2008 Barcelona - European Society of Human Genetics

Cytogenetics
P02.110
CSMD , a candidate gene for autism found in two patients with
autistic disorder and balanced translocations
C. Floris 1 , S. Rassu 2 , L. Boccone 3 , D. Gasperini 3 , A. Cao 1 , L. Crisponi 1 ;
1 Istituto di Neurogenetica e Neurofarmacologia INN-CNR, Monserrato (CA),
Italy, 2 Dipartimento di Scienze Biomediche e Biotecnologie, Università degli
Studi di Cagliari, Cagliari, Italy, 3 Ospedale Regionale per le Microcitemie, Clinica
Pediatrica II, Azienda U.S.L. 8, Cagliari, Italy.
The study of chromosomal rearrangements associated with abnormal
phenotypes has proven to be a powerful method for the identification
of disease-related genes . Recent studies estimated a rate of 3-5% of
cytogenetic abnormalities involving many different chromosomes in
autistic spectrum disorders (ASDs) . We report here on two unrelated
males with de-novo translocations, autistic behaviour and psychomotor
delay . They carry balanced chromosome translocations, respectively a
t(5;8)(q14 .3;q23 .3) and t(6;8)(q13;q23 .2) . A detailed physical map covering
the regions involved in the translocations was constructed and
FISH analyses were carried out using BAC clones mapping on chromosomes
5q14.3, 6q13 and 8q23. We fine mapped the two translocation
breakpoints on chromosomes 8 identifying their positions within a
short 5 Mb genomic region . The results of these analyses showed that
breakpoints on chromosomes 8 in both patients do not interrupt any
known gene but both map in a region containing the CSMD3 gene .
No genes were interrupted on chromosomes 5q14 .3 and 6q13 . Taking
into account that CSMD3 is expressed in fetal and adult brain, our
observations suggest that this gene is a good candidate for the pathogenesis
of ASDs . To exclude an over-expression or under-expression
of CSMD3 leaded by the rearrangement, we verified the expression
of this gene in the leukocytes of the translocated patient by RT-PCR,
but any transcript was detected . Future studies, including mutational
analysis of CSMD3 in a large number of patients affected by autism
and behavioural studies on a Csmd3 knockout mouse, will be necessary
to confirm or decline this hypothesis.
P02.111
cytogenetic study of the BPEs cases
M. Kumar 1 , M. Tanwar 1 , P. Gupta 2 , N. Pushkar 2 , R. Kumar 1 , R. Dada 1 ;
1 Laboratory for Molecular Reproduction and Genetics, Deptt. of Anatomy, All
India Institute of Medical Sciences, New Delhi, New Delhi, India, 2 Dr. Rajendra
Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences,
New Delhi, New Delhi, India.
Blepharophimosis ptosis epicanthus inversus syndrome (BPES) is a
rare genetic disorder with autosomal dominant pattern of inheritance
with a frequency of 1 in 50,000 . Patients with BPES have a combination
of congenital anomalies as small palpebral fissures, epicanthus
inversus, low nasal bridge and congenital ptosis . Other features like
microphthalmos, anophthalamos, microcornea, hypermetropia, divergent
strabismus, high arched palate, cup shaped ears, mental retardation
and infertility in females has been reported . BPES has been
categorized into two types: type I associated with primary ovarian follicle
and type II involves only eye malformation in both sexes . Penetrance
is 100% in type I (transmission by males only) and 96 .5% in
type II (transmission through both sexes) . Review of reported cases
concluded that a locus for eyelid development is situated at 3q . Various
reports linked the deletion in 3q21, 3q22, 3q23, 3q24, 3q25 and
translocations t(3:7)(q26-qter:q+), t(X:3)(p22:q21), t(3:8)(q23:p22 .1) to
the BPES . We analyzed 10 cases of BPES by GTG banding . Six were
males with mean age of 24 years and four were females with mean
age of 27 years . Different deletions and translocation of chromosome
3 has been linked with the BPES but there is no case reported with
3q26-28 and 5q31 .3-33 .2 deletions which we found in two cases . We
also found 3qter deletion which has already been linked to the BPES .
These findings represent severe manifestation of the disease. BPES
is a heterogeneous entity, and evaluation and counseling of affected
individuals should be undertaken with caution .
P02.112
Are evolutionary chromosome rearrangements triggered by nonrandom
nuclear neighbourhoods?
