European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Clinical genetics
midline defects and epilepsy. The cause of WHS is heterogeneous;
some individuals have deletions which may be large or small whereas
others have unbalanced translocations. The epilepsy may be of early
onset and difficult to control but there have been some reports of the
seizures ceasing after a period of years. However, relatively limited
information exists detailing the seizure activity in adults with WHS.
We investigated seizure onset and frequency in 21 young adults over
the age of 16 years diagnosed with WHS. They had a mean age of 24
years; range 17-34 years. Data were obtained by contacting parents
using a telephone interview.
Epilepsy was found to occur in all 21 cases, with one exception onset
of seizures was between 1 and 2 years of age. In 8 cases (mean age
26 years; range 17 - 34 years), a seizure had occurred within the last 3
years. Whereas in 13 cases (mean age 23 years; range 17 - 33 years),
the most recent seizure had occurred more than 3 years previously
(mean number of years 15; range 6 - 28 years). For those 13 cases
the last year of seizure occurred at a mean age of 9 (age range 2 - 15
years).
These data may be valuable in counselling families of a newly diagnosed
child.
P0277. Detection of genomic copy number changes in patients
with idiopathic mental retardation by high-resolution X-array-
CGH: frequent increased gene dosage of known XLMR genes
G. Froyen 1 , H. Van Esch 2 , M. Bauters 1 , S. Frints 3 , J. Vermeesch 2 , K. Devriendt
2 , J. Fryns 2 , P. Marynen 1 ;
1 VIB, Dept. Human Genetics, K.U.Leuven, Leuven, Belgium, 2 University Hospital,
Dept. Human Genetics, Leuven, Belgium, 3 University Hospital, Dept. Clinical
Genetics, Maastricht, The Netherlands.
A tiling X-chromosome-specific genomic array with a theoretical resolution
of 80 kb was developed to screen mental retardation (MR) patients
for submicroscopic copy number differences. We first validated
the X-array using 4 MR patients with aberrations previously detected
at lower resolution. This allowed for delineation of the location and
extent of the aberration at high resolution and subsequently, more
precise genotype-phenotype analyses. Next, we screened a cohort of
108 patients with idiopathic MR consisting of 57 patients suspected
of X-linked mental retardation (XLMR), 27 probands of brother pairs,
and 24 sporadic patients. We identified 15 copy number changes in 14
patients (13%). These include 2 deletions and 13 duplications ranging
from 0.1 - 2.7 Mb. The aberration is considered to be associated
with the phenotype in 5 patients (4.6%) based on the following criteria:
de novo aberration; involvement of a known or candidate MRX(S)
gene; segregation with the disease in the family; absence in control
individuals, and skewed X-inactivation in carrier females. These include
deletions that contain the MRX(S) genes CDKL5, OPHN1 and
CASK, and duplications harboring CDKL5, NXF5, MECP2 and GDI1.
In addition, seven unbalances are apparent novel polymorphic regions
because they do not follow the proposed criteria. Taken together, our
data strongly suggest that not only deletions but also duplications on
the X chromosome might contribute to the phenotype more often than
expected, supporting the increased gene dosage mechanism for deregulation
of normal cognitive development.
P0278. Female phenotype with karyotype 47,XYY
K. Ørstavik 1 , C. van der Hagen 2 , E. Ormerod 2 , T. Saether Hagen 3 , L. Walaas 4 ,
C. Mørk 5 , B. Andersen 6 , A. Wedell 7 , A. Myhre 8 ;
1 Department of Medical Genetics, Rikshospitalet -Radiumhospitalet Medical
Centre, Oslo, Norway, 2 Department of Medical Genetics, Ullevål University
Hospital, Oslo, Norway, 3 Section of Pediatric Surgery, Surgical Department,
Rikshospitalet -Radiumhospitalet Medical Centre, Oslo, Norway, 4 Department
of Pathology, Rikshospitalet -Radiumhospitalet Medical Centre, Oslo, Norway,
5 Department of Dermatology, Rikshospitalet -Radiumhospitalet Medical Centre,
Oslo, Norway, 6 Bussedalen Legekontor, Kongsberg, Norway, 7 Department of
Molecular Medicine and Surgery, Karolinska Institutet/Karolinska University
Hospital, Stockholm, Sweden, 8 Department of Pediatrics, Rikshospitalet -Radiumhospitalet
Medical Centre, Oslo, Norway.
Our patient is a 7 year old girl with blood karyotype 47,XYY. Her development
has been normal with the exception of growth retardation.
On examination at age 5 years height was 5cm below the 2.5 th centile,
weight at the 50 th centile for height and head circumference at the 10-
25 th centile. Her neck was broad and her posterior hairline somewhat
low. She had minimal cubitus valgus. A striking feature was a hypertrichosis
which was congenital and had increased over time. She had
long, coarse, fair, hairs along her entire spine, most pronounced in the
lumbar region, as well as hypertrichosis of her forearms.
Her external genitalia were normal. A normal sized uterus, but no gonads,
were identified on ultrasound. At laparoscopy she was found to
have small gonads which were excised. Histological examination revealed
ovarian stromal cells and bilateral gonadoblastoma. No testicular
differentiation was seen.
The karyotype of all 34 analysed lymphocytes was 47,XYY. The karyotype
in cultured fibroblasts was 45,X in 7 and 47,XYY in 14 of 21 metaphases.
FISH analysis of 199 interphases also revealed mosaicism:
XYY in 68, X in 114, XY in 4 and XX in 13 cells. Gonadal mosiacism
was present with 45,X in 37 and 47,XYY in 13 of 50 cell. Sequencing
of the SRY gene revealed no mutation.
A 47,XYY karyotype in lymphocytes is usually associated with a male
phenotype. The presence of cells without a Y chromosome in the gonads
may explain the female phenotype in this patient.
P0279. Mutation screening of ARX gene in male patients with
non-specific mental retardation from Russia
D. V. Islamgulov, A. S. Karunas, E. K. Khusnutdinova;
Institute of Biochemistry and Genetics, Ufa, Russian Federation.
Mutations of the ARX gene, considered to be the second most common
cause of X-linked mental retardation (XLMR), give rise to a wide
variety of distinguishable syndromes (Partington syndrome, X-linked
infantile spasm, etc.), and they are also an important cause of nonsyndromic
XLMR. The striking finding concerning ARX is the phenotypic
heterogeneity associated with the most frequent and recurrent
mutation (identified in >5% of XLMR families): the in-frame 24-bp duplication
(c.428_451dup24) expanding the 16 polyalanine tract to 23
(amino acids 100-115). In order to evaluate the frequency of ARX mutation
in mentally retarded (MR) males from Volga-Ural region of Russia,
we performed mutational analysis of ARX gene in 214 unrelated
MR (diagnosis based on the ICD-10) male patients (Russians N=72,
Tatars N=56 and Bashkirs N=34) with average age of 13.02±3.47
years (range, 5-18 years) negative for mutations in the FMR1 and
MECP2 genes. The recurrent c.428-451dup24 mutation was identified
by sequencing in three (1.4%) MR males (Russians N=1, Tatars
N=1 and Bashkirs N=1). The subsequent genotype-phenotype analyses
confirmed that polyalanine tract expansion can result in a highly
variable disease phenotype, even with respect to mental retardation a
great deal of variability, with intellectual impairment ranging from mild
to severe, which mitigates against early clinical diagnosis. These data,
together with those reported in the literature, imply that screening for
c.428_451dup24 mutation should be recommended in males with nonspecific
MR, especially in population Volga-Ural region of Russia. The
work was supported by grant of RFH, project (No.05-06-06168a).