2009 Vienna - European Society of Human Genetics

Cytogenetics
method used to detect small copy number changes within the genome
that are not always visible by conventional karyotyping (>5-10Mb).
Thirty patients with various degrees of MR, seizures, dysmorphic features
and/or single or multiple congenital abnormalities and normal
previous conventional karyotype, many of which had also received a
variety of other genetic tests (FRAX, RETT, single FISH tests or metabolic
screens), were analyzed with Agilent 244K oligoarrays, allowing
a theoretical resolution of >50Kb. Clinically significant submicroscopic
imbalances were detected in 15 (50%) patients. We are currently in the
process of confirming our findings with QPCR. The high percentage of
positive patients is probably due to the strict criteria of patient selection.
The clinically relevant results are presented in the table below. Array
CGH is a powerful tool for the identification of novel chromosomal
syndromes and for more accurate prognosis and phenotype-genotype
correlations.
iD chromosome
Gain/
Loss
Position start
(Ucsc hg18)
Position End
(Uscs hg18)
Length
(mb)
Known
syndrome Genes*
1 1p36.33-p36.32 Loss 554,268 3,332,604 2.8 Yes PLCH2, SKI, GABRD
1q41 Gain 220,916,807 221,288,347 0,371 No AIDA, DISP1
2 Xp11.3 Loss 44,005,210 44,048,137 0,043 No EFHC2
Xq21.31 Loss 90,917,565 91,035,630 0,118 No PCDHX
3 2q35 Loss 216,986,022 217,664,090 0,68 Yes SMARCAL1
3p14.1 Loss 70,598,263 71,795,160 1,2 No FOXP1
4 5p15.33 Loss 948,032 2,209,449 1,26 No TERT, SLC6A3, SLC6A19
10q26.3 Loss 133,644,221 135,084,833 1,44 Yes NKX6, CALY
3p14.1 Loss 70,951,444 71,601,477 0,65 No FOXP1
5 11p15.5 Loss 1,515,185 2,499,331 0,984 No DUSP8, TNNI2, TGF2, TH, ASCL2, KCNQ1
11p11.2 Loss 43,833,775 44,553,392 0,719 Yes EXT2, ALX4
6 10q26.3 Loss 134,182,454 135,356,716 1,17 Yes NKX6, CALY
7 17q21.31-q21.32 Loss 41,331,503 42,142,422 0,810 Yes MAPT, STH, NSF
8 17q21.31-q21.32 Loss 41,395,772 41,983,466 0,587 Yes MAPT, STH
9 17q12 Loss 32,024,123 33,121,179 1,09 Yes HNF1B, LHX1, DUSP14
10 Xp11.3 Loss 43,208,140 43,765,770 0,557 No MAOB, MAOA, NDP
11
15q11.2
15q11.2
Gain
Loss
18,454,050
21,982,746
20,249,945
22,396,107
1,79
0,413
Yes?
Yes?
12 15q11.2-q14 Gain 19,109,124 36,837,570 17,73 Yes AS/PWS
13 5q23.2-q31.1 Loss 124,232,611 135,251,538 11,0 No
14 18p11.32-p11.21 Loss 4,316 15,370,683 15,3 No TGIF1, USP14, NDC80, ADCYAP1
15 4p16.3-p16.1 loss 62,447 7,455,153 7,39 Yes WHS**
*clinically relevant
P03.075
De novo 1.2 mb deletion in 2p16.3, disrupting the NRXN gene in
a boy with autism and developmental delay
S. Gimelli1 , P. Makrythanasis1,2 , S. E. Antonarakis1,2 , A. Bottani1 , F. Bena1 ;
1 2 University Hospitals of Geneva, Geneva, Switzerland, University of Geneva,
Geneva, Switzerland.
Autism spectrum disorders (ASD) are a group of neurodevelopmental
conditions characterized by deficiencies in behavior, communication
and socialization. Recent research has shown that different genetic
factors are implicated in the aetiopathogenesis of ASD, including point
mutations of several genes (such as NRXN1, NLGN3, NLGN4) as well
as copy number variants on many chromosomes.
We describe a 6-year-old male with a 1.2 Mb de novo deletion of
2p16.3 detected by aCGH (Agilent 244K). Most of NRXN1 is missing
and no other known genes are within the deletion. The child has minor
dysmorphic features: triangular open mouth, inverted and supernumerary
nipples. Growth parameters, including head circumference are
within normal limits. At the age of 9 months he had several seizure episodes
successfully controlled with valproic acid. Mental development
is delayed (absent speech) and the patient presents typical autistic
features. Brain MRI was unremarkable.
As the deletion is de novο and the missing segment only encompasses
part of NRXN1, it is highly likely that haploinsuficieny of this gene is
causally related to the patient’s phenotype. This finding will hopefully
shed more light in the NRXN1 function, deletions of which have additionally
been associated with susceptibility to schizophrenia.
