2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
MeCP2 acts as a transcriptional repressor, however the gene expression
changes observed in the hypothalamus of MeCP2 disorder
mouse models suggest that MeCP2 can also upregulate gene expression,
given that the majority of genes are downregulated upon loss of
MeCP2 and upregulated in its presence. To determine if this role of
MeCP2 extends beyond the hypothalamus, we studied gene expression
patterns in the cerebellum of Mecp2-null and MECP2-Tg mice,
modeling RTT and MECP2 duplication syndrome, respectively. We
found that abnormal MeCP2 dosage causes alterations in the expression
of hundreds of genes in the cerebellum. The majority of genes
were upregulated in MECP2-Tg mice and downregulated in Mecp2null
mice, consistent with a role for MeCP2 as a modulator that can
both increase and decrease gene expression. Many of the genes altered
in the cerebellum were similarly altered in the hypothalamus.
Our data suggest that either gain or loss of MeCP2 results in gene
expression changes in multiple brain regions and that some of these
changes are global. Further delineation of the expression pattern of
MeCP2 target genes throughout the brain might identify subsets of
genes that are more amenable to manipulation, and can thus be used
to modulate some of the disease phenotypes.
P02.192
molecular karyotyping reveals CDKL Deletions as frequent
cause of mental retardation of unknown origin
A. Rauch 1 , M. Zweier 2 , A. Gregor 2 , C. Zweier 2 , E. Bijlsma 3 , F. Bosch 4 , J. Hoyer 2 ,
A. Ekici 2 , A. Reis 2 ;
1 Institute of Medical Genetics, University of Zurich, Zurich, Switzerland, 2 Institute
of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany,
3 Center for Human and Clinical Genetics, Department of Clinical Genetics,
LUMC, University of Leiden, Leiden, The Netherlands, 4 Pediatric Hospital Fürth,
Fürth, Germany.
In order to further elucidate the causes of mental retardation we performed
a genome-wide copy number variant (CNV) survey in 160 patients
with mental retardation of unknown origin using the Affymetrix
6.0 SNP platform.
Surprisingly, two of the 160 patients (1.3 %) showed microdeletions
involving the CDKL5 gene. Mutations in this gene were only recently
identified as causative for an atypical variant of Rett-syndrome characterized
by intractable early-onset seizures often accompanied by
Rett-like features.
Patient 1 is a 12 months old girl, born after uncomplicated pregnancy,
with secondary microcephaly, severe mental retardation, severe hypotonia
and drug resistant seizures. Karyotyping, testing for Angelman
syndrome and MECP2-analysis showed normal results. By array analysis
a 230kb deletion on Chromosome Xp22.13, including parts of the
CXorf20 gene, the complete SCML2 gene and exon 1 of the CDKL5
gene was detected.
Patient 2, a 7 years old girl was born after an uncomplicated pregnancy
and is severely mentally retarded. She had convulsions in her
first year of life and shows stereotypical movements of her hands. Her
speech is nasal and limited to a few words. MECP2 and TCF4 testing
was normal. In this patient we detected a 157 kb deletion on the Xchromosome,
including a large part of the CDKL5 gene, furthermore
the RS1 gene and parts of the PPEF1 gene.
Our findings demonstrate for the first time, that CDKL5 microdeletions
are a major pathomechanism in female patients with severe mental
retardation and seizures and seems to constitute a relatively frequent
cause of mental retardation.
P02.193
two novel cases of congenital variant of Rett syndrome related
to mutations in the FOXG gene
J. Nectoux1 , N. Bahi-Buisson2 , B. Girard3 , H. Van Esch4 , T. De Ravel de l’Argentière4
, Y. Fichou1 , J. Chelly1 , T. Bienvenu1 ;
1Université Paris Descartes, Institut Cochin, CNRS (UMR8103), Paris, France,
2Service de Neuropédiatrie, Hôpital Necker-Enfants-Malades, Paris, France,
3Laboratoire de Biochimie et Genetique Moleculaire, Hôpital Cochin, Paris,
France, 4Centre for Human Genetics, Leuven, Belgium.
