2008 Barcelona - European Society of Human Genetics

Cytogenetics
P02.160
characterization of nine small supernumerary marker
chromosomes detected in 7,000 fetal karyotypes
N. Ploumis 1 , E. Manolakos 2 , M. B. Petersen 1 , H. Kontos 1 , P. Malligiannis 3 , A.
Bolli 4 , T. Liehr 5 , R. Neroutsou 2 ;
1 Genomedica, Athens, Greece, 2 Bioiatriki S.A., Athens, Greece, 3 Embryo Research
Center, Athens, Greece, 4 Research Center for Prenatal Diagnosis, Larissa,
Greece, 5 Institute Of Human Genetics and Anthropology, Jena, Germany.
Small supernumerary marker chromosomes (sSMCs) are structurally
abnormal chromosomes that cannot be characterized unambiguously
by conventional cytogenetic banding techniques . Until recently, the
great variety of marker chromosomes and difficulties with their identification
presented a problem for the cytogenetic interpretation of the
karyotype . The risk for an abnormal phenotype is about 7% when de
novo sSMCs derived from chromosomes 13, 14, 21, and 22 are ascertained
prenatally .
In a Greek survey of 7,000 amniotic fluid samples, nine fetuses with
marker chromosomes were detected in our laboratory . Using combined
approaches of conventional cytogenetics including special staining
techniques and fluorescence in situ hybridization (FISH), we successfully
characterized all of them, which assisted subsequent genetic
counseling and decision making . Eight of the SMCs were proven to
be of autosomal origin . Of the autosomal SMCs, two originated from
chromosome 15, one from chromosome 9, one from chromosome
18, one from chromosome 20, and three from chromosome 22 . One
marker chromosome was of sex chromosome origin . Euchromatin material
was detected in 7 cases . Five of seven de novo marker chromosomes
were associated with abnormal findings and were terminated.
Our study demonstrates that molecular cytogenetic characterization
of marker chromosomes detected at prenatal diagnosis, is of crucial
significance to risk evaluation and decision making of the couple.
P02.161
A complex chromosome 7q rearrangement identified in a patient
with mental retardation, anxiety disorder and autistic features
J. G. Dauwerse, C. A. L. Ruivenkamp, K. B. M. Hansson, D. J. M. Peters, M.
H. Breuning, Y. Hilhorst-Hofstee;
LUMC, Leiden, The Netherlands.
We present a 15 year old girl, the second child of healthy parents .
The girl is mentally retarded, suffers from a severe anxiety disorder
and has autistic features . Her mean IQ was 48 . She has a coordination
disorder and hypotonia. She has small palpebral fissures, simply
formed low set ears, abnormal palmar creases, scoliosis, long halluxes
and her thumbs are proximally implanted . Length and skull circumference
were -1 and -2,5 SD respectively . G-banding indicated a de novo
paracentric inversion 46,XX,inv(7)(q31 .3q34) . SNP-array analysis,
however, revealed a ~10Mb, 7q21 .11-7q21 .3 deletion in the paternal
chromosome . Subsequent FISH analysis with ± 90 BAC/PAC clones
in the 7q21-q35 region confirmed this deletion, but the expected paracentric
inversion turned out to be an intra-chromosomal insertion of
the fragment 7q31 .31-q35 into band 7q21 .3 . PAC clone RP4-545C24
spans the breakpoint in band 7q35, positioning the breakpoint between
the genes NOBOX and TPK1. The 7q31 .31 breakpoint disrupts clone
RP5-1047E14 and the predicted gene NP079189 .
Six other patients with a deletion of 7q21 .1-q21 .3 have been reported
previously . They share with our patient the following clinical features:
mental retardation/developmental delay, microcephaly, mild facial dysmorphism,
hypotonia, ear anomalies and small palpebral fissures. Our
patient did not show any hearing loss, genital anomalies or growth
deficiency, found in all of the previously reported patients. However
none of the previous cases were reported to have anxiety disorder
and/or autistic features . Therefore it is possible that disruption of the
NP079189 gene contributes to the anxiety disorder and the autistic
features in our patient .
P02.162
cytogenetics Results in 301 consanguineous iranian Patients
with mental Retardation
F. Behjati 1 , S. Ghasemi Firouzabadi 1 , K. Kahrizi 1 , R. KarimiNejad 2 , J. Oveisi 3 , P.
Jamali 4 , F. Mojahedi 5 , I. Bagherizadeh 1 , J. Ansari 1 , M. Fallah 1 , F. Mojtahedi 1 , S.
