Scale. Serum creatinine,
hemoglobin and iron levels were determined to exclude secondary
RLS in this family.
RLS was ascertained in twenty-six subjects. Serum levels of creatinine,
hemoglobin and iron all were in normal ranges. Mean age at examination
was fifty years (20-93). The average age at symptom onset
was 17.8 years (6-35), which is younger (17 versus 27) as described in
literature. RLS symptoms were quantified using the RLS rating scale,
with a mean initial score of 12 (0-29) and 12,3 (0-29) after two years.
In this family the phenotype is very heterogeneous, including vanishing
RLS symptoms in 2 patients. A genome-wide scan for linkage is in
progress using the Affimetrix GeneChip® Human Mapping 250K Array
set. Affected-only linkage analysis is performed considering the
patients with a severe or stably moderate RLS rating scale score as “
affected”. Due to the large pedigree size and early-onset phenotype,
this family has great potential for linkage analysis and the results will
be presented.
P02.013
Heterozygous deletion of the PitX2 gene in a patient with
Axenfeld Rieger syndrome
N. Weisschuh 1 , M. Walter 2,3 , B. Wissinger 1 ;
1 Institute for Ophthalmic Research, Tuebingen, Germany, 2 Institute of Human
Genetics, Tuebingen, Germany, 3 Microarray Facility, Tuebingen, Germany.
Axenfeld Rieger Syndrome (ARS) is a genetically heterogenous disorder
mainly characterized by developmental defects of the anterior
chamber and extraocular anomalies. ARS is inherited as an autosomal
dominant trait with high penetrance and has been linked to different
chromosomal loci. Two genes - PITX2 and FOXC1, which both encode
developmental transcription factors and map to chromosomes 4q25
and 6p25, respectively - are the most frequently associated. PITX2
mutations show great variety, from point mutations to microscopic or
submicroscopic deletions, and apparently balanced translocations
in few cases. Microscopic or submicroscopic deletions of PITX2 are
known to result in ARS through haploinsufficiency but only in few cases
the extent of the deletion was characterized by molecular means.
Quantitative genomic polymerase chain reaction is the method of
choice to analyze patients in which sequencing did not reveal putative
mutations as the resolution limit of FISH or array-CGH is too low to
detect mid-size deletions. We identified a cytogenetically invisible submicroscopic
deletion at 4q25 in a patient diagnosed with ARS applying
quantitative genomic PCR analysis. Further genotyping of the patient
and her parents with polymorphic microsatellite markers showed that
the maternal allele was not transmitted indicating a de novo deletion
event in the patient. The deletion comprised the entire sequence of the
PITX2 gene but did not include adjacent genes.