2008 Barcelona - European Society of Human Genetics

Cytogenetics
land, 2 MRC Human Genetics Unit, Edinburgh, United Kingdom.
The t(11;22)(q23;q11) is the only recurrent non-Robertsonian translocation
in humans . Carriers are phenotypically normal, but at risk of
having progeny with Emanuel syndrome . It is conceivable that this
large chromatin rearrangement influences the transcription levels of
genes mapping both near, and distant, to chromosome breakpoints . To
test this, we compared gene expression profiles of lymphoblastoid cell
lines from 13 cytogenetically normal individuals, to those of 9 balanced
translocation carriers and 4 unbalanced Emanuel syndrome patients .
Comparison of unbalanced individuals with controls revealed twice as
many gene expression changes than the balanced/control comparison
. This was anticipated as individuals are partially aneuploid for both
HSA11 and 22 and are phenotypically affected . Consistently, a statistically
significant fraction of the differentially expressed genes mapped
to these two chromosomes .
Permutation tests showed that, despite being lower, the number of
differentially expressed genes between the two groups with complete
genome complements is significantly higher than that observed when
one compares control samples alone . This suggests that balanced rearrangements
have a greater effect on gene expression than normal
variation even though individuals are phenotypically normal .
Interestingly, in balanced individuals, expression of HSA11 genes is
affected to a much higher degree than those on HSA22 . We hypothesize
that the position of the derivative chromosomes is altered within
the nucleus, with derivatives chromosomes being moved to a position
comparable to the normal HSA22 . This would result in HSA11 genes
being placed into an altered chromatin environment, thus altering their
expression . We are currently investigating this possibility .
P02.201
New report of an unbalanced Xp/Yq translocation detected in a
mentally retarded patient with short stature and icthyosis
J. Oliveira, N. Oliva-Teles, M. Mota Freitas, R. Santos, M. Pinto, A. Fortuna;
Centro de Genética Médica Jacinto Magalhães - INSA, Porto, Portugal.
Deletion of Xp22 .3 causes different X-linked disorders in males; in females,
depending on the X-inactivation patterns or gene disruptions,
the phenotype may be variable (Schinzel, 2001) . Patients with deletions
in this region have been previously reported in a restrict number
of cases, and presented with distinct combinations of usually nonrelated
clinical manifestations such as short stature, mental retardation,
ichthyosis, chondrodysplasia punctata, attention deficit hyperactivity
disorder, ocular albinism and epilepsy (Lonardo et al ., 2007) .
The phenotype is correlated with the deletion breakpoints on the X
chromosome and the respectively affected genes . As a result of gene
sequence similarities between Xp22 and Yq11, homologous recombination
between these two regions has been suggested as the cause
of X/Y translocations .
The authors report on a male patient aged 17 presenting with mild
mental retardation, short stature, X-linked ichthyosis and with steroid
sulphatase deficiency. High resolution GTG, QFQ and CBG banding
revealed the following karyotype: 46,Y,der(X)t(X;Y)(p22 .3;q11 .2)mat .
The study of the parents proved that the translocation was of maternal
origin . PCR-based techniques positioned the centromeric breakpoint
between genes VCX2 (Xp22 .31) and AMELX (Xp22 .2) . The analysis
of the DYS385 marker, located in Yq11 .21, suggested that this region
is duplicated in the patient .
A review of cases described in the literature with similar cytogenetic
findings will be equally addressed and compared with the present
case . The authors highlight the importance of careful evaluation of
Xp22 .3 deletions in terms of clinical prognosis, follow-up and genetic
counselling .
P02.202
telomere length and Random Aneuploidy in Hepatitis c patients
A. Amiel1 , L. Goldberg-Bittman1 , M. D. Fejgin1 , R. Hadari2 , Y. Kitay-Cohen2 ;
1 2 Genetic Institute, Meir Hospital, Kfar Saba, Israel, Liver Unit, Meir Hospital,
Kfar Saba, Israel.
