2008 Barcelona - European Society of Human Genetics

Cytogenetics
Medizin München, Munich, Germany.
We investigated 98 children referred for unexplained mental retardation
using Hap550 oligonucleotides arrays (Illumina) . Conventional
karyotyping did not reveal any abnormality . Data analysis were performed
with median normalization and genotypes-specific dosage calculation
using R-scripts . We used standard deviation (mean SD: 0 .15)
and mean absolute deviation (mean MAD: 0 .11) of the log2 intensity
ratios to assess data quality . We also calculated a signal-to-noise ratio
(mean SNR: 5 .44) in male DNA samples (median log2 intensity ratio
of the X-chromosomal SNPs minus median log2 ratio of the autosomal
SNPs divided by MAD) . 254 candidate regions were evaluated with 2
or 3 quantitative PCRs each . 58% were determined to be true-positive
findings. Our experiments are likely to underestimate the true positive
rate because we excluded all known CNV polymorphisms . Under the
assumption that all detected know CNV polymorphisms are true positive,
this rate would be 89 .7% . 65 .5% of the false positive CNVs were
detected in regions defined by 20 SNPs . Preliminary results revealed 15 de novo CNVs, 13
deletions and 2 duplications (15%), which varied in size from 125 kb to
13 Mb . Seven CNVs were known genomic disorders . Two CNVs overlapped
approximately 0 .9 Mb with a DECIPHER entry . The remaining
6 CNVs were not described before .
ID Chromosome
Gain/
Loss
Position Start
(UCSC hg18)
Position End
(UCSC hg18)
Number Length Known
of SNPs (Mb) Syndrome
1 1q44 Loss 241 .559 .266 241 .684 .687 18 0,125 no
2 17p13 .1 Loss 7 .054 .704 7 .348 .051 57 0,293 no
3 13q32 .2 Loss 99 .000 .207 99 .549 .209 156 0,549 yes
4 19p13 .3 Loss 218 .039 1 .103 .656 180 0,885 no
5 1q43-q44 Loss 241 .477 .990 24 .3498 .562 398 2,021 yes
6 16q22 .2-q23 .1 Loss 70 .464 .098 74 .053 .487 722 3,589 no
7 7q31 .2-q31 .31 Loss 113 .212 .019 117 .409 .113 593 4,197 yes
8 12q24 .31-q24 .32 Loss 120 .674 .768 125 .508 .628 875 4,834 no
9 15q11 .2-q13 .1 Loss 21 .200 .233 26 .208 .861 1 .130 5,009 no
10 16p11 .2-p12 .2 Loss 21 .512 .681 29 .223 .380 1 .373 7,711 yes
11 2q37 .1-q37 .3 Loss 233 .320 .827 242 .656 .041 2 .254 9,335 yes
12 6q25 .3-q27 Loss 157 .812 .841 170 .723 .055 3 .545 12,910 no
13 6p22 .1-p23 Loss 14 .554 .649 27 .849 .661 3 .265 13,295 no
14 22q11 .21-q11 .23 Gain 17 .345 .628 22 .757 .878 1 .155 5,412 yes
15 16q11 .2-q12 .2 Gain 45 .096 .893 53 .506 .358 1 .453 8,409 no
P02.039
Elucidation of complex structural Variations at 17q21.3, the NSF
Locus
G. W. Tam, K. Porter, N. Carter, S. Grant, R. Redon;
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
Multiple studies have recently described extensive structural variation
in the human genome . Among the regions with most extensive variation,
the 17q21 .31 locus harbours a complex architecture, with several
structural variants previously associated with abnormal phenotypes .
This locus is the site of a ~900kb inversion polymorphism responsible
for two divergent haplotypes, named H1 and H2 . In addition, the H1
haplotype is divided into subtypes which show considerable structural
heterogeneity . While the H2 haplotype has been associated to one
microdeletion syndrome causing learning disability and dysmorphic
features, certain H1 sub-haplotypes have been linked to neurodegenerative
disorders, including progressive supranuclear palsy and frontomental
dementia . By using published copy number variation data on
270 HapMap individuals, we have defined several structural variations
within the 17q21 .31 locus, including a duplication polymorphism involving
the 5’ portion of the N-ethylmaleimide sensitive factor (NSF) gene
and a second distinct CNV upstream of NSF, which is detected only in
European individuals on both H1 and H2 alleles . CNV breakpoints in
each sub-type were also delineated using high-resolution oligo array .
We have further developed a set of quantitative PCR assays to resolve
the different H1 and H2 sub-haplotypes . Given the previous association
of the 17q21 .31 locus with disease and the presence in this interval
of several genes related to the brain function, this new genotyping
assay will be a valuable resource for testing the involvement of H1/H2
subtypes in neuro-psychiatric disorders .
