2008 Barcelona - European Society of Human Genetics

Clinical genetics
between 35 to 53 repeats. Clinical findings in this group of patients will
be commented .
CONCLUSIONS: We have detected a big number of alleles in the premutation
and grey zone in the population analyzed . Large independent
samples are required to confirm our impression that the grey-zone and
premutation in FXS may be associated with important developmental
disabilities and to establish the genotype-phenotype relation in children
with this range of repeats .
P01.095
is FRAXE over-represented among Newfoundland children with
cognitive impairment?
A. Dohey1 , M. Crowley2 , R. Green1 , B. Younghusband1 , B. Fernandez1 ;
1 2 Memorial University of Newfoundland, St. John’s, NL, Canada, Provincial
Medical Genetics Program, St. John’s, NL, Canada.
Fragile X syndrome due to mutations in the FMR1 gene is the commonest
cause of inherited mental retardation . In contrast, mutations in
FMR2 (FRAXE) are a much rarer cause of MR . In Newfoundland, only
one family segregating an FMR1 expansion has been identified, but 3
males from 2 families with FRAXE disease have been identified. In this
study, I reviewed the charts of all boys seen from 1994-2004 who had
negative FMR1 testing . Participants were recruited using the following
criteria - males with developmental delay, between the ages of 2
and19 and without a specific diagnosis. 139 of 378 individuals met the
inclusion criteria, 95 (68%) consented . DNA was collected and amplified
using previous published primers. 93 samples were in the normal
FRAXE range, 2 failed to amplify . These 2 samples are being further
studied as possible FRAXE mutations . FRAXE alleles ranged from 4
to 23 repeats with the most common allele size being 13 . A second
part of the study describes the previously identified FRAXE families:
One proband has an FMR2 expansion of 620 repeats . He has a FSIQ
of 54 and is dysmorphic with facial features reminiscent of FRAXA
syndrome. He has a non-dysmorphic first cousin with a learning disability
and an expansion of 200 repeats . His mother and maternal aunt
carry premutations of 120 and 87 repeats respectively . The second
proband is a non-dysmorphic 11-year-old with attention deficit disorder
and a FSIQ in the 80’s . He has a mosaic FMR2 expansion of 120-820
repeats .
P01.096
Homozygous R316Q mutation in obesity-associated FtO gene
causes a novel polymalformative syndrome
S. Boissel* 1 , O. Reish* 2 , F. Molinari 1 , H. Etchevers 1 , A. Munnich 1 , L. Colleaux 1 ;
1 INSERM U781 and département de Génétique, Université Paris Descartes,
Paris, France, 2 Department of Medical Genetics, Assaf Harofeh * Equally contributors,
Israel.
We report on the analysis of a large inbred family including 8 affected
children presenting a newly described syndrome characterized by intra-uterine
growth retardation, characteristic facies, cleft palate, cardiac
and genital abnormalities, central nervous defects with delayed
myelinization, severe hypertonicity and premature death . Extensive
workup was normal .
Since the pedigree suggested an autosomal recessive mode of inheritance,
autozygosity mapping was performed identifying a unique
region of shared homozygosity of 6,5 Mb on 16q12 between D16S411
and D16S3140 markers. We identified a homozygous missense mutation
within FTO gene (c .947G>A, p .R316Q), which altered a highly
conserved residue, co-segregated with the disease and was not found
in 400 control alleles .
While recent studies have revealed a strong association between
intronic variants in FTO gene and childhood and adult obesity, the
pathophysiological mechanism underlying the phenotype observed in
our family remains questionable . Noticeably, in-situ hybridization experiments
on human embryos showed predominant FTO expression
in tissues affected in patients (central nervous system, heart and frontonasal
prominence) .
Interestingly, a recent study showed that FTO encodes a 2-oxoglutarate-dependent
nucleic acid demethylase likely involved in toxic DNA
and/or RNA lesions repair . Moreover, a R316A substitution completely
abolishes Fto activity in-vitro . We consequently propose that the patients’
mutation is a null mutation and that their phenotype is the consequence
of defective DNA repair . Mass spectrometry assays and cellular
sensitivity to methylating agents measurements are underway to
validate this hypothesis .
