European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Cytogenetics
P0399. Molecular Characterization of a case of ring chromosome 9
O. González1 , I. Marco1 , S. Ramiro1 , C. Fernández-R. 1 , A. Fernández-Jaén2 , E.
Arranz1 , M. Renedo1 ;
1 2 Gemolab, Madrid, Spain, Servicio de Neurología.Hospital de la Zarzuela,
Madrid, Spain.
Ring chromosomes are rare and are typically de novo;the syndrome
associated to the 9 ring is not commonly observed and is characterized
by constant signs, such as microcephaly, psychomotor retardation
of varying entity and facial dysmorphism.
We report a boy, born of non-consanguineous parents in 2005, and
referred to the genetics laboratory because of microcephaly. Cytogenetics
study showed a karyotype interpreted as 46, XY, r(9). Parental
studies showed the ring was de novo in origin.
C-banding showed the ring chromosome was monocentric. Using a
painting chromosome 9 fluorescent in situ hybridization (FISH) probe
we confirmed no other chromosome involved. To define the breakpoint
on the 9p and 9q arms, FISH was performed with Telvysion 9p and
Telvysion 9q probes covering both regions. We detected at least a
95Kb deletion in 9q but no deletion was detected with the telomeric
9p FISH probe.
To define the chromosomal breakpoints more closely, FISH-mapping
with the RCPI-11 Human Male BAC Library using clones spanning
chromosome 9 telomeres is undertaken.
Using FISH we have defined the loss of material more precisely and
have shown that the subsequent monosomies are responsibles of the
clinical evolution of the patient.
P0400. Inverted duplications associated with terminal deletions
in six different ring chromosomes
E. Rossi 1 , J. Messa 1 , S. Gimelli 1 , P. Maraschio 1 , S. Perrotta 2 , T. Mattina 2 , P.
Riva 3 , A. Schinzel 4 , O. Zuffardi 1 ;
1 Biologia Generale e Genetica Medica, Pavia, Italy, 2 Genetica Medica, Catania,
Italy, 3 Biologia e Genetica Medica, Milano, Italy, 4 Genetica Medica, Zurich,
Switzerland.
Inverted duplications associated with a distal deletion (inv dup del)
have been reported for several chromosomes, but hardly ever in ring
chromosomes. Characterizing, by array-CGH (Kit Agilent, 75 Kb and
6,5 Kb) and FISH, 25 different ring chromosomes in patients with phenotypic
abnormalities, we identified in six of them inverted duplications
associated with a terminal deletion at one end. At the opposite end no
deletion was present in four cases, whereas a second deletion was
present in two cases. Moreover, in one case with an inv dup del(13q),
a further duplication of (13)(q12.21-3.1) was present in mosaic state.
Peripheral chromosomes analysis of the patients showed the following
karyoptypes:
Case 1: 46,XX,r(13)(p11q34); case 2: 46,XX,r(15)(p11q26); case 3:
46,XX,r(18)(p11q23);
Case 4: 46,XX,r(13)(p11q34); case 5: 46,XX,r(22)(p11q26); case 6:
46,XX,r(18)(p11q23)
Mental retardation and dysmorphic features are common findings in
the six patients.
Our results suggest that a more complex mechanism may be involved
in the formation of some ring chromosomes and that ring formation
may represent a new mechanism involved in the stabilization of broken
chromosomes.
This new mechanism of ring formation has important phenotype/genotype
implications since it implies that phenotypic correlations cannot
be done assuming a simple deletion before having excluded this type
of rearrangement.
P0401. Characterization of ring X chromosome by FISH: Role of
X inactivation
A. M. Mohamed, A. K. Kamel, H. F. Kayed, N. M. A. Meguid, H. A. Hussein, H.
A. Atteia;
National Research cetre, Cairo, Egypt.
Some ring X [r(X)], have been described with MR. This is the result
of functional disomy of the genes in the r(X) secondary to loss of the
X-inactivation locus (XIST). We aimed to study the effect of r(X) on the
clinical features, to correlate the presence of XIST and the pattern of
X replications to the IQ level. The subject of this study was 54 cases
with TS. Patients were subjected to clinical examination, estimation of
I.Q. and cytogenetic analysis. Cases with atypical TS were further subjected
to FISH using WCP for X , locus specific for XIST. , differential
12
replication studies with BrDU for r(X).
