European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Genetic analysis, linkage, and association
controls with clinically verified benign prostatic hyperplasia. DNA was
extracted from venous blood and genotyping of a set of 17 SNPs at the
SDR5A2 locus was carried out by PCR and cycling-gradient capillary
electrophoresis (CGCE), a technique based on heteroduplex analysis
in temperature gradient. Case-control association analyses were performed
using PLINK (http://pngu.mgh.harvard.edu/~purcell/plink/data.
shtml).
Results: We have identified 5 SNPs showing significant allele frequency
and genotype distribution differencies between cases and controls. The
SNP markers with their respective p values are: rs4952219 (p=0.0186),
rs413836 (p=0.0261), rs2300697 (p=0.0124), rs2208532 (p=0.0142)
and a novel marker assigned as SRD5A2_SNP4 (p=0,0358). In addition
we have identified 5 haplotypes showing strong association with p
values between 0,001 and 0,005.
Discussion: Many of the significant SNP markers are from noncoding
regions, therefore the haplotype association may mostly be related to
alternate gene regulation. Haplotype analyses on a larger patient cohorts
is desirable in order to evaluate potential of the identified SNPs
and haplotypes for identification of risk groups.
This project was supported by Czech Ministry of Health grant no.
8039-3.
P1079. Linkage to 13q in a novel autosomal dominant
pseudoarthrogryposis-like syndrome
S. A. Ugur 1 , D. Gul 2 , A. Tolun 1 ;
1 Bogazici University, Department of Molecular Biology and Genetics, Istanbul,
Turkey, 2 Gülhane Military Medical Academy and Medical Faculty, Department of
Medical Genetics, Ankara, Turkey.
Distal Arthrogryposis (DA) Syndromes are characterized by nonprogressive,
congenital contractures of two or more different body areas
without primary neurological and/or muscle disease that affects limb
function. Features common to all DA syndromes include a consistent
pattern of distal joint involvement, limited proximal joint involvement, an
autosomal dominant inheritance pattern, and widely variable expressivity.
Mutations in genes encoding the fast skeletal muscle regulatory
proteins troponin T, troponin I, and beta-tropomyosin have been shown
to cause DA syndromes. Pseudoarthrogryposis-like syndrome (PAG-
L), a novel disorder, has been observed in a large Turkish kinship.
Manifesting multiple contractures in patients, and an autosomal dominant
mode of inheritance, the syndrome may be classified as a new
form of DA. However, PAG-L is progressive with a preadolescence age
of onset, which makes it distinct from DA syndromes. A genome-wide
scan has identified a locus on chromosome 13q suggestive for linkage.
Further genotyping in the candidate locus with additional family
members is in progress.
P1080. Genome-wide association studies for complex diseases
using samples from the Quebec founder population: examples
with psoriasis and ADHD
B. Paquin, J. Raelson, P. Van Eerdewegh, V. Bruat, P. Croteau, J. Segal, S.
Debrus, J. M. Vidal, M. Lapalme, S. Kebbache, J. W. Hooper, A. Belouchi, T.
Keith;
Genizon BioSciences, St. Laurent, PQ, Canada.
Genizon is involved in the discovery of disease susceptibility genes
in more than 20 diseases using samples from the Quebec founder
population (QFP). We have successfully completed nine genome-wide
association studies for complex diseases. To illustrate our process and
the evolution of our strategy, examples from the psoriasis and ADHD
studies are shown. The psoriasis study was performed using 500 trios
and a custom marker map of 80,654 SNPs spaced according to the
variation in the extent of local LD across the genome in the QFP. The
ADHD study was performed using 459 trios with an upgraded custom
marker map of 374,187 SNPs, consisting of the HAP300 chip from Illumina
supplemented by 56,683 SNPs, optimizing the SNP selection
to the QFP samples. For both studies, single-marker and haplotype
association analyses were performed and genome-wide significance
of the obtained P values was evaluated based on permutation tests.
For both studies, regions with P-values that met the criteria of genomewide
significance were identified. We describe the identified regions
and the encoded genes. Many regions contained a single, druggable
gene representing immediate opportunities for drug development and
genes with biologically relevant function. Genes in novel pathways
were identified in both studies. Additional disease genes were also
found from conditional and sub-phenotype analyses. The disease
genes were then used to infer a GeneMap that consists of a network
of interacting disease genes and their biological pathways. The shown
GeneMap reveals the genetic etiology of the disease and represents a
comprehensive tool toward personalized medicine.
