2008 Barcelona - European Society of Human Genetics

Cytogenetics
P02.064
22q11 microduplication syndrome across four generations of a
single family
S. A. McKee, S. McCullough, D. McManus;
Northern Ireland Regional Genetics Service, Belfast, United Kingdom.
Microduplication, as opposed to deletion, of the “DiGeorge region” on
chromosome 22q11 is an increasingly-recognised finding, associated
with a very wide phenotypic range . Patients vary in the degree of dysmorphism,
intellectual disability and cardiac abnormalities, and many
patients have now been reported who are classified as phenotypically
normal .
We report a Northern Irish family in which the proband was diagnosed
with a microduplication at the age of 20 . She has mild learning problems
and minimal facial dysmorphism, but has subtle abnormalities of
the fingers. Her daughter developed severe seizures at birth, and has
an atrial septal defect with patent ductus arteriosus . She has ocular
hypertelorism, a small mandible, and significant developmental and
growth delay; she tested positive for the duplication . The proband’s
mother and one of her brothers also carry the duplication . This makes
it highly likely that one of her parents in turn also carried the duplication
(these are reported as phenotypically normal; analysis is ongoing
in this family) .
Counselling as to the likely effects of this microduplication is very difficult,
as the spectrum is so broad even within families . In particular, prenatal
counselling presents significant challenges. As data continues to
accumulate, more accurate risks and prevalences may be established,
and potential modifying factors identified.
P02.065
Report of three cases with the 22q11.2 proximal deletion
R. Queralt1,2 , M. Vallecillos1 , Y. Viedma1 , M. Obon3 , M. Alsius3 , E. Margarit1,2 ;
1Servei Bioquímica i Genètica Molecular. Hospital Clínic, Barcelona, Spain,
2 3 Ciberer, Barcelona, Spain, Laboratori Clínic. Hospital Dr. Josep Trueta, Girona,
Spain.
Hemizygosity for the human chromosome region 22q11 .2 is associated
with a wide range of overlapping phenotypes including DiGeorge
syndrome, velocardiofacial syndrome . The acronym CATCH 22 (Cardiac
anomaly, Abnormal facies, T cell deficit due to thymic hypoplasia,
Cleft palate, Hypocalcaemia due to hypoparathyroidism resulting
from 22q11 deletion) has been proposed to describe the broad clinical
spectrum of phenotypes with 22q11 .2 deletions . The frequency of this
microdeletion is approximately 1:4000-1:8000 live births . Two types of
deletions have been described . The most common, affects about 85%
of patients and spans a ~3 Mb proximal region . The less common, affects
about 7% of patients and spans a smaller, nested ~1 .5 Mb distal
region . Both types of microdeletion were found to occur as a result
of nonallelic homologous recombination by means of low-copy repeat
sequences located in the 22q11 .2 region .
We describe the cytogenetic and molecular cytogenetic analysis of
three patients having the most common proximal 22q11 .2 microdeletion
. Karyotype analysis from lymphocyte cultures performed by conventional
G banding, at the level of 500 bands, revealed normal karyotype
in all cases . Fluorescence in situ hybridization (FISH) analysis
performed with the commercial dual probe LSI TUPLEI (22q11 .2)/LSI
ARSA (22q13) (Vysis) showed hemizygosity of 22q11 .2 region in all
three cases .
P02.066
Prenatal detection of 22q11.2 deletion:case report with wide
intra-familial phenotypic variation
A. Gomez Pastor 1 , J. Ubeda Arades 2 , J. L. Santome Collazo 2 , R. Fernandez
Gonzalez 2 , P. Blanco Soto 2 , M. Carballido Viejo 2 , M. A. Orera 2,3 ;
1 Complejo Hospitalario Universitario de Albacete, Albacete, Spain, 2 Hospital
Gregorio Maranon, Madrid, Spain, 3 Laboratorio Circagen, Madrid, Spain.
INTRODUCTION: 22q11 .2 deletion constitutes a contiguous gene
syndrome that encompasses the clinical phenotypes formerly described
as DiGeorge syndrome, velocardiofacial syndrome, conotruncal
anomaly face syndrome, Opitz G/BBB syndrome and Cayler cardiofacial
syndrome .
The diagnosis is routinely performed by FISH analysis .
CASE REPORT: We present a 33 years old healthy woman on is 13 th
gestational week that is sent to our office for genetic counseling because
of a previous pregnancy that produced a newborn with Fallot te-
tralogy . Later on she had a healthy boy and a third pregnancy ended at
the 9th gestational week in spontaneous miscarriage . The 450 bands
karyotype of the girl was 46,XX .