13 cases had ring (X). By FISH, the origin of these rings was derived
entirely from the X chromosome. XIST was found in all the rings. Ten
cases had small rings, 3 had large rings. MR was found in 90% of
cases with small r(X), the large r(X) had normal mentality. A significant
relation was detected between the presence of r(X) and the lower I.Q..
Replication pattern showed the I.Q. level decreased with the presence
of active r(X).
We conclude that abnormal stigmata different from the typical T.S. may
suggest the presence of the r(X). The mechanism of the presence of
active r(X) in our cases was not due to deletion of XIST gene and may
be due to silencing of the gene due to interruption or mutation. Failure
of inactivation does not necessarily lead to MR. We recommend more
extensive studies on XIST.
P0402. Translocation Down syndrome; report of four de novo
cases from Iran
C. Azimi, M. Khaleghian, F. Farzanfar, M. Safavi;
Cancer Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic
of Iran.
Down syndrome occurs in about one of 750 live births and is associated
with a variety of karyotypes. Nearly 92.5% have simple trisomy-21,
which is related to the maternal age. In about 4.8% the extra
chromosome 21 material is present in the form of an unbalanced Robertsonian
translocation or as an isochromosome of the long arm of
chromosome 21, and does not vary with age. The remaining 2.7% are
heterogeneous and include mosaicism, double trisomies and reciprocal
translocations. In about three-fourths of translocation Down syndrome,
neither parent is a carrier, and a mutation in the germ cells of
one parent has caused the translocation. No one knows what causes
these mutations.
We report four infants (three boys and one girl) from the four different
families, all showed typical clinical features of the Down syndrome.
The parental age of the four cases were between 20-30 years old.
Chromosomal analysis were made, using the standard banding techniques,
for the cases and their parents. The karyotypes of the three
cases were 46,XY,der(21;21)(q10;q10),+21 and for the fourth one was
46,XX,der(14;21)(q10;q10),+21. The karyotypes of the parents of the
four infants were normal.
P0403. Segregation and pathogenesis of balanaced/unbalanced
homologous Robertsonian translocations, t(13;13), t(14;14);
t(15;15), t(21;21) and t(22;22) - Case reports and review
D. S. Krishna Murthy, F. M. M. Al-Kandari, M. A. Redha, K. K. Naguib, L. A.
Bastaki, S. A. Al-Awadi;
Kuwait Medical Genetics Center, Sulaibikat, Kuwait.
One in 900 humans is born with a Robertsonian translocation. The
most frequent forms of Robertsonian translocations are between
chromosomes 13 and 14, 13 and 21, and 21 and 22. Robertsonian
translocations (balanced or unbalanced) involving acrocentric chromosomes,
13,14,15 and 21, 22 are well known chromosomal abnormalities
leading to multiple congenital anomalies, infertility, repeated
fetal loss, dysmorphism and mental retardation. However, homologous
Robertsonaian translocations, t(13;13q),t(14;14),t(15;15) and t(22;22)
are relatively rare. Carriers of balanced ROBs are at an increased
risk of having chromosomally unbalanced, phenotypically abnormal
offspring. These individuals are trisomic for one of the chromosomes
involved in the translocation, with three copies instead of the normal
complement of two. Carriers of ROBs are also at an increased risk of
uniparental disomy (UPD), the inheritance of both chromosome copies
from a single parent. Uniparental inheritance of some chromosomes
has been shown to be deleterious due to the effects of imprinting (the
differential expression of genes depending on the parent of origin).
Risk estimates vary depending on the type of rearrangement. Carriers
of homologous acrocentric rearrangements are at very high risk of
having multiple spontaneous abortions and chromosomally abnormal
offspring. Parents of fetuses and children with unbalanced homologous
acrocentric rearrangements are rarely found to be carriers or mosaic
for the same rearrangement.