P02.040
A Novel familial 2q32 duplication associated with distinct
behavioural phenotype
S. G. Mehta 1 , C. Shaw-Smith 1 , E. Kivuva 1,2 , R. Reading 3 , G. Parkin 1 , I. Simonic
1 , L. Willatt 1 ;
1 Department of Medical Genetics, Addenbrookes Hospital, Cambridge, United
Kingdom, 2 2. Department of Clinical Genetics, Royal Devon and Exeter Hospital,
Exeter, United Kingdom, 3 3. Department of Paediatrics, Norfolk and Norwich
Hospital, Norwich, United Kingdom.
We have identified a patient with a novel 4 megabase duplication of
2q32 .2-q32 .3 chromosome region using GeneChip 250K Nsp SNP
array from Affymetrix . The proband has global developmental delay,
speech delay, and is aggressive with violent behaviour towards others
and a tendency towards self-mutilation . She has foraging behaviour
leading to obesity . She has striking blonde, dry, wiry hair, straight eyebrows
and low-set ears . She has brachydactyly, and 5 th finger clinodactyly
. Her feet are broad, with a sandal gap, short toes and mild 2/3
toe syndactyly . The FISH studies have shown that this 4 megabase
duplication has been inherited from her mother who has depression,
and left school without any qualifications suggestive of a lower than
average IQ . An unaffected sibling has not inherited the duplication . A
recent report of a larger 2q32 deletion partially overlaps the duplication
in this family . The duplicated region includes INPP1, previously
implicated in bipolar disorder, and COL3A1 and COL5A2, which are
candidate genes for wrinkly skin syndrome but the proband does not
share any characteristics of this syndrome except the mental retardation
. Similarities with patients with the larger 2q32 deletion include a
common behavioural phenotype and hair abnormalities . This suggests
that copy number variation of 2q32 is a necessary, but perhaps not sufficient
component for the behavioural phenotype and further analysis
of the minimum region of overlap may help to identify important genes
involved with this in particular . We discuss the clinical phenotype, review
the literature, and discuss the difficult counselling issues involved
where the link between submicroscopic DNA copy number change and
phenotype is unclear .
P02.041
Confirmation of the new microdeletion syndrome of 16p11.2p12.2
A. Battaglia 1,2 , A. Novelli 3 , L. Bernardini 3 , T. Filippi 1 ;
1 Stella Maris Clinical Research Institute, Calambrone (Pisa), Italy, 2 Division
of Medical Genetics, Dept Pediatrics, University of Utah, Salt Lake City, UT,
United States, 3 Ospedale CSS-IRCCS, San Giovanni Rotondo e Istituto CSS
Mendel, Roma, Italy.
We have identified a pericentromeric deletion, spanning about 8.2 Mb,
in 16p11 .2-p12 .2, in a patient with DD and dysmorphic features, by
aCGH . This deletion arose de novo and is flanked by segmental duplications
. The proposita was the only child of healthy non-consanguineous
parents, born after an uneventful pregnancy, at 40 weeks gestation,
by normal delivery . She suffered from perinatal distress . Birth
weight was 2,740 g, length 48 cm, and OFC 33 cm . Family history is
non-contributory . Hypotonia and DD were present from early on . She
started walking alone at 18/12. We first saw her at age 3 10/12 years.
On examination, there were flat face; low-set, posteriorly rotated ears;
high-arched palate; hypotonic face; left single palmar crease; long, thin
fingers; a sacral dimple; and no speech. Height was at the 50th centile,
weight at the 25th, and OFC at the 30th . DNA FraX , HRB, metabolic
work-up, audiologic evaluation, brain MRI, electroencephalogram,
heart/abdomen ultrasonography were normal . When last seen, aged
7 7/12 years, she had a mild-moderate MR, with a comprehension
of a 4-year-old child, and was able to pronounce simple words and a
few telegraphic phrases . Hypotonia was still present . Over the 3 9/12
years follow-up, we observed a slow, but constant, overall improvement
. Our patient shows common clinical features to the four individuals
described by Ballif et al (2007), and aCGH suggests that the deletions
of all cases share the same distal breakpoint . Our observation
validates the possibility that deletions in 16p11 .2-p12 .2 constitute a
distinct syndrome .
P02.042
complex genomic structure underlying an interrupted
microdeletion in 16p11.2-p12.1 with breakpoints mapping to nonhomologous
LcRs
B. Nowakowska 1 , A. Midro 2 , B. Panasiuk 2 , D. Rychter 3 , P. Stankiewicz 4 , E.
Bocian 1 ;
1 Institute of Mother and Child, Warsaw, Poland, 2 Medical University Białystok,
Bialystok, Poland, 3 University Hospital Leuven, Leuven, Belgium, 4 Baylor College
of Medicine, Houston, TX, United States.
The LCR-rich proximal chromosome 16p has been shown recently
to be associated with the novel genomic disorders: the 7 .1-8 .7 Mb
microdeletion 16p11 .2-p12 .1, and the proximally adjacent, recurrent