2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
well-recognized genetic component based on family and twin studies .
However, no genetic variants have been convincingly established for
common forms of migraine . In about 30% of all migraine attacks visual,
sensory or dysphasic symptoms precede the headache phase
manifesting migraine with aura (MA) . Here, we present the results of a
genome-wide linkage scan on 37 Finnish migraine families having visual
aura symptoms . The families were extracted from a large Finnish
migraine patient collection ascertained from neurology clinics nationwide
during the last 15 years . For this study the families presenting
with migraine with typical aura (according to the International Headache
Society (IHS) criteria) were selected. Data on IHS defined attack
symptoms as well as other clinical features were collected using the
validated Finnish Migraine Specific Questionnaire for Family Studies
and by a neurologist’s examination of index patients . We genotyped
372 individuals using microsatellite markers with an intermarker distance
of 10 cM. We detected a locus on 9q31 with significant evidence
of linkage (HLOD 4 .5 at 104 cM) using two-point parametric linkage
analysis . Multipoint parametric and non-parametric analyses support
this finding. An additional set of microsatellite markers is currently genotyped
to maximize linkage information across the region . In conclusion,
our finding indicates a locus for visual aura on 9q31 region previously
linked to epilepsy in a Belgian family also suffering from MA .
P06.152
Haplotype analysis for 12 loci in 11 small Portuguese families
with autosomal recessive non-syndromic hearing loss
H. Teixeira 1,2 , T. Matos 1 , F. Moreno 2 , G. Fialho 1 , H. Caria 1,3 , I. del Castillo 2 ;
1 Center of Genetics and Molecular Biology, University of Lisbon, Lisbon, Portugal,
2 Unidad de Genética Molecular, Hospital Ramón y Cajal, Madrid, Spain,
3 Higher College of Health, Polytechnic Institute of Setúbal, Setúbal,, Portugal.
Mutations in DFNB1 were shown to account for ~19% of the cases of
congenital deafness in the Portuguese population . The cause of deafness
in the remaining cases, including the GJB2/GJB6 monoallelic
ones, has to be elucidated . We have thus performed linkage analysis
in order to investigate the spectrum of genes/mutations responsible for
hearing impairment in the Portuguese population .
This study was conducted in eleven small families with apparent nonsyndromic
congenital deafness . Haplotype analysis was performed for
DFNB1, DFNB4, DFNB7/11, DFNB8/10, DFNB9, DFNB12, DFNB18,
DFNB28, DFNB35, DFNB49, DFNB59 and DFNB67, using at least
three microsatellite markers for each locus . Sequencing analysis of
the related genes was carried out in the case of compatibility with linkage
.
In a consanguineous family we found compatibility with linkage to
DFNB4 with autozygosity for this region . Sequencing of the SLC26A4
gene revealed a novel mutation, c.1615 -2 A>G (IVS14 −2 A>G), in
homozygosity in the severely deaf siblings . In a non-consanguineous
family, we found compatibility with linkage to DFNB8/10 in heterozygosity
. Sequencing of the TMPRSS3 gene revealed a known mutation,
c .646C>T (p .Arg216Cys), in compound heterozygosity with a novel
mutation that affects the LDLA domain of the protease, c .346G>A
(p .Val116Met), in the profoundly deaf siblings . In both families, the
genotype is likely to be the cause of deafness .
These are the first DFNB4- and DFNB8/10-related cases of deafness
described in Portuguese families, which also provide a first evidence of
the genetic heterogeneity of deafness in the Portuguese population .
P06.153
combined linkage analyses of four isolated populations suggest
novel loci for plasma lipid concentrations
A. Isaacs 1 , H. Campbell 2 , U. Gyllensten 3 , T. Meitinger 4 , B. Oostra 1 , P. Pramstaller
5 , I. Rudan 6 , A. Wright 7 , Y. Aulchenko 1 , C. van Duijn 1 ;
1 Erasmus University MC, Rotterdam, The Netherlands, 2 University of Edinburgh,
Edinburgh, United Kingdom, 3 University of Uppsala, Uppsala, Sweden,
4 Technical University Munich, Munich, Germany, 5 Institute of Genetic Medicine,
Eurac Research, Balzano, Italy, 6 University of Split Medical School, Split, Croatia,
