2009 Vienna - European Society of Human Genetics

Cytogenetics
P03.082
High-resolution array analysis detects microdeletions of
chromosome region 16q22.1 in two unrelated individuals with
mR/ mcA syndrome
T. Zagoras 1 , M. Kibaek 2 , M. Kirchhoff 3 , S. Kjaergaard 3 , J. Dahlgren 4 , A. Erlandsson
1 , M. Stefanova 1 ;
1 Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg,
Sweden, 2 Department of Paediatrics, University Hospital of Odense, Odense,
Denmark, 3 Department of Clinical Genetics, Rigshospitalet, University Hospital
of Copenhagen, Copenhagen, Denmark, 4 Department of Paediatrics, Sahlgrenska
University Hospital, Gothenburg, Sweden.
Here we report a detailed clinical and molecular investigation of two unrelated
individuals, an 18-months-old boy and a 13-years-old girl with
de novo overlapping deletions of 16q22.1, sized 1.48Mb and 0.28Mb,
respectively. Clinically they both presented with dysmorphic features,
moderate developmental delay, sleeping disturbances, and abnormal
behaviour. The boy had low birth weight, short stature (-4SD), microcephaly
(-4SD), high forehead, thin eyebrows with “medial flaring”,
strabismus, narrow flat nasal bridge, prominent columella, short flat
philtrum, thin lips, late erupted dysplastic teeth, dysplastic ears, short
fingers and toes, broad 1 st toe, delayed skeletal age. He showed distinct
externalising behaviour, friendly and continuously smiling. The girl
had autistic behaviour, hypermetropia (+6), no signs of puberty at the
age of 13, and dysmorphism such as hypertelorism, thick eyebrows,
long eyelashes, epicanthic folds, wide pronounced nasal bridge, low
set posteriorly rotated dysplastic ears, long prominent philtrum, thin
lips, hairy skin, sandal gap, broad 1 st toe. Chromosome aberrations
were detected by high-resolution array analysis, 250k SNPs array (Affymetrix)
for the 1.48Mb deletion and 244k CGH array (Agilent) for
the 0.28Mb deletion. Breakpoints on chromosome 16 were defined
as 65101151-66582496 (hg18) and 65958487-66235411 (hg18), respectively.
Several possibly relevant genes are located in the overlapping
gene-rich region such as CTCF, ZDHHC1, TPPP3, LRRC36,
and AGRP. Authors discuss reasons for partially overlapping/partially
distinct phenotypes of the two individuals. To our knowledge these
are the first two cases reported with microdeletions confined to the
16q22.1 region.
P03.083
A de novo 305 kb interstitial dup(3)(p25.3) encompassing the
VHL and IRAK genes in a patient with mental retardation/
multiple congenital anomalies, epilepsy, spasticity and
ectomorphic habitus
E. Chabchoub 1 , G. Michils 1 , J. R. Vermeesch 1 , P. De Cock 2 , J. P. Fryns 1 ;
1 Centre for Human Genetics - University Hospital Gasthuisberg, Leuven, Belgium,
2 Department of Neuropaediatrics - University Hospital Gasthuisberg,
Leuven, Belgium.
Partial duplications of the short arm of chromosome 3 are very rare.
Often they are reported in translocations involving other chromosomes,
whereas deletions encompassing the VHL gene in 3p25.3 predispose
to Van-Hippel Lindau syndrome.
While screening for genomic copy number variations (CNV) with a
1 Mb resolution bacterial artificial chromosome (BAC) array-based
comparative genomic hybridisation (aCGH) in a 17 year-old male referred
for the aetiological diagnosis of mental retardation and multiple
congenital anomalies (MR/MCA) and ectomorphic habitus, a de novo
3p25.3 microduplication was detected and refined by Multiplex Ligation-dependent
Probe Amplification (MLPA) to a 305 kb region encompassing
the VHL and IRAK2 genes and disrupting the GHRL gene.
This is not reported as a benign CNV in the database of genomic variants
(DGV). Moreover, we have not found similar duplication in the
DNA of parents of nearly 1000 patients we tested by aCGH.
The patient was followed since the age of six years. He has no tumour
and there is no history of familial cancer. Brain MRI was normal.
Interestingly, duplication of IRAK2 can cause epilepsy by activating
the NFκB signalling pathway, both controlling the postsynaptic glutamate
receptor density. Disruption of the GHRL gene can explain the
ectomorphic habitus described here, since patients with larger dup(3p)
involving GHRL show short stature and obesity.
To our knowledge, this is the smallest duplication of chromosome 3p
encompassing the VHL region reported yet. The prognosis of this cytogenetic
imbalance is unknown and a long-term follow-up is essential
for an early diagnosis of malignancy.
