2009 Vienna - European Society of Human Genetics

Cytogenetics
P03.165
interpretation of copy number changes of the 1p36.3 terminal
region detected by high resolution oligonucleotide array cGH
E. J. Seo 1 , K. R. Chun 1 , J. O. Lee 2 , H. W. Yoo 3 , I. S. Park 3 ;
1 Dept. of Laboratory Medicine, University of Ulsan College of Medicine and
Asan Medical Center, Seoul, Republic of Korea, 2 Genome Research Center for
Birth defects and Genetic disorders, Asan Medical Center, Seoul, Republic of
Korea, 3 Dept. of Pediatrics, University of Ulsan College of Medicine and Asan
Medical Center, Seoul, Republic of Korea.
Breakpoints of the 1p36 deletion syndrome have been observed between
0.5 and 10.5 Mb from the 1pter and common deleted regions
are terminal 2.5-2.7 Mb. While deletions or duplications of less than
0.5 Mb from the 1pter are regarded as benign CNVs, copy number
changes of more than 0.5 Mb should be assessed cautiously in factors
influencing the risk. We detected various copy number changes of the
1p36.3 terminal region using Agilent 244K whole human genome CGH
oligonucleotide array in 60 Korean patients with congenital anomalies.
Out of 6 patients with copy number changes at 1p36.3, three showed
the recurrent copy number changes of 1.56 Mb with low log2 ratio: 1
loss, and 2 gains. A patient with 1.56 Mb loss had total 5.86 Mb deletion
at 1p36.3 including extended 4.3 Mb loss with high log2 ratio,
which was resulted from derivative unbalanced translocation, der(1)t
(1;14)(p36.3;p11.2)dn. The 1.56 Mb gain of two patients appeared to
be benign CNV. Another two patients with copy number loss of high
log2 ratio had 2.2 Mb simple terminal deletion inherited from a affected
mother, and 2.7 Mb deletion by derivative unbalanced translocation,
respectively. Remaining one patient with 2.7 Mb gain of low log2 ratio
revealed 1q12-1q23.2 gain of high log2 ratio which was compatible
with his marker chromosome. These findings suggest that a recurrent
breakpoint of CNV could be located 1.56 Mb from the 1p telomere, and
the log2 ratio should be considered when interpreting the array CGH
data in constitutional disorders.
P03.166
Array cGH analysis of 4q terminal deletion diagnosed in a girl
with mild dysmorphic features, developmental delay and no
major congenital anomalies
K. Schlade-Bartusiak 1 , A. Innes 2 , M. Chan 1 , M. Anderson 2 , J. Chernos 1,2 ;
1 Cytogenetics Laboratory, Alberta Children’s Hospital, Calgary, AB, Canada,
2 Department of Medical Genetics, University of Calgary, Calgary, AB, Canada.
The 4q deletion syndrome, comprising all cytogenetically visible deletions
(interstitial or terminal) of the long arm of chromosome 4, is a wellrecognized
distinctive disorder, described in more than 100 patients.
Common phenotypic features of 4q- syndrome are mild dysmorphic
features, mild to severe mental retardation, growth deficiency, cleft
palate, limb anomalies, cardiac and genitourinary defects. A unique
finding consisting of a stiff, pointed 5 th finger with a hypoplastic distal
phalanx and either a hooked or a volar nail is observed in two thirds
of patients. Patients with large terminal deletions, with breakpoints in
4q31, are most severely affected. More distal 4q deletions involving
bands 4q33 to 4q35 have been found so far in about 25 cases. These
patients present less characteristic dysmorphisms and less severe
mental retardation. Some authors suggest that the region 4q31-q34
is critical for most of the clinical phenotype. HAND2 in 4q33 has been
proposed as a candidate gene for the cardiac defects, and a gene involved
in limb deficiencies was tentatively assigned to 4q33. It is clear
that phenotypes associated with 4q deletion are grossly related to the
breakpoint location and the amount of genetic material lost.
We present a 12-year old girl with mild dysmorphic features and developmental
delay with learning difficulties. Karyotype analysis revealed
a terminal deletion on chromosome 4q. Array CGH showed a deletion
of over 17 Mb, with the breakpoint within the 4q34.2 band.
Literature review and genotype-phenotype correlations in 4q deletion
syndrome will be discussed.
P03.167
two new cases of pure 2q terminal deletion
K. T. Abe, I. M. P. O. Rizzo, A. L. V. Coelho, L. M. Formigli, D. R. Carvalho, M.
F. Pereira, N. Sakai Jr., A. F. Castro, C. E. Speck-Martins;
SARAH Network of Rehabilitation Hospitals, Brasilia, Brazil.
