2009 Vienna - European Society of Human Genetics

Complex traits and polygenic disorders
Results: Significant association between analyzed IRF6 gene SNPs
was found in different study groups. In patients with CLP/CL four of
seven SNPs showed significant association with P value < 0.05. CP patient
group showed the stongest association with two SNPs (rs658860,
rs642961), P value < 0.001.
Conclusion: Obtained results showed IRF6 gene as important contributing
factor in CP etiology with some impact on CLP/CL patients what
allow us to hypothesize that IRF6 gene possibly is one of the major
gene in the development of isolated cleft palate.
P09.028
Cleft palate caused by 12q24.33 amplification
L. Desmyter 1 , A. Ghalamkarpour 1 , M. Ghassibe 1 , H. Antoine-Poirel 2 , C.
Labrèze 3 , F. Morice-Picard 4 , M. Vikkula 1 ;
1 Laboratory of Human Molecular Genetics, de Duve Institute, Brussels, Belgium,
2 Centre de Génétique Médicale - Secteur Hématologique, Cliniques
universitaires Saint-Luc, Brussels, Belgium, 3 Unité Dermatologie Pédiatrique,
Hôpital Pellegrin Enfants, Bordeaux, France, 4 Unité de Génétique Médicale,
CHU Bordeaux, Bordeaux, France.
Orofacial clefts are the most frequent craniofacial malformations in humans.
Occurrence estimates range between 1/500 and 1/2500 births
for cleft lip with or without palate (CL/P) and around 1/2000 births for
cleft palate only (CPO). The majority of clefts are isolated, nonsyndromic.
The remaining syndromic cases are subdivided into categories
on the basis of chromosomal abnormalities, Mendelian single gene
syndromes, teratogenic effects and of unknown cause. We performed
chromosomal and molecular karyotyping using Affymetrix GeneChip
SNP chips on a total of 200 individuals with CL/P or CPO. In one female
patient we observed a 3Mb duplication encompassing the region
12q24.3-qter and a 1Mb deletion of the telomeric part of the 22q13.3
region. The girl was the only affected member of the family and presented
congenital progressive lymphedema, hypotonia, mental retardation,
facial dysmorphism and CPO indicative of a 22q13 deletion
syndrome, also known as the Phelan-McDermid syndrome. Interestingly
she had CPO, a feature not linked to this well characterized syndrome.
We hypothesize that the presence of CP is due to the trisomy
12qter. This locus has not been incriminated in CL/P nor CPO before.
This study shows that molecular cytogenetics is a valuable tool for the
identification of new genes related to complex diseases.
P09.029
FAF1 is Associated with cleft Palate and Pierre Robin sequence
M. Ghassibe1 , L. Desmyter1 , B. Bayet2 , N. Revencu1 , R. Vanwijck2 , M. Vikkula1 ;
1 2 de Duve Institute, Brussels, Belgium, Centre Labiopalatin, Cliniques universitaires
St Luc, Brussels, Belgium.
Nonsyndromic clefts occur in a wide geographic distribution with an
average prevalence of 1/700. Genetic factors involved in cleft lip and
palate (CL/P) are thought to be different from those having a role in
cleft palate only (CPO). We have recently reported FAF1 as a new
gene responsible for CPO and Pierre Robin sequence (PRS). Moreover,
we showed that Faf1 is needed for craniofacial development in
human, mouse and zebrafish.
In order to replicate our positive association study, we conducted TDTs
in an independent series of 160 European families with CL/P. The
same FAF1 variant as in our first study was genotyped. In the replication,
FAF1 showed positive tendency for association only in the CPO/
PRS subgroup (p=0.09). Pooling together our 500 patients reinforced
the earlier association, giving a more stringent p-value of 0.001 for the
CPO/PRS subgroup. In order to identify other genes contributing to
the occurrence of this multifactorial condition, we are testing in parallel
association of IRF6 and SATB2, two cleft genes, to the cleft condition
in our 500-patient cohort. Preliminary results suggest that, contrary to
FAF1, IRF6 predisposes to CL/P, but not to CPO.
This illustrates the benefit of testing greater number of patients in
complex diseases in order to well delineate the true predisposed subgroups.
Moreover, it confirms that FAF1 and IRF6 play a role in the
occurrence of isolated complex clefts, but most likely in distinct pathways.
P09.030
Large cNVs are involved in the pathogenesis of schizophrenia
G. Kirov, D. Grozeva, N. Norton, D. Ivanov, K. Mantripragada, P. Holmans, N.
Craddock, M. Owen, M. O’Donovan;
Cardiff University, Cardiff, United Kingdom.