Abedini 1 , R. Vazifehmand 1 , G. Bahrami Monajemi 1 , H. Darvish 1 , F. Rakhshani 3 ,
A. Zadeh-Vakili 3 , A. Naghavi 3 , G. Mollashahi Sanatgar 3 , H. Najmabadi 1 ;
1 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences,
Tehran, Islamic Republic of Iran, 2 Kariminejad and Najmabadi Pathology
and Genetics Center, Tehran, Islamic Republic of Iran, 3 Zahedan University of
Medical Sciences, Zahedan, Islamic Republic of Iran, 4 Shahroud Behzisty Organization,
Shahroud, Islamic Republic of Iran, 5 Mashhad Genetics Counselling
Center, Mashhad, Islamic Republic of Iran.
Mental Retardation (MR) has heterogeneous etiology mostly with genetic
causes . Chromosomal aberrations are one of the most common
causes of MR and are responsible for 4-28% of all the mental retardation
. In order to identify genes involved in mental retardation, 301 Iranian
families with consanguineous marriage and positive family history
for MR have been investigated in Genetics Research Center in collaboration
with Max Planck Institute in Berlin . In these families at least
two sibs were affected. As a first step, both chromosome investigation
and fragile-X screening were carried out to exclude any abnormality .
Molecular investigations were done on all the normal karyotype and
fragile X negative patients . Standard Cytogenetics techniques using
high resolution and GTG banding were carried out on all the patients .
The overall chromosome abnormality rate was 3% (8 patients) . The
abnormalities included der(18)t(4;18)(q31 .1;q23)mat, der(22)t(21;22
)(q11;q13), 46,XY karyotype with female phenotype, and premature
chromosome condensation in three different MR patients with microcephaly
.However, our abnormality rate is lower than the reported
cases . This is due to biased referral reasons, as all our cases are due
to consanguineous marriage and therefore suggestive of autosomal
recessive inheritance .
P02.163
Premature chromosome condensation, microcephaly and mental
Retardation: A report of three large consanguineous iranian
families
S. Ghasemi Firouzabadi 1 , F. Behjati 1 , K. Kahrizi 1 , M. Garshasbi 2 , M. Motazacker
2 , S. Esmaeili Nieh 2 , S. Abedini 1 , M. Mohseni 1 , H. Darvish 1 , G. Bahrami
Monajemi 1 , R. Vazifehmand 1 , F. Rakhshani 3 , A. Zadeh-Vakili 3 , J. Oveisi 3 , A.
Naghavi 3 , G. Mollashahi Sanatgar 3 , H. Ropers 2 , H. Najmabadi 1 ;
1 Genetics Research Center, University of Social Welfare and Rehabilitation
Sciences, Tehran, Islamic Republic of Iran, 2 Max Planck Institute for Molecular
Genetics, Berlin, Germany, 3 Zahedan University of Medical Sciences, Zahedan,
Islamic Republic of Iran.
We report three out of a total of 50 Iranian consanguineous families
affected with microcephaly, growth retardation, and mental retardation .
These three families were unrelated and from northern and southern
parts of Iran . Six members of one family and two of the other two were
affected. Parents in all families were first cousins. Chromosome analysis
using GTG banding technique on the probands showed a high
frequency of prophase-like cells (80%) compared to normal controls
(13%) . The morphology of chromosomes was very poor and appeared
fragile, twisted, curly and with raised breakage and overall very unusual
looking . This phenomenon is due to premature chromosome
condensation. Molecular investigation in the first family, using arraybased
homozygosity mapping and array CGH revealed deletion in the
MCPH1 gene, one of four genes that have previously been implicated
in autosomal recessive mental retardation with mirocephaly . In the
other two families, using homozygosity mapping, linkage to MCPH1
locus was suggested . MCPH1 gene is the only microcephaly gene associated
with premature chromosome condensation .
The Cytogenetics findings demonstrating premature entry of cells into
mitosis suggested mutation of genes involved in cell cycle regulation,
which was then confirmed by molecular investigation. Our findings
emphasize the importance of chromosome studies on patients with
mental retardation and microcephaly . Findings of chromosomes with
premature condensation in such patients implicate mutation in MCPH1
gene, which would therefore warrant further molecular investigations .
P02.164
Pseudo-Angelman phenotype in two patients with a 2q23.1
microdeletion identified by array-CGH
S. Jaillard 1,2 , C. Dubourg 3,2 , M. Gérard 4 , A. Delahaye 5 , L. Pasquier 6,2 , C. Dupont
4,5 , C. Henry 1 , A. Tabet 4 , J. Lucas 1 , A. Aboura 4 , V. David 3,2 , B. Benzacken 4,5 ,
S. Odent 6,2 , E. Pipiras 5 ;
1 Laboratoire de Cytogénétique, Rennes, France, 2 UMR 6061, IFR 140 GFAS,
Faculté de Médecine, Rennes, France, 3 Laboratoire de Génétique Moléculaire,