P03.084
Array-CGH for the identification of constitutional copy number
changes
A. C. Obenauf, T. Schwarzbraun, M. Mach, E. Vallant, P. M. Kroisel, S. Uhrig,
J. B. Geigl, K. Wagner, M. R. Speicher;
Institute of Human Genetics, Graz, Austria.
Up to date, we have analyzed 331 patients with a conspicuous phenotype
e.g. dysmorphic features, metal retardation, and developmental
delay by array-CGH. We employed different array platforms, including
the 1 Mb or 8k large insert clone arrays and the commercially available
44K and 244K oligoarrays from Agilent.
We identified copy number changes (CNCs) in 79 patients (=23.8%).
Subsequent analyses usually include evaluation of the parental genomes
and verification of the array-CGH results either by FISH, MLPA
or qRT-PCR.
We identified well-known microdeletion/duplication syndromes like
Prader-Willi-, Smith-Magenis-, Di-George-, Miller-Dieker-, Williams-
Beuren-, Phelan-McDermid-, Cri-du Chat-, Wolf-Hirschhorn-, or the
2q37 microdeletion syndrome. In addition to the detection of these well
known syndromes array technologies paved the way for the detection
of new deletion/duplication syndromes. The recently described deletions/duplications
of 1q21.1, 8p23.1, 15q24, 16p13.11, 16p11.2 were
also detected in our patients demonstrating the great clinical implication
of these array-CGH findings. However, most of the detected CNCs
are private. To achieve better genotype/phenotype correlations and to
identify new clinically relevant syndromes, clinical and genetic data
from all consented patients are entered into the DECIPHER database
and are compared with the other entries in the database.
An especial interesting case represented a de novo deletion of 770 kb
on chromosome 17p13.1, harboring the tumor suppressor gene p53,
which was identified in a girl with developmental delay. Furthermore,
we found that in this patient the breakpoint disrupted the transcriptional
control of the GUCY2D gene, which likely causes the amaurosis of the
patient.
P03.085
interstitial de novo del(1)(q25.1q31.3): clinical presentation and
molecular description with array-cGH
E. Dimitriadou 1 , K. Theodoropoulos 2 , I. Lalou 1 , M. Tzoufi 3 , J. Vermeesch 4 , J. P.
Fryns 4 , S. Kitsiou 5 , M. Syrrou 1 ;
1 Cytogenetics Unit, Laboratory of General Biology, Medical School, University
of Ioannina, Ioannina, Greece, 2 General Hospital of Ioannina “Hatzikosta”,
Ioannina, Greece, 3 Child Health Department, Medical School, University of
Ioannina, Ioannina, Greece, 4 Center for Human Genetics, University Hospital
Leuven, Leuven, Belgium, 5 Department of Medical Genetics, Athens University
School of Medicine, Athens, Greece.
We report a 11-year-old male child with prenatal onset of growth retardation,
growth hormone deficiency, developmental delay and several
dysmorphic features including significant orthodontic problems, severe
malocclusion, protrusion of upper jaw and narrow high-arched palate
with triangular shaped palate, low hairline posteriorly, hypertelorism,
long palpebral fissures, mild epicanthal folds bilaterally, long eyelashes
and reversion of lower eyelid, relatively prominent ears, small
hands and digits with 5th finger clinidactyly bilaterally and apparently
persistent finger pads, small feet and toes with right 2nd-3rd toe syndactyly
and increased gap between 1st and 2nd toes bilaterally and
Achille’s tendon contractures bilaterally. He also has severe myopia,
strabismus and mild astigmatism.
Molecular karyotyping using a 1 Mb resolution BAC array demonstrated
the presence of a 21 Mb sized deletion on the long arm of
chromosome 1. The deletion flanking clones are RP11-552K17 and
RP3-433G19. The karyotype is arr cgh 1q25.1q31.3 (RP5-1045J21-
>RP11-435N12)x1. The case is compared with similar cases from the
literature of postnatally detected interstitial deletion on 1q. This is the
first time that array-CGH analysis is used for a more accurate assessment
of the breakpoints in a patient carrying a deletion in the 1q25-q31
region.
P03.086
Array-cGH in fetuses with polymalformations
P. Callier 1 , N. Laurent 2 , L. Faivre 1 , T. Rousseau 3 , C. Thauvin-Robinet 1 , N. Marle
1 , S. Couvreur 3 , A. Mosca 1 , H. Guy 2 , S. Pigennat 2 , G. Herve 2 , F. Dos santos 1 ,
A. Masurel-Paulet 1 , P. Sagot 3 , F. Mugneret 1 ;