2008 Barcelona - European Society of Human Genetics

Cytogenetics
- 60 .0) per 100 cells accordingly . In this group 13 persons with hidden
chromosome instability (from 22 .2 till 60 .0 aberrations per 100 cells)
had been found . The data received permit to assume that high radiation
doses even in delayed terms following irradiation can modify inherited
human chromosomes susceptibility to mutagen exposure .
P02.124
chaotic banding pattern of a chromosome 3 in a patient with
mental retardation
M. Martinez-Fernandez 1,2 , L. Rodriguez 1,2 , T. Liehr 3 , K. Mrasek 3 , M. Martinez-
Frias 1,2,4 ;
1 Joint Centre for Biomedical Research on Rare Diseases (CIBERER), Madrid,
Spain, 2 Estudio Colaborativo Español de Malformaciones Congénitas (ECEMC)
del Centro de Investigación sobre Anomalías Congénitas (CIAC), Instituto de
Salud Carlos III, Ministerio de Sanidad y Consumo, Madrid, Spain, 3 Institut für
Humangenetik und Anthropologie, Friedrich Schiller Universität Jena, Jena,
Germany, 4 Departamento de Farmacología, Facultad de Medicina, Universidad
Complutense, Madrid, Spain.
Constitutional complex chromosomal rearrangements (CCRs) are very
unusual, and most of them involve more than one chromosome . As far
as we know there are only eight published cases having a CCR involving
four or more breakpoints within a single chromosome .
Here we present an intrachromosomal CCR in a chromosome 3 having
five breakpoints, which was found in a patient without major congenital
defects but presenting mental retardation .
The patient was a 30-year-old male, product of the second pregnancy
of healthy and non-consanguineous parents . He was born at 42 weeks
of gestation by normal vaginal delivery . Few hours after birth, he suffered
a hypoxia episode without an apparently cause, that required
oxygen therapy . His evolution showed psychomotor delay .
The patient was referred to us for diagnostic evaluation at the age of
30 years, refering mental retardation and a previous karyotype with
an inversion in chromosome 3 with breakpoints in p12-q32 . We performed
a high resolution G-band karyotype and found a chromosome
3 with a chaotic banding pattern . This alteration was “de novo” .
Fluorescence in situ hybridisation (FISH) with subtelomeric probes
3p/3q showed that they were located at normal position . FISH with
WCP3, showed the derivative chromosome 3 homogeneously stained,
demonstrating the intrachromosomal nature of the rearrangement .
Multicolour-banding FISH was performed and revealed the presence
of five breakpoints.
We postulate the different steps that happened to generate the chaotic
banding pattern of this CCR .
ACKNOWLEDGEMENTS . This work was supported by a Grant
PI020028 (FIS), Spain and the Evangelische Studienwerk e .V . Villigst
.
P02.125
comprehensive copy Number Variant (cNV) analysis of
neuronal pathways genes in mental retardation
A. Brunet 1 , E. Saus 1 , M. Gratacòs 1,2 , L. Armengol 1 , E. Gabau 3 , M. Guitart 3 , X.
Estivill 1,2,4 ;
1 Center for Genomic Regulation (CRG), Barcelona, Spain, 2 CIBERESP, Barcelona,
Spain, 3 Corporació Sanitària Parc Taulí, Sabadell, Spain, 4 Pompeu Fabra
University, Barcelona, Spain.
Cryptic copy number variants (CNVs), including deletion and duplication,
translocation and inversions, in chromosomes have been identified
in about 10% of patients with mental retardation (MR) of unknown
origin . The aim of this work is to perform a comprehensive screening
of CNVs that contain genes related to neurodevelopment . We selected
364 genes involved in neuronal pathways and used the Database of
Genomic Variants to identify genes predicted to be in CNVs (n=75) .
We designed four Multiple Ligation Probe Amplification (MLPA) assays
to detect variations in copy number between patients and controls . We
studied 93 children with unexplained MR and normal karyotype and
332 control samples . We discovered 13 CNVs in MR patients, 5 of
which were not present in controls . When available, parental samples
were also analysed by MLPA to assess the inheritance of the CNV .