P03.076
molecular cytogenetic analysis of a boy with proximal 3q
deletion syndrome
A. Vazna 1 , M. Vlckova 1 , A. Baxova 2 , A. Puchmajerova 1 , J. Djakow 3 , Z. Sedlacek
1 ;
1 Department of Biology and Medical Genetics, Charles University 2nd Faculty
of Medicine and University Hospital Motol, Prague, Czech Republic, 2 Depart-
ment of Biology and Medical Genetics, Charles University 1st Faculty of Medicine
and General University Hospital, Prague, Czech Republic, 3 Department of
Paediatrics, Charles University 2nd Faculty of Medicine and University Hospital
Motol, Prague, Czech Republic.
Interstitial deletions of proximal 3q are rare. To our knowledge 11 cases
have been described in literature, and just one of them was analysed
at the molecular level. The patients show distinct and recognisable
facial dysmorphism with prominent forehead, epicanthal folds, flat and
broad nasal root, and anteverted nares. Structural brain, genitourinary
and musculoskeletal abnormalities are also observed in the majority
of cases. The severity of the phenotype usually correlates with the
deletion size, but a clear genotype-phenotype correlation has not been
established yet.
We present a male patient with prenatally detected hydrops. Karyotyping
of umbilical cord blood showed a large deletion of the proximal
3q (karyotype 46,XY,del(3)(q13.2q21)). Caesarean section in the 34th
week of gestation was performed due to foetal distress. Intensive care
with ventilation support was necessary to combat the apnoea. The
newborn had depressed nasal bridge, hypertelosism, low set ears,
short neck, thick arms, single palmar crease on the right hand, hepato-
and splenomegaly, and hypoplastic penis. Head ultrasound detected
agenesis of corpus callosum. Microarray CGH analysis showed a deletion
between Mb 108.3 and 129.0 of chromosome 3 affecting about
130 protein-coding genes. When compared to other published cases,
the extent of the deletion in our patient is rather large, and this is in accord
his relatively severe phenotype. The detailed analysis of deletion
overlaps and their gene content allows a speculation about the role
of individual genes in the symptoms of the syndrome. Supported by
grants IGA NR/9457-3 and MZO00064203.
P03.077
A new case of proximal interstitial deletion of 6q analysed using
array cGH
M. Vlckova 1 , D. Raskova 2 , M. Trkova 2 , Z. Zemanova 3 , Y. Tan 1 , Z. Sedlacek 1 ;
1 Department of Biology and Medical Genetics, Charles University 2nd Faculty
of Medicine and University Hospital Motol, Prague, Czech Republic, 2 Gennet,
Prague, Czech Republic, 3 Center of Oncocytogenetics, Institute of Clinical
Biochemistry and Laboratory Diagnostics, Charles University 1st Faculty of
Medicine and General University Hospital, Prague, Czech Republic.
Interstitial 6q deletions are relatively rare. About 60 cases have been
described in literature. Three different phenotypic groups according to
the localisation of the deletion have been suggested: proximal (6q11q16),
characterised by upslanted fissures, thin lips and hernias; middle
(6q15-q25), with microcephaly, hypertelorism, intrauterine growth
retardation, respiratory problems and limb malformations; and distal
(6q25-qter), with cleft palate, retinal abnormalities, genital hypoplasia,
and seizures. Hypotonia, ear anomalies, facial dysmorphism and mental
retardation are common to all three groups. The localisation of the
distal breakpoint is more important for the phenotype than the proximal
one.
We present a girl with mental retardation, hypotonia, facial dysmorphism
(high forehead, hypertelorism, epicanthal folds, dysplastic
ears), single palmar crease on the right hand, pectus excavatum, delayed
myelinisation, and bilateral frontal lobe atrophy. Her karyotype
was 46,XX,del(6)(q13q15). The phenotype was in agreement with that
of the proximal 6q deletions. mBAND analysis and high resolution array
CGH showed that the deletion was more centromeric, involving
the 6q11-q14.1 region. The length of the deletion was about 15 Mb
and it contained about 45 protein-coding genes. The distal breakpoint
mapped to intron 1 of the MYO6 gene. The proximal breakpoint was in
the centromeric genome assembly gap. At present we are attempting
to obtain the nucleotide sequence of both breakpoints. To our knowledge,
only 19 patients with proximal 6q deletions have been described,
and none of them was analysed using array CGH. The deletion in our
patient is unique. Supported by grants MZO00064203, MZOVFN2005,
INCORE and CHERISH.
P03.078
Further delineation of the phenotype of the 21q22.11q22.12
deletion encompassing the RUNX gene
C. Popovici 1 , M. Mathieu 2 , J. Andrieux 3 , C. Missirian 1 , A. Receveur 4 , L. Lecerf 5 ,
A. Moncla 1 , M. Goossens 5 , N. Philip 1 ;
1 Hopital d’Enfants de la Timone, Marseille, France, 2 Service Génétique Clini-