The forkhead box G1 (FoxG1) is a transcription factor that is critical for
forebrain development where it promotes progenitor proliferation and
suppresses premature neurogenesis. Recently, the FOXG1 gene was
implicated in the molecular aetiology of the congenital variant of Rett
syndrome. So far, seven mutations have been reported. We screened
the FOXG1 gene in a cohort of 206 MECP2/CDKL5 mutation negative
patients with severe encephalopathy and microcephaly (136 females
and 70 males). The screening was negative in all males. Two de novo
mutations (c.1248C>G, p.Y416X and c.460dupG) were identified in two
girls. Both patients showed neurological symptoms from the neonatal
period with poor reactivity, hypotony, and severe microcephaly. During
the first year of life, both weakly progressed and presented feeding
problems. At 5 years, girls showed severe neurological impairment
with gross hypotonia, no language, convergent strabismus, and no
voluntary hand use. Instead, both presented the combination of jerky
movements, hand-mouthing and hand-washing activities. Although
our patients demonstrate severe encephalopathy compatible with the
congenital variant, several features previously highlighted in FOXG1
mutations patients were not observed : absent eye contact, inconsolable
crying during perinatal period, and thin corpus callosum. Others
signs were not systematically observed: protruding tongue, scoliosis,
and epilepsy. Although the overall frequency of mutations in FOXG1
in females with severe mental retardation and microcephaly appears
to be low (1.5%), our findings suggest the requirement to investigate
both point mutations and probably gene dosage in the FOXG1 gene
in patients with severe encephalopathy with microcephaly, and some
Rett-like features.
P02.194
DNA Resequencing and Variant Identification Using a Nonsyndromic
X-linked mental Retardation (mRX) Panel
C. Davidson1 , F. Bartel2 , E. Nordman1 , B. Johnson1 , L. Joe1 , A. Pradhan1 , A.
Felton1 , M. Friez2 ;
1 2 Applied Biosystems, Foster City, CA, United States, Greenwood Genetic Center,
Greenwood, SC, United States.
The prevalence of X-linked mental retardation (XLMR) is estimated to
afflict ~1/1000 males. To date, there have been ~90 X-linked genes
implicated in causing XLMR with the majority of these genes being
associated with syndromal MR (MRXS). A smaller set of genes on the
X chromosome have been associated with nonsyndromal MR (MRX)
where the only discernible feature is mental retardation. Significant
overlap between these two sets of genes indicates that syndromal
and nonsyndromal can both be caused by alterations in many of the
XLMR genes. From a clinical perspective, proper diagnosis of males
with nonsyndromal XLMR is more straightforward when a positive family
history exists. Unfortunately, many undiagnosed males with MRX
exist, and the absence of an X-linked pedigree makes the identification
of their underlying etiology much more difficult. Indicative of this
difficulty is that MRX accounts for roughly 2/3 of the total number of
XLMR cases. To test for MRX, the Molecular Diagnostic Laboratory at
the Greenwood Genetic Center has designed a resequencing panel
consisting of 95 amplicons encoding the exons and intron junctions
of 9 X-linked genes. To demonstrate the advantages of a new capillary
electrophoresis (CE) instrument, 19 blinded probands suspected
of having MRX were directly sequenced using the Greenwood MRX
resequencing panel. Variant detection in the 9 genes across the 19
samples will be discussed. The MRX Resequencing Panel coupled
to the Fast Resequencing Workflow highlights the advantages of using
CE for DNA resequencing and variant identification across a large
number of samples and genes.
P02.195
Developmental delay and a distinctive facial appearance in two
families with Xq25 duplications
A. Philippe 1 , V. Malan 1 , M. L. Jacquemont 1 , N. Boddaert 2 , J. P. Bonnefont 1 , A.
Munnich 3 , L. Colleaux 1 , V. Cormier-Daire 1 ;
1 INSERM U781 et Département de Génétique, Hôpital Necker-Enfants Malades,
Paris, France, 2 Service de Radiologie Pédiatrique, Hôpital Necker Enfants-
Malades, Paris, France, 3 INSERM U781 et Département de Génétique , Hôpital
Necker-Enfants Malades, Paris, France.
We have previously reported a duplication (1.2 Mb) at Xq25 using
whole-genome array Comparative Genomic Hybridization in a 20year-old
man with syndromic mental retardation (MR) (Jacquemont et
al.2006).
This duplication contains four known genes, one of which is GRIA3
(Glutamate Receptor, Ionotropic, AMPA subunit 3). Mutations, deletion
and partial duplication of the GRIA3 gene have been reported in males
with non-syndromic MR (Wu et al., 2007; Chiyonobu et al., 2007).