Hepatitis C virus (HCV) is one of the major causes of hepatocellular
carcinoma and has recently been recognized to play a role in the
pathogenesis of B-cell lymphoma . Random aneuploidy is one of the
genetic instability parameters observed in cancer . Telomeres are the
end structures of each chromosome . These structures protect from
shortening at each replication cycle . Telomerase is the enzyme which
is responsible for the elongation of the telomeres, and exists only in
cancer, stem and progenitor cells . A reduction in telomerase levels was
observed in HCV patients lymphocytes compared to healthy individuals
.
The aim of this study was: 1) Evaluating random aneuploidy rate in lymphocytes
of chronically infected HCV patients compared to individuals
who eradicated the virus (remission group) and to healthy controls . 2)
Developing new method for measuring relative telomere length .
For random aneuploidy, we applied the FISH technique with probes
from chromosome 9 and 18 . For the telomere detection we used the
PNA telomere kit .
A significantly higher random aneuploidy rate was found in the HCV
group as compared to the control group, while the remission group had
intermediate rates between the other tow groups .
We observed significantly shorter telomere length in HCV patients
compared to the controls and to the group in remission . We found a
reverse correlation between shorter telomeres and the rate of aneuploidy
.
Random aneuploidy and short telomeres are two co-existing biological
phenomena found in HCV patients; it may represent pre malignant
changes which could play a role in the cascade leading to neoplasia .
P02.203
A new candidate gene for mental retardation and severe central
hypotonia
A. Moncla1,2 , C. Missirian1,2 , P. Cacciagli1 , B. Chabrol1 , L. Villard2 ;
1 2 La Timone Children’s Hospital, Marseille, France, Inserm U910, Marseille,
France.
We report a female patient affected by mental retardation and severe
central hypotonia. At birth, the patient had normal parameters. The first
clinical signs were noticed during the first months of life when she was
unable to hold her head .
At first examination, CT scan, muscle enzymes, metabolic parameters
(including amino acids and organic acids chromatography), muccopolysaccharides
and thyroid were normal . At one year of age, she
showed major axial and peripheral hypotonia and she was not able to
hold her head. She was not able to sit and has no tendon reflexes. She
displayed abnormal and permanent choreic movements . She does not
suffer from epilepsy . Nerve conduction velocity and electromyogram
are normal . She is not deaf and her EEG and MRI are normal . At age
3, her OFC is normal, she shows major hypotonia and she is still unable
to hold her head or to roll-over and suffers from oculomotor dyspraxia
. She has no motor autonomy . She can speak 3-4 words and has
a very good eye contact .
Routine cytogenetic analysis revealed an apparently balanced de
novo t(10;13)(p14;q13) translocation . The molecular characterization
of the chromosomal rearrangement shows that a gene is interrupted
on chromosome 13 . This gene encodes a protein of unknown function
. Preliminary analysis reveals that it is only expressed in brain and
testis, making it a good candidate for the neurological phenotype of
our patient. However, more patients need to be screened to confirm its
implication in this new phenotype .
P02.204
De novo t(1;2)(q25;q21) case with various dysmorphic features
and mental retardation
H. Akin 1 , O. Kirbiyik 1 , A. Alpman 1 , E. Karaca 2 , O. Cogulu 2 , F. Ozkinay 2 ;
1 Ege University Faculty of Medicine Department of Medical Genetics, Izmir,
Turkey, 2 Ege University Faculty of Medicine Department of Pediatrics, Izmir,
Turkey.
Translocation is the most clinically significant abnormality of all the
structural chromosome rearrangements . Balanced de novo chromosome
rearrangements may be found in patients with mental retardation;
however their role in the developmental phenotype of the patient
is usually unclear . Loss of genetic material within the breakpoint regions
may be responsible for the phenotype .
We describe a 9-year-old boy with various facial dysmorphic features
such as telecanthus, epicanthic folds, upslanting palpebral fissures,
long eyelashes, hypoplastic alae nasi, thin upper lip and high palate .
In addition, mild mental retardation, developmental delay, bilateral fifth
finger clinodactyly, valgus deformity in the second toe, skin syndactyly
between the second and third toes and pes planus were also present .
Because of the diagnosis of mental retardation and the physical ab-