2009 Vienna - European Society of Human Genetics

Cytogenetics
donation program of possibly “expanded” trinucleotids of this region
provides greater security to the receptor patients in our processing of
Assisted Reproduction.
P03.156
Fragile X syndrome screening of families with consanguineous
and non-consanguineous parents in the iranian population
S. Abedini 1 , A. Pouya 1 , N. Mansoorian 2 , F. Behjati 1 , N. Nikzat 1 , M. Mohseni 1 , S.
Esmaeeli Nieh 3 , L. Abbasi 3 , H. Darvish 1 , G. Bahrami Monajemi 1 , S. Banihashemi
1 , R. Kariminejad 2 , K. Kahrizi 1 , H. Ropers 3 , H. Najmabadi 1,2 ;
1 Genetics Research Center, University of Social Welfare and Rehabilitation
Sciences, Tehran, Islamic Republic of Iran, 2 Kariminejad-Najmabadi Pathology
and Genetics Center, Tehran, Islamic Republic of Iran, 3 Max Planck Institute for
Molecular Genetics, Berlin, Germany.
Fragile X syndrome is the most common form of inherited mental retardation
(MR). It is caused by the expansion of CGG triplet repeats in
the fragile X mental retardation 1 (FMR1) gene. In mentally retarded
males, the frequency of fragile X syndrome is approximately 2 to 3
percent, but little is known about its proportion in mentally retarded
patients from countries where parental consanguinity is common.
The objective of this study was to estimate the frequency of fragile X
syndrome (FXS) in mentally retarded patients from Iran. We examined
a total of 508 families with MR that had been referred to the Genetics
Research Center (GRC) in Tehran. 467 of these families had at
least two mentally retarded children, and in 384 families, the parents
were related. Full FMR1 mutations were found in 32 of the 508 families
studied (6.3%), in 19 out of 124 families with apparently unrelated
parents (15.3%), and in 13 of the 384 consanguineous families (3.4%).
Thus, in Iran, the relative frequency of FXS seems to be higher than
in Central Europe and other Asian countries, and much higher in patients
with unrelated parents. We also show that even in families with
consanguineous parents, FXS has to be ruled out before assuming
that familial MR is due to autosomal recessive gene defects. Molecular
studies are in progress to explain the high proportion of FMR1 mutations
in mentally retarded offspring of unrelated Iranian parents.
P03.157
simultaneous analysis of FmR1 and ARX genes improves the
efficiency of the fragile X screening.
F. Martinez, S. Oltra, I. Ferrer-Bolufer, M. Roselló, S. Monfort, C. Orellana;
Hospital Universitario La Fe, Valencia, Spain.
Fragile X syndrome is the most frequent form of inherited mental retardation,
caused by the expansion of a CGG triplet in the FMR1 gene.
On the other hand, microduplications or expansions in ARX gene,
leading to elongations of a polyalanine tract, are considered the second
most frequent cause of X-linked mental retardation. However, the
genetic screening of this gene is not routinely performed.
We conducted a prospective analysis of both genes, by the simultaneous
amplification of FMR1 exon 1 and a fragment of ARX gene where
the polyalanine elongations cluster, in a total of 700 developmentally
retarded males remitted for fragile-X screening.
We found nine unrelated cases with the fragile X syndrome and three
index cases (four patients) with ARX elongations. Given the relative
frequencies between both genes and the prevalence of the fragile-X
expansions (about 1:5,000 males), the prevalence of ARX elongations
can be estimated in 1:15,000 males.
The duplex analysis we propose offers several advantages: 1) An increased
sensitivity of the fragile-X screening in about 30%, with no
substantial cost increment. 2) As large fragile-X expansions cannot be
detected by PCR, the amplification of another fragment with similar
size, GC content and presence of repeats, serves as internal reference
to differentiate mutations (expansions or deletions) from technical pitfalls.
3) Similarly, weak co-amplification of a normal FMR1 allele can
be suggestive of mosaicism with full mutation. Although rare, mosaic
cases represent a limitation of any PCR-based method for the screening
of the fragile-X expansion.
P03.158
FmR2 protein, whose absence causes the FRAXE associated
mental retardation, is a splicing factor
B. Bardoni 1 , M. Melko 1 , J. Gecz 2 , E. Lalli 1 , M. Bensaid 1 ;
1 Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France, 2 Department
of Genetic Medicine, Women’s and Children’s Hospital,, Adelaide,
Australia.