S. Mueller, F. Grasser, T. Cremer, M. Neusser;
Human Genetics, Munich, Germany.
We investigated whether non-random nuclear neighbourhoods may
have triggered evolutionary chromosome rearrangements, focussing
on the fusion of human chromosome 2 and the reciprocal translocation
t(5;17) in the gorilla .
We analysed the nuclear topology of breakpoint flanking loci in pre-
and post-meiotic cells from cryo-sections of Rhesus macaque testis
tissue, where the fixation of chromosomal rearrangements is expected
to occur. Chromosome 5 and 17 breakpoint flanking BAC clones did
not co-localise, but were positioned toward the nuclear centre and
at the chromosome territory surface. Both findings can be correlated
with their rather gene-dense local genomic environment . The resulting
short distances between the two loci may have acted as probabilistic
trigger for evolutionary rearrangements of gene-dense genomic
regions, even more if these reside exposed at the territory surface .
Indeed, in silico analysis indicates that the majority of breakpoints in
great apes characterized so far reside in genomic environments with
elevated local gene density compared to the average of the respective
chromosome .
In the light of these results it was surprising to find chromosome 2
fusion point flanking BAC clones localized in the nuclear periphery.
Despite this, the two loci were frequently positioned in close physical
proximity in Rhesus macaque spermatocytes, and even to a higher
degree in spematogonia .
In conclusion, non-random nuclear positioning of genomic loci during
meiosis may have triggered these two evolutionary rearrangements .
These triggers may be probabilistic, as shown for the t(5;17), or specific
side-by-side arrangements in the case of the fusion of human
chromosome 2 .
P02.113
chromosomal mosaicism of the skin: A preliminary study
M. Pérez-Iribarne 1,2 , C. Fons 3,2 , M. González-Enseñat 4,2 , A. Vicente 4,2 , I. Plensa
1,2 , P. Poo 3,2 , M. Pineda 3,2 , C. López 1,2 , T. Zabala 1,2 , E. Geán 1,2 ;
1 Secció Genètica, Esplugues (Barcelona), Spain, 2 Hospital Sant Joan de Déu,
Esplugues, Spain, 3 Servei Neurologia, Esplugues (Barcelona), Spain, 4 Servei
Dermatologia, Esplugues (Barcelona), Spain.
Introduction : The concept of cutaneous mosaicism has now been
proved by numerous studies . It seems likely that the two skin types
represent two different genotypes, even though this has been remarkably
difficult to prove. Our aim is to describe the neurocutaneous
symptoms and skin chromosomal mosaicism spectrum in a series of
14 pediatric patients .
Patients and Methods: We have reviewed the karyotype of cultured
fibroblasts from 75 pediatric patients, who presented skin lesions suggestive
of pigmentary mosaicism, studied in our institution from August
1998 to October 2007 . Biopsies were obtained from both hypopigmented
and hyperpigmented skin . Conventional chromosome banding
studies were performed and karyotyped (ISCN, 1995) .
Results: We reported 14 patients with skin mosaicism: three boys and
eleven girls . Six of them presented numerical abnormalities: three
cases with diploid/triploid mosaicism, two patients with a marker chromosome
(one of them with persistence of the marker in peripheral
blood karyotype); and one patient with a chromosome 20 trisomy and
West syndrome . The rest of patients (n=8) had structural chromosomal
abnormalities, with different chromosomes involved . All of them had
typical linear cutaneous lesions except a two-year-old girl with Pallister-Killian
syndrome .
Conclusion: There is an association between chromosomal mosaicism
and hypopigmentation and hyperpigmentation especially following
Blaschko lines. We did not find in all patients direct correlation between
a specific chromosomal abnormality and neurological affection.
Patients with atypical cutaneous lesions or with neurological symptoms
could be candidates to perform a skin karyotype even though
blood karyotype is normal .
P02.114
cytogenetic effects in somatic cells of irradiated individuals with
developed thyroid gland cancer
E. Dyomina;
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology
of NAS of Ukraine, Kyiv, Ukraine.
Essential growth of thyroid gland cancer (TGC) among population of
extensive territories of Ukraine, Russia and Byelorussia suffered after
“iodine stroke” testifies that thyroid gland pathologies - one of the most
expressed health consequences of the Chernobyl accident . Data of