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

Genetic analysis, linkage, and association
ity and find novel loci for the MetS (IDF, 2003) and correlate inflammation
and visceral obesity with MetS, in a Dutch isolate.
Methods: The Erasmus Rucphen Family study (ERF) consists of some
3000 individuals that descend form a limited set of founders. Waist circumference
(WC), blood pressure, HDL-C, triglycerides and glucose
levels were obtained. Variance component analysis was applied to extended
family data to test for evidence of heritability (SOLAR).
Results: The prevalence of MetS, according to the IDF definition, in
the ERF cohort is 36.8% in males and 31.0% in females. Our results
indicate that HDL-C and WC are the main contributors to the MetS.
Heritability of the MetS (as binary trait) was 14.3% (P < 0.0001). The
heritability for the MetS corrected for household, decreased to 10.6%
(P = 0.012). Also the heritability of individual components of MetS were
analyzed (as quantative traits). The highest heritability was obtained
for HDL-C (42.9%, P < 0.0001).
Discussion: The heritabilities of MetS in the ERF population are found
to be highly significant. Moreover, our results indicate that the HDL-C
component is a main contributor to the MetS and was found to have
the highest individual heritability. Our data on prevalence and heritability
of the MetS, indicate that determining loci for MetS by linkage
analysis, with emphasis on the individual traits, is feasible.
P1024. Homozygous silencing of the T-box transcription factor
TBR2/EOMES locus. Results in a microcephaly syndrome with
polymicrogyria and corpus callosum agenesis
L. Baala 1,2 , S. Briault 3 , H. C. Etchevers 2 , F. Laumonnier 3 , A. Natiq 1 , J. Amiel 2 ,
N. Boddaert 4 , C. Picard 5 , A. Sbiti 1 , A. Asermouh 6 , T. Attié-Bitach 2,7 , F. Encha-
Razavi 2,7 , A. Munnich 2,7 , A. Sefiani 1 , S. Lyonnet 2,7 ;
1 Dép. Génétique Médicale, Institut National d’Hygiène, Rabat, Morocco,
2 INSERM U-781, Hôpital Necker-Enfants Malades (AP-HP), Paris, France,
3 INSERM U-619 Faculté de Médecine, Tours, France, 4 Service de Radiologie
Pédiatrique, Hôpital Necker-Enfants Malades (AP-HP), Paris, France, 5 Centre
d’étude des Déficits Immunitaires, Hôpital Necker-Enfants Malades (AP-HP),
Paris, France, 6 Hôpital d’Enfants Avicenne, Rabat, Morocco, 7 Université René
Descartes, Paris, France.
Mechanisms regulating brain size during neurogenesis include the
regulation of neural progenitor proliferation and migration. We report
an autosomal recessive microcephaly syndrome co-segregating with
a homozygous balanced translocation between chromosomes 3p and
10q in a large inbred family. The translocation was found at the homozygous
status in all affected individuals (46,XY,t(3;10)(p24;q23)2x),
while unaffected parents were heterozygous. We established a physical
and characterized the BACs that encompassed the breakpoints on
3p24 and 10q23 (BAC RP11-9a14 and RP11-104H24). Interestingly,
neither of the two translocation breakpoints disrupted a known or predicted
gene coding sequence.
However, we showed that a position effect at the breakpoint on chromosome
3 silences the Tbox-brain2/Eomesodermin (TBR2/EOMES)
transcript. Together with its expression pattern in the developing human
brain, our data suggest an involvement of TBR2/EOMES in neuronal
division and/or migration. Thus, mutations in not only mitotic and
apoptotic proteins but also transcription factors may be responsible for
malformative microcephaly syndromes.
P1025. Identification of a gene involved in hereditary microcytic
anemia due to defective iron absorption in a Sardinian family
M. A. Melis 1 , M. Cau 1 , R. Congiu 1 , G. Sole 2 , A. Cao 2 , R. Galanello 1 ;
1 University of Cagliari, Cagliari, Italy, 2 CNR, Cagliari, Italy.
We report the study of a large sardinian family where five patients
show iron deficiency resulting in microcytic hypochromic anemia, not
responsive to oral treatment but partially responsive to parenteral treatment.
Known causes of hereditary microcytic anemia such as thalassemia,
hemorrages, gastrointestinal disorders have been excluded by
specific tests. By the pedigree analysis it seems an autosomal recessive
disorder. Since clinical data suggest that it could be a defect of
iron metabolism, especially a defect of iron absorption and/or mobilization
of intracellular iron storage, initially we studied all the known gene
involved in iron metabolism (Tf, TfR, ZIRTL, HJV and DMT1). Linkage
analysis for these genes resulted negative, therefore we supposed
that a different gene could be involved. Wide genome screening using
300 microsatellite markers was performed and a chromosome 22q13
region showing 5.6 multipoint LOD SCORE near marker D22S1177
and 5.4 multipoint LOD SCORE near marker D22S423. This region
2 1
spans 7.2 cM and the affected subjects share two homozygous tracts.
