2008 Barcelona - European Society of Human Genetics

Normal variation, population genetics, genetic epidemiology
P07.049
Identification of point mutation pattern in the LDLR gene among
Bulgarians with severe hypercholesterolemia
S. Bichev 1,2 , L. Vladimirova-Kitova 3 , J. Genova 2 , R. Kaneva 2 , I. Kremenski 4 , V.
Ganev 5 ;
1 Medical University of Sofia, Sofia, Bulgaria, 2 Molecular Medicine Center, Sofia,
Bulgaria, 3 Medical University of Plovdiv, Plovdiv, Bulgaria, 4 National Genetic
Laboratory, Sofia, Bulgaria, 5 Sofia University, Sofia, Bulgaria.
Familial hypercholesterolemia (FH) is a common, autosomal dominant
disorder of lipid metabolism and is a major risk factor for coronary vascular
disease . FH affects approximately 1 in 500 individuals worldwide .
Mutations in LDLR, APOB and recently described PCSK9 genes have
been associated with this disease . The aim of the present study is
to provide information about the spectrum of point mutations in the
LDLR gene in sample of 200 Bulgarian patients with severe hypercholesterolemia
. We applied Single Strand Conformation Polymorphism
(SSCP) analysis to screen for sequence variations in the coding regions
and splice sites of the LDLR gene . The detected samples with
different SSCP patterns were sequenced . In 29 cases the diagnosis
FH was genetically confirmed. We found 7 point mutations (ex.4bG>A
at 590, ex .9G>A at 1195, ex6C>A at 858, ex .8G>A at 1073 and T>C
at 1061-8, ex .5A>C at 761, ex .11G>A at 1646) and 7 polymorphisms,
one (ex .11C>T at 1705+23) not previously described . Our results have
shown that exons 8, 9, 11 should be considered as “hot- spots” for Bulgarian
population . In 3 out of 9 patients with determined mutations in
the 11th exon we have observed in addition 2 different polymorphisms
- C>T at 1705+23 and C>T at 1617 . On the contrary, exons 16, 17,
18, 2, and the previously described as “hot- spots” exons 3 and 14 did
not show aberrant profiles in the SSCP screening. Exons 7, 13 and 15
appear to be very polymorphic, however no mutations were observed
in those exons .
P07.050
Distribution of FmR1 alleles in two populations with different
ethnic background: madeira (caucasian) and Guinea-Bissau
(sub-sahara African)
A. T. Fernandes1 , A. Ferreira1 , R. Gonçalves1 , R. Vasconcelos2 , A. Brehm1 ;
1 2 Human Genetics Laboratory, University of Madeira, Funchal, Portugal, Pediatric
Service, Central Hospital of Funchal, Funchal, Portugal.
The fragile X syndrome is the most common cause for inherited mental
retardation . This syndrome results from an abnormal expansion of the
CGG repeat in FMR1 gene which causes the inactivity of the gene,
leading to the absence of the FMRP . The frequency of the alleles of
FMR1 polymorphism was analyzed to the Madeira and Guinea-Bissau
populations. Madeira and Guinea-Bissau population show significant
differences (P 35 CGG), a pattern similar to others observed in African
populations but quite different from that of Caucasian populations .
In the Madeira population (n=141) no intermediate or permutated alleles
were identified while in Guinea-Bissau population (n=104) 4 intermediate
alleles (prevalence: 1/26) were observed . These results can
explain why there are no X-fragile reported patients in the Madeira
population of 250 .000 inhabitants .
(cGG)n
mA
(N =141)
GB
( N =104)
7 0 .007 -
8 0 .007 0 .009
13 0 .007 -
14 0 .035 -
16 0 .007 -
19 0 .028 -
20 0 .071 0 .009
21 0 .028 0 .009
22 - 0 .019
23 0 .064 0 .077
24 0 .014 0 .019
25 0 .014 0 .019
27 0 .007 0 .009
28 0 .100 0 .067
29 0 .262 0 .231
30 0 .248 0 .221
31 0 .057 0 .144
32 0 .021 0 .019
33 - 0 .009
34 - 0 .019
35 - 0 .019
36 0 .007 0 .009
38 0 .014 0 .038
39 - 0 .009
40 - 0 .009
41 - 0 .029
43 - 0 .009
He 0 .849 0 .870
P07.051
The genome-wide patterns of variation confirms significant
substructure in a founder population
K. Rehnström 1,2 , E. Jakkula 1,3 , T. Varilo 1,2 , O. Pietiläinen 1 , T. Paunio 1 , N. Pedersen
4 , M. Järvelin 5 , S. Ripatti 1,4 , S. Purcell 3 , M. Daly 3 , A. Palotie 3,6 , L. Peltonen 1,6 ;
1 National Public Health Institute, Helsinki, Finland, 2 University of Helsinki,
Helsinki, Finland, 3 Broad Institute of Harvard and Massachusetts Institute of
Technology, Cambridge, MA, United States, 4 Karolinska Institute, Stockholm,
Sweden, 5 Imperial College, London, United Kingdom, 6 Wellcome Trust Sanger
Institute, Cambridge, United Kingdom.
The genome-wide SNP genotyping platforms enable detailed association
studies, but at the same time offer new insight into population
genetics . Here we present an example of a founder population by scrutinizing
nine geographically distinct Finnish subpopulations representing
different eras in the population history to study the effect of bottlenecks
and isolation using high-density SNP data . We demonstrate that
population substructure and even individual ancestry are detectable
at high resolution and support the concept of multiple historical bottlenecks
resulting from founder effects .
We performed multidimensional scaling (MDS) of pairwise identityby
state (IBS) sharing data to delineate population structure . Within
Finland the two primary dimensions of the MDS-analysis correspond
remarkably with the east-west and north-south directions, respectively,
showing a distribution of individuals corresponding closely with the
geographical distribution of parents’ birthplaces . The youngest subisolates
showed higher IBS similarity compared to other subgroups and
separation using an extremely fine resolution. We analyzed linkage
disequilibrium (LD) and extended regions of homozygosity (ROHs) to
further explore the genomic structure of the subpopulations . Highest
LD and the largest number of long (>10Mb) ROHs was identified in the
youngest regional population and showed a gradual decline of these
measures in older and more outbred, subpopulations .
The study shows the power of GWA data to trace the population history
and also exemplifies the power to identify stratification even within
homogeneous populations. A deeper insight into fine-scale population
substructure also emphasizes the importance of adjustment of GWA
studies aiming at identifying smaller and smaller genetic effects to
avoid confounding .
P07.052
Epidemiological study of Fraser syndrome in Europe
L. Odak 1 , I. Barisic 1 , V. Tokic 1 , M. Loane 2 , F. Bianchi 3 , E. Calzolari 4 , E. Garne 5 ,
D. Wellesley 6 , H. Dolk 2 ;
1 Childrens Univ. Hospital Zagreb, Zagreb, Croatia, 2 EUROCAT Central Registry,
University of Ulster, Newtonabbey, Co Antrim, United Kingdom, 3 Unit of
Epidemiology, CNR Institute of Clinical Physiology, Pisa, Italy, 4 Department of