2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
morphism (SSCP) techniques were performed for scanning of the all
functional-important regions of the F9 gene. An abnormal SSCP profile
was identified in exon 4 of the gene for this patient. Then, direct sequencing
was done by chain termination method .
The deletion of 19 nucleotides ( 10503-10521 del ) was detected in
this patient in exon 4
which is not reported in hemophilia B mutation database, previously .
The patient’s mother and his sister were heterozygous for this deletion
.
A novel deletion of 19 nucleotides (10503-10521 del ) in exon 4 leading
to frame shift in the epidermal growth factor1( EGF1) domain . Exon
4 encoded a first epidermal growth factor-like domain, which shows
homology to epidermal growth factor (EGF) and, in addition, contains
conserved carboxylate residues including a β-hydroxyaspartate at
amino acid 64. This domain binds an additional Ca2+ with high affinity
. In conclusion, this deletion causes a severe form of disease as
observed in this patient .
P05.080
complete maternal isodisomy causing Reduction to
Homozygosity for a Novel LAMB mutation in Herlitz Junctional
Epidermolysis Bullosa
D. Castiglia 1 , M. Castori 1 , G. Floriddia 1 , E. Pisaneschi 2 , C. Covaciu 1 , I. Torrente
2 , G. Zambruno 1 ;
1 IDI-IRCCS, Rome, Italy, 2 CSS-Mendel Institute, Rome, Italy.
Herlitz junctional epidermolysis bullosa (HJEB) is a very rare lethal
genodermatosis characterized by blister formation with tissue separation
within the lamina lucida of the basement membrane zone . It is genetically
heterogeneous, being caused by null mutations in the LAMA3
(18q11 .2), LAMB3 (1q32), or LAMC2 (1q25-q31) genes encoding for
the alpha3, beta3 and gamma2 subunits of laminin 332 . Although it is
usually inherited in an autosomal recessive fashion, four cases have
been described in which the disease arose from reduction to homozygosity
for a mutant allele caused by uniparental disomy (UPD) . Here,
we report on a baby presenting with multiple blister formation at birth
and who died due to acute respiratory insufficiency secondary to upper
airway obstruction at 1 year of age . The diagnosis of HJEB was
first confirmed by immunoepitope mapping of a skin biopsy. Molecular
analysis identified a novel frameshift mutation at the homozygous
state in LAMB3 . Parental genotyping established the mother as a
healthy carrier, while in the father the mutation was absent . Haplotype
analysis of 8 intragenic and 15 extragenic polymorphisms, spanning
the entire chromosome 1, demonstrated that the proband was homozygous
for a single maternal haplotype . The present case represents
the fifth example of UPD in HJEB. Based on literature data and our
experience in genotyping 20 HJEB patients from several European
countries, reduction to homozygosity due to UPD is not exceptional in
this condition and should be considered in sporadic cases in order to
properly counsel the couple .
P05.081
Genetic causes of hearing loss in the iranian population a 10
year study
H. Najmabadi 1 , C. Nishimura 2 , K. Kahrizi 1 , N. C. Meyer 2 , N. Bazazzadegan 1 , J.
L. Sorensen 2 , M. Mohseni 1 , Y. Riazalhosseini 1 , M. Malekpour 1 , G. Asaadi Tehrani
1 , A. Daneshi 3 , M. Farhadi 3 , P. Imani 1 , A. Anousheh 1 , A. Nazeri 1 , S. Abedini 1 ,
N. Nikzat 1 , S. Arzhangi 1 , R. J. H. Smith 2 ;
1 Genetics Research Center, University of Social Welfare and Rehabilitation
Sciences, Tehran, Islamic Republic of Iran, 2 Molecular Otolaryngology Research
Laboratories, Department of Otolaryngology, University of Iowa, Iowa,
IA, United States, 3 Research Center of Ear, Nose, Throat, and Head and Neck
Surgery, Iran university of Medical sciences, Tehran, Islamic Republic of Iran.
Approximately one in 1000 newborns has severe-to-profound deafness,
which has a genetic basis in more than half of this group . In
~70% of congenitally deaf newborns the loss is nonsyndromic .
The purpose of this study has been to determine the cause of syndromic
and non-syndromic hearing loss in the Iranian population .