We found 6 genes located in de novo genomic alterations corresponding
to four different genomic loci: 1q42 .1 (DISC1 and TSNAX), 3p26 .1
(GRM7 and CNTN6), 7q31 .33 (GRM8) and 17q21 .31 (MAPT) . The
locus on chromosome 17q21 .31 has been validated by CGH-array
and coincides with the recently described 17q21 .31 microdeletion syn-
drome . Some of the regions described here were previously described
in other patients with MR . Our results indicate that a considerable proportion
of genes involved in neuronal pathways show variability in copy
number and that de novo events might be related to the aetiology of
MR . Further investigation in larger cohorts of patients should allow a
definition of the potential role of genomic variability in MR.
P02.126
Cryptic deletion Xp21 with the loss of the genes DMD, GK and
NR0B1 in a female child with mild psychomotor retardation and
stereotypies
D. Orteschi 1 , G. Marangi 1 , V. Leuzzi 2 , E. Tabolacci 1 , G. Neri 1 , M. Zollino 1 ;
1 Institute of Medical Genetics, Università Cattolica del Sacro Cuore, Roma,
Italy, 2 Department of Child Neuropsychiatry, Università “La Sapienza”, Roma,
Italy.
We present the case of a female child at age of 21 months who presented
the following clinical features: delayed motor milestones, hypotonia,
lethargy during the first months of life, attention deficit, motor
limitations (i.e. running difficulties), stereotypies and some autistic features,
sleep disturbance, hyperCKaemia . Her psychomotor development
improved significantly after the age of 1 year.
By the mean of Array-CGH analysis (BAC-array at an average resolution
of 1 Mb) we revealed a de novo deletion of about 4,5 Mb on chromosome
Xp21, with the complete loss of the genes DMD (dystrophin),
GK (glycerol kinase), NR0B1 (nuclear receptor subfamily 0, group B,
member 1) and, probably, of part of the gene IL1RAPL1 . The deletion
arose on paternal X-chromosome . A random X-inactivation pattern
was found .
Clinical-pathogenetics features are discussed, mainly with regard to
the early onset of signs of dystrophinopathy in a female patient with an
heterozygous deletion of the gene DMD and to the possible phenotypic
causal role of the gene IL1RAPL1, whose mutations in hemizygous
males has been reported in literature as responsible of some cases of
X-linked mental retardation .
P02.127
Proximal interstitial deletion in the short arm of chromosome 3:
a report of a child whose mother carries a balanced reciprocal
translocation t(7;14)(p32;q32)
C. Vinkler1 , M. Michelson1 , T. Lerman-Sagie2 , D. Lev1 ;
1 2 Institute of Clinical Genetics Wolfson Medical Center, Holon, Israel, Pediatric
Neurology Wolfson Medical Center, Holon, Israel.
Proximal 3p deletion is a rare condition . To date, 14 patients have been
described . This recognizable phenotype consists of growth retardation,
developmental delay, hypotonia and dysmorphic features (plagiocephaly,
broad forehead . Broad nasal bridge, low set ears, long
philtrum) .
We describe a boy with a de novo interstitial deletion at band 3p13p12 .3,
who presented with a phenotype similar to the previously described
cases . However, his mother carries a balanced translocation involving
different chromosomes,t(I7;14)(p32;q32) .
The patient was born at 36 weeks gestation and was diagnosed with
hypotonia, feeding difficulties, dysmorphic features and ASD. Brain CT
showed partial agenesis of the corpus callosum . G-banded metaphase
chromosomes revealed a normal karyotype 46,XY .
At the age of five years, he came for genetic reevaluation. He has
psychomotor retardation, severe speech delay and he suffers of seizures
. He has dysmorphic features similar to those described in other
patients with proximal 3p deletion . CGH microarray analysis was performed
using 4685 BAC clones (Signature Genomics Laboratories,
Spokane,WA) . An interstitial deletion at the short arm of chromosome
3p13p12.3 was identified. FISH analysis, confirmed the microdeletion
on the patient’s karyotype, but not on the parents’ karyotype .
Although the mechanism underlying this cytogenetic event is not understood,
we suggest that offsprings of balanced reciprocal translocation
carriers, may be more prone to other cytogenetic abnormalities
warranting further investigation .
P02.128
Accuracy of analysis in cytogenetics
R. J. Hastings 1 , O. Bartsch 2 , G. Floridia 3 , K. Held 4 , B. Quellhorst-Pawley 1 , C.
Ramos 5 , M. Rodriguez de Alba 5 , K. Simola 6,7 , D. Taruscio 3 , R. Howell 1 ;
1 John Radcliffe Hospital, Oxford, United Kingdom, 2 Universitaet Mainz, Mainz,