2008 Barcelona - European Society of Human Genetics

Clinical genetics
creased dosage of ATRX and perhaps other genes are involved in the
pathogenic mechanism of this XLMR phenotype .
In conclusion, the association of MR, facial dysmorphisms, broad thorax,
genital anomalies, and short stature might contribute to the recognition
of male patients with a microduplication encompassing the entire
ATRX gene . We suggest that male patients with a similar phenotype
should be screened for duplications of the ATRX gene .
P01.086
Functional disomy Xqter du to duplication mecp2 gene
A. A. Aboura1 , M. Mathieu2 , S. Drunat1 , A. Tabet1 , C. Dupont1 , B. Benzacken1 ,
F. Guimont1 , A. Verloes1 ;
1 2 Robert debré, Bd Sérurrier, France, Département de Génétique C.H.U nord,
Amiens, France.
We report on three patients : 2 boys and a girl, with an additional Xq28
chromosome segment translocated onto 5pter, Ypter, and 13p . The karyotypes
were 46,XY,der(5)t(X;5)(q28;pter) 46,X,der(Y)t(X;Y)(q28;pter
) and 46,XX,der(13)t(X;13)(q28;p10) . In all cases, the de novo cryptic
unbalanced X-autosome translocation and Xq-Yp translocation resulted
in a Xq28 chromosome functional disomy by duplication of Mecp2
(methyl-CpG binding protein 2) gene . In all, 20 patients carrying a Xq28
functional disomy could be selected from the literature . Common craniofacial
findings include microcephaly, a small mouth. Most patients
have prenatal onset growth retardation . Postnatal growth retardation
was present in all cases . Major axial hypotonia is constant and usually
present at birth . Severe constipation frequently reported . Severe devlopmental
delay is observed in most patients . Functional disomy for the
Xq28 chromosome region yields a recognizable phenotype including
distinctive facial features, major axial hypotonia, severe feeding difficulties,
abnormal genitalia and proneness to infection (pneumonia) .
Severe developmental delay is almost constant . A clinically oriented
FISH study using subtelomeric probes
P01.087
Functional characterization of the X-linked mental retardation
gene ACSL
I. Meloni 1 , V. Parri 1 , R. De Filippis 1 , F. Ariani 1 , M. Bruttini 1 , I. Longo 1 , F. Mari 1 , C.
G. Dotti 2,3 , A. Renieri 1 ;
1 Medical Genetics, Siena, Italy, 2 Department of Human Genetics, University
of Leuven Medical School, Leuven, Belgium, 3 Department of Molecular and
Developmental Genetics, Flanders Institute of Biotechnology (VIB 11), Leuven,
Belgium.
ACSL4 is a gene involved in non-syndromic X-linked mental retardation
. It encodes for a ubiquitous protein that adds Coenzyme-A to
long-chain fatty acids, especially arachidonic acid; it presents a brainspecific
isoform resulting from alternative splicing and containing 41
additional N-terminal aminoacids. In order to define how ACSL4 absence
causes mental retardation, we have characterized the protein
and analyzed the consequences of its absence in neurons . Our data
suggest that ACSL4 is located in endoplasmic reticulum . Quantitative
mRNA expression analyses indicate that ACSL4 is expressed at higher
levels in fetal than in adult brain . Moreover, differential expression
of the alternative transcripts in different adult brain regions has been
observed. Protein analysis has confirmed this variability and revealed
a lack of linear correlation between mRNA and protein levels, suggesting
the presence of post-transcriptional regulatory mechanisms . To
characterize ACSL4 function in neurons we have silenced the gene by
siRNA technology in rat primary hippocampal neurons . Our data suggest
that ACSL4 might be important for dendritic spine formation and/
or maintenance. In fact, ACSL4 absence seems to cause a significant
reduction in dendritic spine density and alteration in spine distribution
among different morphological categories . Moreover, abnormal actin
accumulation has been observed in a significant percentage of cells.
This last finding suggests that ACSL4 might directly or indirectly influence
actin cytoskeleton organization; it could be thus hypothesized
that the observed spine anomalies are a secondary effect of an abnormal
actin organization due to ACSL4 absence . Additional experiments
will be necessary in order to confirm these hypotheses.