The subtelomeric regions are gene-rich and often involved in chromosomal
rearrangements. We report two patients referred to medical
evaluation at the Genetic Service of SARAH Network of Rehabilitation
Hospitals-Brasília with subtelomeric chromosome 2q deletion.
Patient 1 is a female referred because of developmental delay at 17
months with epicantal folds, asymmetric palpebral fissures, small
nipples and abnormal palmar and plantar creases. She returned after
16 years, at 20 years, mild mental retardation (MR) is evident requiring
support for daily life activities. Only height is below the 3 th centile.
She has round face, down-slanted palpebral fissures, depressed
nasal bridge, small posteriorly angulated ears, shortened forearms,
brachydactyly, hallux valgus and joint hypermobility. The 3 rd , 4 th and 5 th
metacarpals and metatarsals are shortened. Cytogenetic study at 550band
levels revealed a terminal de novo deletion with the breakpoint at
2q36, confirmed by subtelomeric probe FISH.
Patient 2 is a female referred because of MR, eczema and obesity. At
14 years, we noted up-slanting palpebral fissures, eczema involving
scalp and her small hands and feet. Moderate MR, tantrums and controlled
seizures were present. Cytogenetic study at 700-band levels
revealed a tiny terminal de novo deletion at 2q37.2~37.3, confirmed by
subtelomeric probe FISH.
These two cases demonstrate the clinical variability involving confirmed
chromosome 2q terminal deletion. Broadening its clinical spectrum
could help health professionals recognize subtle manifestations
in the context of idiopathic MR. It also stresses the importance of using
subtelomeric FISH studies in cases of suspected cryptic rearrangements,
when investigating patients with idiopathic MR.
P03.168
Detection of subtelomere imbalances using mLPA
L. Hila 1 , Y. Chagrani 1 , H. Tébourbi 1 , L. ben Jemaa 2 , H. Chaabouni 2 ;
1 Laboratoire de Génétique Humaine Faculté de Médecine de Tunis, Tunis, Tunisia,
2 Service des Maladies Congénitales et Héréditaires EPS Charles Nicolle,
Tunis, Tunisia.
Subtelomeric rearrangements significantly contribute to idiopathic
mental retardation and result in several mental retardation syndromes.
New molecular techniques like Multiplex Ligation dependent probe Amplification
(MLPA) allow subtelomeric microduplications/microdeletions
identification in approximately 5% mentally retarded patients. However
most of subtelomeric defects lack a characteristic phenotype.
We analyzed Tunisian mentally retarded patients by MLPA Multiplex
Ligation Probe dependent Amplification with SALSA MLPA kit P036B/
MLPA kit P036D and MLPA kit P070 (which test all the subtelomeres).
MLPA results for the short arm of the acrocentric chromosomes were
not considered as significant as these probes hybridise to the long arm
near the centromere.
DNA was extracted from blood, quantified by spectrophotometry
(Nanodrop) and checked for degradation on an agarose gel, degraded
DNA was not used for MLPA analysis.
Patients with known sex chromosome abnormalities were used as
controls (45, XO; 47, XXY).
Relative probe signals of each probe was determined by dividing each
measured peak height by the height of patient reference peak divided
by the mean of height of control test peak divided by the height of
control reference peak. All peaks were insured to be between 50-6000
arbitrary fluorescents units.
We found subtelomeric deletions and duplications. These results will
be discussed upon the patient’s clinical features to make imbalancephenotype
correlations to discern which abnormalities are disease
causing or probable polymorphisms, in fact 15 subtelomeric copy number
changes are reported in phenotypically normal individuals.
P03.169
subtelomeric rearrangements in patients with idiopathic mental
retardation
R. Pinto Leite, M. Souto, P. Botelho, M. Martins, E. Ribeiro;
Centro Hospitalar de Tras-os-Montes e Alto Douro, Vila Real, Portugal.
Mental retardation affects between 1 to 3% of the general population
and is associated with several causes including environmental factors,
chromosomal abnormalities and monogenic diseases. 50% of the cases
have no etiologic diagnosis. Recently mental retardation was linked
to subtelomeric chromosomal abnormalities.
The objective of this work is the study of patients with idiopathic mental
retardation associated with dysmorphic features and/or birth defects
and/or family history of mental retardation in Trás-os-Montes region
- Portugal, by standard cytogenetic and FISH (Fluorescent in situ hy-