2008 Barcelona - European Society of Human Genetics

Cytogenetics
P02.030
investigation of cryptic chromosomal imbalances in patients
with mental retardation and/or multiple congenital abnormalities
using array-cGH
C. Sismani 1 , G. Koumbaris 1 , V. Anastasiadou 2 , G. Stylianidou 2 , S. Hadjiloizou 3 ,
P. Evangelidou 1 , P. C. Patsalis 1 ;
1 The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus, 2 Department
of Paediatrics, Makarios Hospital, Nicosia, Cyprus, 3 ”Paidi” Center for Specialized
Paediatrics, Nicosia, Cyprus.
Chromosomal abnormalities constitute the major cause of mental retardation
(MR) . Conventional chromosomal analysis still remains the
most important tool for identification of genomic imbalances causing
MR, however subtle aberrations smaller than 5Mb are missed by routine
karyotyping . Array-CGH was recently introduced to clinical practice,
significantly increasing the detection rate of chromosomal abnormalities
. The aim of the current study was to investigate 70 patients with
various degrees of mental retardation and/or congenital abnormalities
for cryptic chromosomal imbalances . All patients were clinically examined
and tested by karyotyping and FISH, in order to exclude large
chromosomal abnormalities and suspected microdeletion syndromes .
Array-CGH was performed using BAC microarray Cytochip platform
(BlueGnome) with a median resolution of 565kb. Clinically significant
submicroscopic chromosomal imbalances were detected in 4 patients
(5.7%). Abnormal results were confirmed by FISH. The percentage of
identified abnormalities in the current study is lower than previously
reported by other studies, probably due to the fact that no specific
selection criteria were applied in our patients . One deletion, one duplication,
one unbalanced translocation and one mosaic case with
both a deletion and duplication were identified. One of the detected
abnormalities was de novo, one was familial, while the remaining two
are still under investigation . Two out of the four detected abnormalities
would have been identified by subtelomeric screening and two would
have been missed. Array-CGH is a powerful tool for the identification
of novel chromosomal syndromes and identification of new cases of
known syndromes that will allow more accurate prognosis and phenotype-genotype
correlations .
P02.031
modelling human microdeletion syndromes by chromosome
engineering in mice
C. J. Shaw-Smith1 , M. Storer1 , D. Szumska2 , P. Scambler3 , S. Bhattacharya1 ,
A. Bradley1 ;
1 2 Wellcome Trust Sanger Institute, Cambridge, United Kingdom, Wellcome
Trust Centre for Human Genetics, Oxford, United Kingdom, 3Institute of Child
Health, London, United Kingdom.
Array-based diagnostics and the pooling of information in databases
such as DECIPHER has accelerated discovery of novel microdeletion
syndromes . Examples include the recently described 17q21 .31 and
22q11.2 microdeletion syndromes (refs 1 and 2). The identification
of the individual genes responsible for the phenotype is facilitated by
chromosomally engineered mouse models . We are using such models
to analyze the chromosomal loci for recently described microdeletion
syndromes (see Table) .
Our strategy is to target MICER clones (ref 4) to the proximal and distal
endpoints, respectively, of each deletion . Following Cre treatment,
mouse ES cells are microinjected into blastocysts to generate male
chimaeras . Phenotyping of offspring is carried out by MRI scanning at
embryonic day 15.5. Where an appropriate phenotype is identified, a
series of nested deletions is made in order to identify a candidate gene
or genes . Ultimately, suitable candidates are tested by BAC rescue
of the deletion . The 6 .8 Mb mouse deletion at human 17q22-23 was
made by this method and has a cardiac phenotype; generation of other
mouse deletions is in progress . .
Size of Syntenic mouse Salient phenotypic
Syndrome
Ref
deletion chromosome features
MR, seizures, neo-
Del 17q21 .31 500 kb 11
1
natal hypotonia
Del 22q11 .2 2 .1 Mb 16 Truncus arteriosus 2
Cleft palate, atrial
Del 15q14 5 .3 Mb 2
5
septal defect
Del 6q24 .3-25 .1 2 .6 Mb 10 Atrial septal defect 6
Del 17q22-23 6 .8 Mb* 11 Tetralogy of Fallot 7
*deletion in chromosomally engineered mouse
Table: Chromosomal microdeletions amenable to modelling by mouse chromosome
engineering
1. Nat Genet . 2006: 38(9):1032-7
2. Am J Hum Genet . 2008: 82(1):214-21
3 . Nature . 2001: 410(6824):97-101
4. Nat Genet . 2004 36(8):867-71
5 . Am J Med Genet A . 2007: 143(2):172-8
6 . Eur J Med Genet . 2007: 50(4):315-21
7 . Genetics. 2006:173(1):297-307 .
P02.032
scanning copy number variations (cNV) in Angelman syndrome,
mental retardation and autism
S. Villatoro 1 , L. Armengol 1 , I. Crespo 2 , E. Gabau 2 , L. Comadran 2 , M. Coll 3 , M.
Guitart 2 , X. Estivill 1,4 ;
1 Center for Genomic Regulation (CRG), Barcelona, Spain, 2 Corporació Sanitària
Parc Taulí, Sabadell, Spain, 3 Departament de Biologia Cel•lular Universitat
Autònoma de Barcelona, Bellaterra, Spain, 4 Pompeu Fabra University, Barcelona,
Spain.
Angelman syndrome (AS) is a neurodevelopmental disorder with a
recognizable molecular cause in about 85% of cases . Copy number
variations (CNV) are an important source of variation and genes located
therein are likely to have altered expression patterns, therefore contributing
to phenotypic changes . Twenty AS patients without the typical
molecular alterations but with well-defined clinical features were analysed
by aCGH using the 244K Agilent platform . Altered regions that
contained rare CNVs (