We investigated the involvement of rare (< 1%) CNVs in 471 cases
of schizophrenia recruited in the UK, and 2792 controls from the UK,
used by the Wellcome Trust Case Control Consortium. All samples
had been genotyped with the Affymetrix GeneChip 500K Mapping Array.
We accepted only CNVs >100kb identified independently on both
arrays (Nsp and Sty), with at least 10 SNPs each. Large CNVs >1Mb
were 2.26 times more common in cases (p=0.00027), with the effect
coming mostly from deletions (OR=4.53, p=0.00013) although duplications
were also more common (OR=1.71, p=0.04). Two large deletions
were found in two cases each, but in no controls (Fisher Exact Test
p=0.02): a deletion at 22q11.2 known to be a susceptibility factor for
schizophrenia, and a deletion on 17p12, at 14,0-15,4Mb. The latter is
known to cause hereditary neuropathy with liability to pressure palsies
(HNPP). Another large deletion affects neurexophilin (NXPH2), a gene
that interacts with neurexins. NRXN1 was also disrupted by deletions
in one case and three controls (0.2% vs 0.1%, p=0.5).
One large duplication on 16p13.1, between 15,0 and 16,2Mb, was
found in three cases and six controls (0.6% vs 0.2%, p=0.13). It has
been previously implicated as a susceptibility factor for autism by Ullmann
et al (2008). The largest duplication, of 5Mb, was in a schizoaffective
case and involved the Prader-Willi/Angelman Syndrome critical
region, and is a known susceptibility factor for autism.
This study confirms the involvement of rare and large CNVs in the
pathogenesis of schizophrenia.
P09.031
No association of polymorphisms within the cD44 gene and the
coeliac condition
C. Vidal1,2 , A. Xuereb-Anastasi1 , C. A. Scerri3 ;
1 2 Institute of Healthcare, Msida, Malta, Department of Pathology, Msida, Malta,
3Department of Physiology and Biochemistry, Msida, Malta.
Coeliac disease is a complex disorder characterised by inflammation,
villous atrophy and hyperplasia of the intestinal mucosa in genetically
susceptible individuals, upon exposure to dietary gluten. Sequencing
of the CD44 gene at locus 11p13-12, revealed a number of sequence
variants, one of whom (rs1071695) was linked with an inherited haplotype
identified in a previous linkage study.
Three single nucleotide polymorphisms (rs1071695, rs3736812,
rs1467558) within the CD44 gene were tested by restriction fragment
length polymorphism in a group of coeliac individuals (n=92) and controls
(n=248). The mean age at diagnosis for the coeliac group was
34 years, with the predominant presenting symptoms being gastrointestinal.
Genotype frequencies observed for all three polymorphisms studied
were in Hardy-Weinberg equilibrium (p>0.05). When testing for linkage
disequilibrium (LD) between polymorphisms within the control
group the rs1071695 variant in exon 3 was in LD with rs3736812 in
exon 4 (p=0.004) but not with rs1467558 in exon 11. The latter, was
in LD with rs3736812 (p=0.003). In the celiac group, LD was only observed
between rs3736812 and rs1467558 (p=0.036; Fisher’s exact
test). No significant association of individual polymorphisms or combined
genotypes was observed with the coeliac condition in the studied
population. Also no significant association was observed between
constructed haplotypes and the coeliac condition (χ2=4.56; p=0.713;
df=7). No association with coeliac was observed between any of the
studied SNPs, including the linked variant identified by linkage, in this
population based study.
P09.032
Novel insights into pathogenesis of coeliac disease: a second
genome-wide association study
G. Trynka 1 , P. C. Dubois 2 , J. Romanos 1 , L. Franke 1 , A. Zhernakova 3 , V. M.
Wolters 4 , G. A. Heap 5 , K. A. Hunt 5 , R. J. Houwen 4 , C. J. Mulder 6 , R. Gwilliam 7 ,
P. Saavalainen 8 , D. Barisani 9 , M. T. Bardella 10 , P. Deloukas 7 , R. McManus 11 , D.
A. Van Heel 5 , C. Wijmenga 1,3 ;
1 Department of Genetics, University Medical Center Groningen, Groningen,
The Netherlands, 2 Institute of Cell and Molecular Science,Barts and The
London School of Medicine and Dentistry, London, United Kingdom, 3 Depart-