P01.088
molecular characterization by acGH of a 3,8 mb duplication at
Xq26.3 in a male with mental retardation
I. Madrigal 1 , M. Fernández-Burriel 2 , L. Rodríguez-Revenga 1 , L. Armengol 3 , X.
Estivill 3 , M. Milà 4 ;
1 Centre for Biomedical Research on Rare Diseases (CIBERER), Barcelona,
Spain, 2 Unidad de Investigación. Hospital de Mérida., Badajoz, Spain, 3 Genes
and Disease Programme. CRG. Barcelona, Barcelona, Spain, 4 Biochemistry
and Molecular Genetics Department, Hospital Clínic and IDIBAPS, Barcelona,
Spain.
Males with duplications in the distal long arm of the X chromosome are
rare and in most cases are inherited from a carrier phenotypically normal
. We report the clinical and molecular characterization of a Xq26 .3
duplication in a male and his brother affected by MR . Chromosome
analysis was normal and Multiplex Ligation Probe Amplification (MLPA)
analysis detected a duplication of the ARHGEF6 gene inherited from
a carrier mother . Both affected brothers presented moderate mental
retardation and displayed dysmorphic features . Further characterization
of the duplication by array CGH and FISH experiments with specific
BAC probes, revealed a deletion of 28 contiguous BAC clones,
spanning a region of 3,8 Mb in Xq26 .3 . X-inactivation studies in the
mother showed a complete skewed X-inactivation (100/0) inactivating
the X-chromosome inherited by the patient . Among the 20 genes
included within the duplicated region we discuss the implication of AR-
HGEF6, PHF6 and HPRT1 in the phenotype of the patient . Mutations
or deletions in these three genes are responsible for syndromic and
non-syndromic forms of mental retardation . Nowadays high-resolution
technologies such as array CGH allow the detection of copy number
aberrations in patients with MR . The characterization of these cryptic
rearrangements is of clinical importance in order to provide a genetic
counselling in carrier women for future pregnancies .
Aknowledgements: This work has been supported by the Instituto Carlos
III (PI04-1126) and Fundación Areces (U-2006-FAERECES-O)
P01.089
Fragile X syndrome and Xp deletion in a girl with autism and
mental retardation
A. Vazna, Z. Musova, D. Novotna, M. Vlckova, M. Havlovicova, Z. Sedlacek;
Department of Biology and Medical Genetics, Charles University 2nd Medical
School and University Hospital Motol, Prague, Czech Republic.
Autism is a complex behavioural disorder characterised by social and
communication impairments, and restricted repetitive and stereotyped
behaviour . It is often associated with mental retardation . Genetic
factors play an important role in the aetiology of autism - heritability
reaches 90 %, one of the highest among psychiatric disorders . The
inheritance is most likely multifactorial with genetic heterogeneity and
complex interactions . Despite of all efforts, until now the success in
finding of autism susceptibility genes has been limited. Cytogenetic
abnormalities and single-gene defects often associated with autism
(e .g . the fragile X syndrome) together account for about 10% of cases .
However, these are the only cases where diagnostics and exact risk
assessment are possible . We present a 7-year-old girl with atypical
autism, mental retardation, hyperactivity, developmental delay, facial
dysmorphism and overweight . Her family showed no history of mental
retardation or autism, but tremor was apparent from sixty years of age
in her maternal grandfather . DNA testing of the patient revealed full
mutation (460 CGG repeats) in the FMR1 gene, consistent with the
diagnosis of fragile X syndrome . In addition, cytogenetic analysis detected
a large deletion on chromosome Xp. We attempted to define in
more detail the breakpoints of the deletion and the inheritance of both
genetic defects in the family . Microarray CGH mapped the 17 .5 Mb deletion
to Xp22 .11-p22 .31 . The deleted segment harboured almost 100
protein-coding genes . The distal breakpoint of the deletion was located
close to NLGN4, a gene implicated in autism and mental retardation .
Supported by grants NR/9457-3 and MZO00064203