The amniocentesis was performed at the 16 th gestational week, and
the karyotype was 46,XY . We extended the cytogenetic analysis and
performed FISH of 4p16 .3, 22q11 .2 and 7q11 .23 and we found that the
fetus had a hemyzygous deletion of the 22q11 .2 region . The father was
a carrier of the same deletion .
MATERIALS AND METHODS: FISH analysis was performed with the
Vysis probe DiGeorge/UCFS (gene TUPLE1) y ARSA (control) . The
karyotype analysis was performed by conventional GTG banding .
DISCUSSION: This case illustrates de advantage of widening the prenatal
diagnostic spectrum beyond the most common aneuploidies, tailoring
the genetics tests to the family history as well as to the prenatal
data . Assuming that both the Fallot tetralogy and the miscarriage were
related to the familial deletion, the intrafamilial variability spans from
lethal to almost normal, adding further data to the few catch 22 families
studied to date .
P02.067
Frequent 22q11 aberrations in patients with non-syndromic
autism spectrum disorders shown by sNP array based
segmental aneuploidy screening
M. Poot 1 , N. Verbeek 1 , R. van ’t Slot 1 , M. R. Nelen 1 , B. van der Zwaag 2 , E. van
Daalen 3 , M. V. de Jonge 3 , W. G. Staal 3 , J. A. S. Vorstman 3 , P. F. Ippel 1 , M. van
den Boogaard 1 , P. Terhal 1 , F. A. Beemer 1 , J. J. S. van der Smagt 1 , E. H. Brilstra
1 , G. Visser 4 , H. van Engeland 3 , J. P. H. Burbach 2 , H. K. Ploos van Amstel 1 ,
R. Hochstenbach 1 ;
1 Department of Medical Genetics, Utrecht, The Netherlands, 2 Rudolf Magnus
Institute of Neuroscience, Utrecht, The Netherlands, 3 Department of Child and
Adolescent Psychiatry, Utrecht, The Netherlands, 4 Department of Pediatrics,
Utrecht, The Netherlands.
Autism spectrum disorders (ASD) are neurodevelopmental conditions
characterized by impaired reciprocal social interaction, communicative
deficits, and restricted behavioral patterns. ASD occurs in syndromic
forms and as non-syndromic cases frequently involving cytogenetic
abnormalities . Recently, array-based genome-wide screens have
demonstrated frequent copy number variation in non-syndromic ASD .
Screening 56 patients with autism and additional major or minor anomalies
with the Infinium HumanHap300 SNP platform (Illumina, Inc.,
San Diego, CA) we found in 16 patients 9 regions with deleted and 9
with duplicated signals . Aberrant signals were distributed among 16
distinct chromosomal loci . Apart from 14 patients with unique aberrations,
2 patients carried duplications and a 3 rd patient a deletion within
the 22q11 region, of 0 .726, 2 .966, and 0 .388 Mb, respectively . The
duplications were confirmed by multiplex ligation-mediated probe amplification
and are likely to involve LCRs A, B and D. We conclude that
SNP array-based screening of ASD patients uncovers an appreciable
number of CNVs, which in part overlap with loci already discovered by
other approaches. Our finding that 3 out of 56 ASD patients carried
aberrations within the 22q11 region is highly unexpected . The relatively
small size of CNVs found in this study may allow us to pinpoint
candidate genes for ASD .
P02.068
A rare recognizable 10p15 microdeletion syndrome of autism
and HDR
V. Herbepin-Granados 1 , A. Combes 1 , M. Gilet 1 , A. Toutain 2 , R. L. Touraine 1 ;
1 CHU Saint etienne, Saint Etienne, France, 2 CHU de Tours, Tours, France.
The HDR syndrome is characterized by hypoparathyroidism, sensorineural
deafness, and renal dysplasia. It is caused by haplo-insufficiency
of the GATA 3 gene located at 10p15 and inherited as an autosomal
dominant trait .
In our study we describe a patient with HDR phenotype and associated
severe autism . Molecular analysis by MLPA showed a de novo heterozygous
deletion at 10p15, encompassing the GATA3 gene without
involvment of the DGCR2. These results were confirmed by microsatellite
analysis, showing that the deleted region is located between
the D10S189 and D10S1649 markers . The size of the deletion can be
estimated around 2,5 Mb . The GATA3 gene has been reported as a
gene important in the embryonic development of the parathyroid, renal
and auditory systems . However mental retardation or autism can not
be ascribed to GATA3 mutations . Therefore we can suspect that this