In conclusion, our data suggest that homozygous FTO null mutations
are responsible for a hitherto undescribed multiple congenital anomaly
syndrome .
P01.097
studies on FMR gene premutations, causing Fragile X tremor
ataxia syndrome (FXtAs) in Polish ataxia patients of unknown
etiology and in controls
M. Rajkiewicz, A. Sulek-Piatkowska, E. Zdzienicka, W. Krysa, W. Szirkowiec,
E. Fidzianska, J. Zaremba;
Institute of Psychiatry and Neurology, Warsaw, Poland.
Fragile X tremor ataxia syndrome (FXTAS) is a late onset (≥ 50) syndrome,
observed generally in male patients, caused by premutation
(range 55 - 200 CGG) in FMR1 gene (Hagerman 2001) . The main
symptoms are: intention tremor, ataxia, parkinsonism, and cognitive
decline . Moreover the MRI shows the presence of white matter lesions
of the middle cerebellar penducles .
The aim of our study was to look for FXTAS in a large group of Polish
patients affected with ataxia of unknown origin and in controls .
The studied group comprised 176 male patients with sporadic cerebellar
ataxia, with/without other neurological symptoms (age of onset ≥
50 years), in whom molecular tests carried out previously, excluded
SCA1,2,3,6,7,8,12,17 and DRPLA .
The group of controls was composed of 516 healthy subjects . The
number of CGG repeats was determined by comparison of PCR product
size with size standard after electrophoresis on ABI PRISM377 in
4% denaturing gel .
In the ataxia group we found no premutation alleles, and the largest
allele found contained 52 CGG repeats .
The FMR1 normal allele obtained for the control group ranged from 14
to 56 CGG repeats, with the most frequent 29 CGG alleles .
These results indicate that Polish control group is characterized by
similar FMR1 gene polymorphism as other populations . And since premutation
in the patients group was not found, we think that FXTAS
among patients with sporadic ataxia is less frequent than we expected;
we plan to enlarge the studied group by including patients with other
neurological symptoms, such as parkinsonism .
P01.098
Frequency of fragile X tremor ataxia syndrome in fragile X
syndrome families
M. Milà 1,2 , C. Berenguer 3,1 , I. Madrigal 4 , J. Kulisevsky 5 , J. Pagonabarraga 5 , B.
Gomez 5 , L. Rodriguez-Revenga 4 ;
1 Hospital Clinic, Barcelona, Spain, 2 IDIBAPS, Barcelona, Spain, 3 Fundació
Cínic, Barcelona, Spain, 4 CIBERER, Barcelona, Spain, 5 Hospital Sant Pau,
Barcelona, Spain.
Fragile X syndrome (FXS), which is caused by a CGG triplet expansion
in the first exon of FMR1 gene, is the leading cause of familial mental
retardation . Premutated individuals (55-200 CGG) do not present
FXS symptoms, but approximately one third on them can present other
manifestations such as a late onset ataxia /tremor syndrome (called
FXTAS) or premature ovarian failure (POF) . In order to determine the
presence of FXTAS among FXS grandparents, we have contacted by
telephone with 92 families. We have identified 24 premutated carriers
(belonging to 18 FXS families) showing FXTAS symptoms . These
results evidence that FXTAS frequency among FXS families is around
20% . The youngest individual is 66 and the oldest 82 y .o . We are now
evaluating these patients psychologically, neurological and with magnetic
resonance imaging. Molecular studies confirm a slight reduction
of FMRP protein and increased levels of mRNA in these patients (x2x5
folds) . The description of associated pathologies (FXTAS and POF)
to premutation carriers has modified genetic counseling for FXS, these
two disorders and their consequences have to be taken into account
by genetic counselor .
Acknowledgements (SAF2004-03083, Marató TV06-0810)