Over a 10 year period, 2434 families segregating deafness have been
referred to Genetics Research Center in Tehran . In each of these families,
informed consent was obtained . Every family was screened for
mutations in GJB2 and GJB6 . Following this screen, in 300 families
with three and more affected individuals with presumed ARNSHL, we
screened total of 22 loci by STR markers . In families in which autozygosity
by descent was not identified at any of these loci, a genomewide
screen was completed .
Our data show that 15 .3% of the Iranian population with ARNSHL segregate
mutations in GJB2 . The most prevalent mutation in this gene
was 35delG, although more than 20 mutations have been identified,
five of which are unique to the Iranian population. We also identified
novel GJB2 mutation in an endogenous population segregating
ADNSHL in village north of Iran .
The second and third most prevalent causes of ARNSHL were mutations
in SLC26A4 and TECTA . We have also found mutations in PJVK
and TMC1 in one family each .
We have identified a number of families segregating syndromic hearing
loss .Totally, we have been able to determine the genetic cause of
hearing loss in over 30% of families referred to our center .
P05.082
the investigation of NPHs1 gene in children with Hereditary
Proteinuria syndrome
O. Ryzhkova 1 , N. Poltavets 1 , L. Prihodina 2 , A. Polyakov 1 ;
1 Research Center for Medical Genetics, Moscow, Russian Federation, 2 Research
Сenter of Pediatrics and Child Surgery, Moscow, Russian Federation.
Hereditary Proteinuria Syndromes (HPS) is a group of inherited diseases
in which proteinuria is the primary clinical manifestation . The
genetic cause of these diseases is mutations in genes providing the
structure and function of filtration barrier.
DNA from 63 children with idiopathic nephrotic syndrome in age are
ranged from 1 to 17 years, consisting of 33 boys and 30 girls, have
been analyzed . The disease manifestation had been observed at the
age ranged from 1 month to 16 years . The control group has consisted
from 50 healthy persons . The mutations in NPHS1 gene were investigated
by using SSCP-analysis and consequent sequencing .
No mutations in coding and regulation regions of this gene were
found .
At researched patients has been revealed five single nucleotide substitution
(table 1), one of which c .605-20 A> C has not been described
earlier. For specification of influence of this substitution by occurrence
of Proteinuria Syndrome, we investigated frequency of occurrence in
control sample . Authentic distinctions have not been revealed .
We have not found significant distinctions allele frequency of four
others polymorphisms NPHS1 gene between our patients and control
group . We think that contribution of these polymorphisms to disease
is unimportant .
Minor allele frequency of polymorphisms NPYS1 gene in our patients
and control group (%)
exon polymorphism HPS
group
control
group
Ex3(c .349G>A) c .349A 25 26 0 .87
Ex10(c .1175C>T) c .1175T 2 4 0 .45
Ex10(c .1223G>A) c .1223A 4 3 0 .72
Fisher exact
test (P)
Minor allele frequency of polymorphisms NPYS1 gene in our patients
and control group (%)
exon polymorphism HPS
control
group
group
(our
data)
Fisher exact
test (P)
Ex7(c .791C>G) c .791G 1 1 1
Ex6(c .605-20A>C) c .605-20C 1 0 0 .5
P05.083
Analysis of SPASTIN in a spanish series shows both recurrent
and novel mutations
M. Zennaro 1 , G. Martinez-Nieto 1 , A. Sesar 2 , M. Arias 2 , I. J. Posada 3 , B. Ares 2 , J.
Pardo 2 , M. Seijo 4 , C. Navarro 5 , C. Andrade 6 , A. Carracedo 1,7,8 , M. J. Sobrido 1,7 ;
1 Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela,
Spain, 2 Department of Neurology, Hospital Clínico, Santiago de Compostela,
Spain, 3 Department of Neurology, Hospital 12 de Octubre-Universidad Complutense,
Madrid, Spain, 4 Sección de Neurología, Hospital do Salnés, Pontevedra,
Spain, 5 Department of Pathology, Hospital do Meixoeiro-CHUVI, Vigo,
Spain, 6 Department of Neurology, Hospital Xeral-Cíes, Vigo, Spain, 7 Centro
para Investigación de Enfermedades Raras (CIBERER) ISCIII, Santiago de
Compostela, Spain, 8 Grupo de Medicina Xenómica-Universidad, Santiago de