P1081. Genetic refinement of PSORS4 and ATOD2 susceptibility
loci in Italian samples
C. Sinibaldi 1 , N. Paolillo 1 , E. Giardina 1 , C. Peconi 1 , L. Chini 2 , V. Moschese 2 , P.
Rossi 2,3 , S. Chimenti 4 , S. Nisticò 4 , E. Galli 5 , G. Girolomoni 6 , G. Novelli 1,5,7 ;
1 Department of Biopathology, Centre of Excellence for Genomic Risk Assessment
in Multifactorial and Complex Diseases, School of Medicine, Tor Vergata
University, Rome, Italy, 2 Department of Pediatrics, Tor Vergata University,
Rome, Italy, 3 Division of Immunology and Infectious Disease, Department of
Pediatrics, Children’s Hospital ‘Bambino Gesu, Rome, Italy, 4 Department of
Dermatology, Tor Vergata University, Rome, Italy, 5 San Peter Hospital, Fatebenefratelli,
Rome, Italy, 6 Department of Biomedical and Surgical Sciences,
Section of Dermatology, University of Verona, Verona, Italy, 7 Department of
Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little
rock, AR, United States.
Psoriasis (PS) and atopic dermatitis (ATOD) are chronic inflammatory
skin disorders triggered by both genetic and environmental factors. A
susceptibility locus mapped on chromosome 1q21 have been identified
in both the diseases (PSORS4-ATOD2). Recently we refined the
PSORS4 and ATOD2 susceptibility loci by using a LD approach in two
cohorts of 128 PS and 120 ATOD Italian trios. We showed that PS and
ATOD shared a risk-haplotype defined by STRs markers MIDDLE and
ENDAL16. We failed to reveal evidence of association for LOR gene
located within the risk-haplotype although a differential gene expression
has been observed in PS and ATOD.
In order to reveal the identity of the susceptibility factor of PSORS4
and ATOD2 we newly refined the risk haplotype and its surrounding
chromosomal regions (650 Kb) by typing a selection of 31 SNPs in our
familial cohorts of trios.
Preliminary statistical analysis identified three distinct associated haplotypes
within the selected region: the first, Hap1 (9.7 kb) generated
significant association in both the diseases (PS p-value 0.0229; ATOD
p-value 0.0077), the second, Hap2 (8.8 kb) is associated in the only
ATOD cohort (p-value 0.0257); the third, Hap3 (38.5 kb) generated
significant p-value in the only PS cohort ( p-value= 0.0270).
The weakness of association data reported could reflect the low penetrance
of PSORS4 and ATOD2 but need to be confirmed in additional
samples. Threfore, an independent set of sporadic psoriatic patients
(n=300) and further 60 ATOD trios are being typed at the moment.
Acknowledgements: This work was supported by A.DI.PSO
P1082. Detection of large deletion of 4.5 Mb in PTCH region in a
Croatian Gorlin syndrome case by semi-quantitative fluorescent
multiplex PCR
V. Musani 1 , A. Basta-Juzbašić 2 , P. Gorry 3 , S. Levanat 1 ;
1 Department of molecular medicine, Rudjer Boskovic Institute, 10000 Zagreb,
Croatia, 2 Department of Dermatovenerology, University School of Medicine,
University of Zagreb, 10000 Zagreb, Croatia, 3 Laboratoire de Génétique, Développement
& Cancer, Université V. Ségalen, Bordeaux, France.
Gorlin syndrome or Nevoid Basal Cell Carcinoma Syndrome (NBCCS)
is a rare autosomal dominant disorder characterized by developmental
abnormalities, cysts of the skin, jaws, and mesentery and cancer predisposition
to basal cell carcinomas (BCC), medulloblastomas, meningiomas,
fibromas of the ovaries and heart.
The syndrome is caused by mutations in the human homolog of the
Drosophila patched gene, PTCH. PTCH is a tumor supressor gene,
located at 9q22.3, and encodes a 12 transmembrane glycoprotein that
acts as an antagonist in the Hedgehog signaling pathway.
We present a Gorlin syndrome patient with typical phenothypical features
of widespread basal cell carcinomas, jaw malformations, strabismus
and mental retardation, with family history that beside basal
cell carcinomas includes lung cancer and gastrointestinal carcinomas.
Since we found no mutations in exons of PTCH gene with conventional
methods of SSCP, dHPLC screening and direct sequencing, we developed
a new method of semi-quantitative fluorescent multiplex PCR
with polymorphic markers surrounding PTCH gene. With this method
we defined a deletion of 4.5 Mb in size between markers SHGC-
110746 and SHGC-132418 (9q22.3-9q31.1).
2