7 Western General Hospital, Edinburgh, United Kingdom.
Despite considerable progress in elucidating genetic influences underlying
circulating lipid levels, large proportions of the variance of
these traits remain unexplained . In this study, data from four genetically-isolated
populations, located in the Netherlands (n eff =1218), Italy
(n eff =918), Sweden (n eff =409), and Croatia (n eff =537) were synthesized
in an effort to increase statistical power to detect genomic regions
which may be involved in total cholesterol (TC), low-, and high-density
lipoprotein cholesterol (LDL-c and HDL-c) levels . Quantitative multipoint
linkage analyses of the four populations were performed individually,
utilizing an integrated map, with SOLAR . LOD scores were combined
post-hoc, and adjusted thresholds were calculated to account
for multiple testing . Diabetics and subjects receiving lipid-lowering
therapy were excluded from analysis . Two models were implemented:
age- and sex-adjusted; and age-, sex-, BMI-, alcohol consumption-
, and smoking-adjusted . Numerous regions surpassed a suggestive
linkage threshold corresponding to LOD=1 .9 in either the combined
sample or in an individual population . For TC, regions centered on
1q21 .3 (LOD max =3 .21) and 9q31 .1 (LOD max =2 .54) were determined;
the chromosome 9 region was also suggestive for LDL (LOD max =3 .22) .
HDL peaks exceeded the threshold at 2p21 (LOD max =3 .77), 10q21 .1
(LOD max =2 .50), 16q12 .2 (LOD max =3 .54), and 21q21 .1 (LOD max =3 .66) .
The HDL peak on chromosome 2 was also detected for TC/HDL-c ratio
(LOD max =2 .48), as was a peak located at 1p31 .2 (LOD max =3 .74) .
The latter was also identified for LDL-c/HDL-c ratio (LOD max =3 .70), in
addition to a peak at 22q11 .2 (LOD max =3 .03) . These peaks, many of
which are novel, contain numerous promising candidate genes . The
EUROSPAN Consortium is currently analysing dense sets of single
nucleotide polymorphisms underlying these peaks .
P06.154
Linkage based on a single family--family size requirement
W. Yang, Y. Lau;
University of Hong Kong, Pokfulam,, Hong Kong.
Determination of required family size for linkage studies is not a simple
task . With genotyping of high-density single nucleotide polymorphism
(SNP) markers replacing that of microsatellite markers in linkage studies,
it is possible to accurately determine the genomic regions shared
by family members, including remote relatives . This may allow linkage
studies to be conducted in a more deterministic fashion . Based on
this advancement, we developed a simple method to allow the users
to evaluate the inheritance information that can be extracted from
their diseased family collection in linkage studies . This includes the
total number of linked regions expected to be identified for the family
under study, the expected sizes for the linked regions, and the portion
of the genome that can be excluded from consideration . We presented
a detailed discussion on family size requirement for linkage
studies by analyzing some typical family structures, and demonstrated
the feasibility of linkage studies on smaller families which are thought
not sufficient by classical linkage analysis methods. Simulation results
by our program showed that the linked regions containing true mutations
are usually larger than regions linked due to random chance . We
have made use of this feature in our program to allow evaluation of the
linked regions through a Bayesian probability calculation .
P06.155
Genetic diversity and structure of linkage disequilibrium in the
mtHFR locus
E. Trifonova, M. Spiridonova, V. Stepanov;
Institute for Medical Genetics, Siberian Branch of Russian Academy of Medical
Sciences, Tomsk, Russian Federation.
Methylenetetrahydrofolate reductase (MTHFR) is a key ferment of folate
cycle, which catalyzes for the conversion of 5,10-methylenetetrahydrofolate
to 5-methyltetrahydrofolate . The reduction to activities of this enzyme,
often conditioned presence of the certain combinations of alleles of MTH-
FR gene, brings to increase the concentrations of homocystein in blood .
In the presented work we explored genetic differentiation and structure
of linkage disequilibrium in MTHFR gene in population of the Russians,
Tuvinians, north and south Kirghizes, using the set of SNPs: rs17037397,
rs4846052, rs1801133, rs1801131 and rs1537516 . In the total sample
19 out of 32 possible haplotypes were found (from 10 + 16 per population)
. The majority of genetic diversity is comprised by 8 main haplotypes,
which accounted for 78% of all chromosomes. The population-specific
patterns of linkage disequilibrium (LD) at MTHFR locus was revealed . In
populations of the Russians, Tuvinians and north Kirghizes 2 LD blocks
were found, where as south Kirghizes demonstrates strong linkage of
all SNPs, within the single block. The significant genetic differences are
discovered between population south Kirghizes and all explored group,
as well as between Russians and Tuvinians . Genetic and demographic
mechanisms of LD formation in local populations are discussed .