No recombination has been observed.
A further linkage analysis based on SNPs study was performed to better
define the locus limits. This study confirmed the homozygous tract
but did not allow to narrow the interval of interest. These results reinforce
the hypotesis that the locus for hereditary microcytic anemia is
on chromosome 22q13.
The 7.2 cM critical region of chromosome has been completely sequenced
and is available from published databases. A large number of
genes have already been characterized in the region.
P1026. Exclusion of ADAMTS10 gene for the isolated
microspherophakia in a consanguineous multiplex Tunisian
family
F. Ouechtati 1 , S. Ben Yahia 2 , I. Chouchen 1 , S. Chakroun 1 , M. Kheirallah 2 , S.
Abdelhak 1 ;
1 UR26/04 Molecular investigation of genetic orphan diseases, Pasteur Institute
of Tunis, Tunis, Tunisia, 2 Department of Ophthalmology, Fattouma Bourguiba
Hospital, Monastir, Tunisia.
Microspherophakia (OMIM 251750) is an eye disease characterized
by a small and spherical crystalline lens with increased anteroposterior
thickness. Autosomal recessive Weill Marchesani Syndrome is
due to mutations within ADAMTS10 gene. The locus responsible for
the isolated form of microspherophakia is still unknown because the
reported cases are rare and sporadic. A consanguineous family with
two patients affected with isolated microspherophakia has been identified
in Central Tunisia. In order to check if ADAMTS10 gene is involved
in microspherophakia in this family, a linkage analysis was performed
using microsatellite markers flanking this gene. Genetic investigation
showed an exclusion of linkage between ADAMTS10 gene and the
disease locus in this family. This result suggests that isolated microspherophakia
is not an allelic disorder to Weill Marchesani Syndrome.
P1027. Mitochondrial mutations in maternally-inherited nonsyndromic
deafness: whole-mitochondrial-genome screening
using a microarray resequencing mitochondrial DNA chip
M. Leveque 1 , S. Marlin 1 , L. Jonard 1 , V. Procaccio 2 , P. Reynier 3 , S. Baulande 4 ,
R. Couderc 1 , E. Garabedian 1 , C. Petit 5 , D. Feldmann 1 , F. Denoyelle 1 ;
1 AP-HP, Trousseau, Paris, France, 2 Université de Califormie, Irvine, CA, United
States, 3 INSERM U688, Angers, France, 4 PartnerChip, Evry, France, 5 INSERM
U587, Institut Pasteur, Paris, France.
Mitochondrial DNA (mtDNA) mutations have been implicated in nonsyndromic
hearing loss, with various degrees of penetrance. As only
part of the mitochondrial genome is usually explored in deaf patients,
their prevalence is probably under-estimated. Among 1350 families
with sensorineural deafness collected through a French collaborative
network, we selected 29 large families with clear maternal inheritance
and screened them for the known mtDNA mutations in 12S rRNA,
tRNAser(UCN), and tRNAleu(UUN) genes. When no mutation could
be identified, a whole-mitochondrial genome screen was performed
using the MitoChip v2.0 microarray resequencing chip (Affymetrix,
Inc). Known mtDNA mutations were found in 9 of the 29 families:
A1555G in five, T7511C in two, 7472insC and A3243G in one each.
In the remaining 20 families, the resequencing Mitochip detected 258
mitochondrial homoplasmic variants and 107 potentially heteroplasmic
variants. The more likely pathogenic variants are displayed based on
allelic frequency and conservation between species. The whole-genome
analysis elicited 5 additional families with a possibly pathogenic
mitochondrial DNA variant: T669C, C1537T, G8078A, G12236A, and
G15077A. These results indicate that the new MitoChip platform is a
rapid and reliable tool for (the) identification of new mtDNA mutations,
whether in deafness or other mtDNA-related diseases.
P1028. Multiple Ligation Probe Amplification analysis in the DMD
gene: hidden results
M. Rodriguez, J. Juan, L. Gonzalez-Quereda, S. Gutierrez, M. Baiget, P. Gallano;
Genetics Dept, Hospital de Sant Pau, Barcelona, Spain.
Duchenne and Becker muscular dystrophies (DMD/BMD) are the
most common form of dystrophinopathies, with a reported incidence of
1:3500 and 1:18000 birth males repectively.
About 65% of DMD/BMD cases are attributable to large deletions of
the DMD gene, whereas the remaining cases are caused by duplica-