FRAXE is a form of mild to moderate mental retardation due to the
silencing of the FMR2 gene. The cellular function of FMR2 protein
is presently unknown. By analogy with its homologue AF4, FMR2
was supposed to have a role in transcriptional regulation, but robust
evidences supporting this hypothesis are lacking. We observed that
FMR2 co-localizes with the splicing factor SC35 in nuclear speckles,
the nuclear regions where splicing factors are concentrated, assembled
and modified. Similarly to what was reported for splicing factors,
blocking splicing or transcription leads to the accumulation of FMR2 in
enlarged, rounded speckles. FMR2 is also localized in the nucleolus
when splicing is blocked. We have recently shown that FMR2 is able
to specifically bind the G-quartet-forming RNA structure with high affinity.
Remarkably, in vivo, in the presence of FMR2 the ESE (Exonic
Splicing Ehnancer) action of the G-quartet situated in mRNA of an alternatively
spliced exon of a minigene or of the putative target FMR1
(fragile X Mental retardation & gene) appears reduced. Indeed, the
absence of FMR2 does not affect the total expression of FMR1 mRNA
but increases the expression of the isoforms containing exon 14 and
encoding a protein localized in the cytoplasm. The role of FMR2 in
splicing is not exclusive to its role in transcriptional regulation, since we
cannot exclude that the function of FMR2 is modulated by the interaction
with transcription factors, as, shown, for example, for SWI/SNF,
a complex involved both in chromatin remodelling and regulation of
alternative splicing.
P03.159
Post axial polidactily and costo-vertebral anomalies in a 31
years old woman with 1qter chromosome deletion.
M. Bertoli, F. Gullotta, S. Considera, V. Brugiati, S. Zampatti, C. Catalli, G.
Novelli, M. Frontali, A. Nardone;
U.O.C. Laboratorio di Genetica Medica Policlinico Tor Vergata, Roma., Rome,
Italy.
Subtelomeric deletion of long arm of chromosome 1 is described as
a recognisable syndrome presenting with mental retardation, microcephaly,
growth retardation, a characteristic facial appearance, corpus
callosum abnormalities, cardiac, gastro-oesophageal and urogenital
defects (van Bon et al., 2008).
We describe a 31 years old women with a de novo 1qter deletion. We
have seen her for the first time at 30 years, identified 1qter deletion by
subtelomeric analysis, and characterized the size of the deletion by
CGH array..
She was born to healthy unrelated parents, pregnancy was complicated
with threatened abortion and growth delay (at term: weight 2.300
gr, length 48 cm, OFC 31 cm). She presented with severe hypotonia,
cianosis, cleft palate, post-axial polydactyly of left foot, bilateral clubfoot,
and dysmorphic features including bulbous nasal tip, thin lips and
left preauricular tag. Echocardiography revealed interventricular septal
defect. Thoracic X-Rays showed dorsal vertebral clefts (D4, D5 and
D6), and rib fusions (I and II, V and VI, VII and VIII at left and VIII and
IX at right). Ectopic left kidney and albinoid fundus oculi were also
present. Since the first months of life she had generalized seizures
treated with anticonvulsivants. This is the oldest patient with 1qter deletion
described to date. Her phenotype includes features not reported
so far such as polydactyly and ribs fusions and confirms that vertebral
anomalies, previously described in 2 patients only, are not uncommon
elements of the syndrome.
P03.160
Evaluation of a case with 5p deletion syndrome
F. Mutlu Içduygu, H. Şamli, K. Hekimler, A. Özgöz, Y. Sivaci, N. Imirzalioğlu;
Afyon Kocatepe University, School of Medicine, Department of Medical Genetics,
Afyon, Turkey.
The case is the second child of the couple who made third cousin marriage.
She had a healthy elder brother. The case was born with a birth
weight of 2,720 kg and a height of 52 cm. Her growth retardation was
realized at the age of 8 months. The case was physically examined
and a pedigree was drawn. Metaphase plaques were obtained from
peripheral blood lymphocytes of the case cultered for 72 hours and
evaluated after GTL banding. The findings of the case were congenital
malformation, mental retardation, cat-like cry at the first 1-2 weeks
after birth, SGA (small for gestational age), growth retardation, microcephaly,
strabismus, micrognathia, stridor, low set ears, high arched