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

Clinical genetics
ing loss (HHL). In many populations mutations in this gene have been
reported as a second cause of HHL. We investigated the prevalence of
SLC26A4 mutations in our HHL consanguineous families. After completing
clinical investigation the signed consent form was taken from
each family. We included 80 families with two or more affected individuals,
who have been referred to GRC. All families who had previously
been tested negative for the DFNB1 locus, were considered as candidates
for homozygosity mapping using STR (Short tandem repeat)s
linked to DFNB4 locus. Families localized to this region were subjected
to complete DNA sequencing for SLC26A4 gene. Ten out of eighty
families were mapped to DFNB4. Sequence analysis of ten linked
families revealed eight mutations in seven families (T420I, 1197delT,
G334Y, R409H, T721M, R79X, S448L, L445W) and
The T420I , G334V and R79X were novel mutations. We have been
able to localize total of 10 families (12.5%) from non-DFNB1 families
to the DFNB4 locus. We detected in all ten families some degrees of
diffuse or nodular goiter, eight out of 10 families showed normal thyroid
function and in six of ten families we found positive prechlorate discharge
test. All of affected had normal temporal bone scan.
This investigation, demonstrated that the SLC26A4 gene mutation is
the most prevalent syndromic hereditary hearing loss in Iran.This result
is in accordance with reports from other countries.
Key words:, SLC26A4, hearing loss,pendred
P0245. Molecular analysis of SMN1 gene common deletions in
some Iranian Spinal muscular Atrophy patients
M. T. Akbari 1,2 , s. zare 1,3 , f. mahjoubi 1,4 ;
1 Akbari Medical Genetic labaratory, No.98, Taleghani Street, Tehran, Islamic
Republic of Iran, 2 Department of Medical Genetics,Tarbiat Modares
University,Al-Ahmad Expressway, Tehran, Islamic Republic of Iran, 3 Islamic
Azad Unversity Science and Research Campus, Tehran, Islamic Republic of
Iran, 4 National Research Center for Genetic Engineering & Biotechnology, Tehran,
Islamic Republic of Iran.
Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular
disorder caused by mutations in the SMN1 gene, mainly intragenic
deletions, the commonest of which are deletion in exons 7 and
8. The disorder is subdivided into three clinical groups (type I - III).
The molecular basis for variation in clinical manifestation depends on
the copy number of SMN2 gene in each patient. In this study we present
fifteen families who had at least one live affected SMA patient,
selected for molecular characterization. They fulfilled criteria for inclusion
by demonstration of the characteristic clinical features of SMA
phenotype. These clinical diagnoses were corroborated with EMG and
NCV investigations as well as CPK measurement for the majority of
the cases. The patients DNA samples were prepared from whole blood
by standard salting out method. Characterization of deletions in exons
7 and 8 of SMN 1 gene was carried out by utilizing a pair of mismatched
primers which differentiate between SMN1 and SMN2 genes.
We found deletion in seven patients, about 50%. Five patients had
both exons 7 and 8 deleted and two patients had just exon 7 deletion.
Although the present sample size is small, it may be concluded that
the observed deletions has lower frequency compared to European
populations which is 95%. Therefore other SMN1 gene defects should
be looked in Iranian patients.
P0246. Case study: “A family with several cases of SMA type 1
due to multiple consanguinous marriages in three consecutive
generations, in the pedigree.”
S. Akbaroghli 1,2 , M. Houshmand 3 , T. Majidizadeh 3 ;
1 Deputy for Cultural Affairs and Prevention of Welfare Organization, Tehran,
Islamic Republic of Iran, 2 Dr. Susan Akbaroghli Genetic Counselling Center,
Tehran, Islamic Republic of Iran, 3 Special Medical Center, Tehran, Islamic Republic
of Iran.
The propand is a three months old floppy boy who is the result of third
degree consanguinous marriage (the first sibling).
At birth his mother had hard NVD and the baby was born with cyanosis.
He had apnea and poor feeding for the first days of his life.
He was hospitalized for 12 days.
His grandparents from both sides have third degree relationships.
He has the typical clinical features and characteristics of SMA type
1.His molecular test for SMA type 1was positive and he has deletion of
exons 7 & 8 of SMN1 gene.
The special point in this family is the existence of several cases of SMA
type 1 due to multiple consanguinous marriages in three consecutive
generations, in the pedigree.
P0247. Clinical forms of Smith-Lemli-Opitz syndrome and their
relation to mutations in the DHCR gene _ classification based
on a group of 50 Polish patients
A. Jezela-Stanek 1 , E. Małunowicz 2 , E. Ciara 1 , E. Popowska 1 , M. Piotrowicz 3 , M.
Gajdulewicz 1 , E. Kostyk 4 , K. Spodar 1 , A. Kruczek 4 , A. Pyrkosz 5 , E. Obersztyn 6 ,
D. Wolnik-Brzozowska 7 , M. Krajewska-Walasek 1 ;
1 Dept. Of Medical Genetics, The Children’s Memorial Health Institute, Warsaw,
Poland, 2 Dept. of Laboratory Diagnostics, The Children’s Memorial Health Institute,
Warsaw, Poland, 3 Dept. of Medical Genetics, Polish Mother’s Memorial
Hospital - Research Institute, Łódź, Poland, 4 Dept. of Medical Genetics, University
Children’s Hospital, Kraków, Poland, 5 Department of General, Molecular
Biology and Genetics, Medical University of Silesia, Katowice, Poland, 6 Dept.
of Medical Genetics, National Institute of Mother and Child, Warsaw, Poland,
7 Dept. of Medical Genetics, Medical University, Poznań, Poland.
Smith-Lemli-Opitz syndrome (SLOS) is a metabolic malformation disorder,
caused by impaired activity of 7-dehydrocholesterol reductase,
the last enzyme in cholesterol biosynthesis. Its best known dysmorphic
features include: microcephaly, ptosis, short and up-turned nose, 2/3
toe syndactyly, and external male genital malformations. Nevertheless,
as the spectrum of observed features is very broad, a question
about phenotype-genotype correlations still emerges.
Poland represents a unique distribution of mutations in the DHCR7
gene. Moreover, one of them is thought to be spreading in our country,
hence our effort to delineate the clinical variability of SLOS in relation
to the causative molecular defect.
The study was based on a group of 50 patients with proven diagnosis
(13 f and 27 m), classified into 3 severity forms: mild (13 cases), moderate/classical
(20 cases) and severe (17 cases). We analyzed: facial
dysmorphy, congenital malformations (expressed as a Severity Score:
0 - 100 points), biochemical chromatographic data (cholesterol and 7-,
8DHC) and molecular data (mutations in DHCR7 gene).
While chromatographic data shown its significant correlation with clinical
forms of SLOS, the genotype-phenotype correlation was no so
clear and we found as below:
Class of
mutation
Number of
patients
0/0 3 55 (n=2), 60
0/TM7 15
0/4L 3 40, 50, 65
0/TM3 3 40, 55, 60
0/TM8 5
Severity Score Congenital anomalies
microcephaly, heart and renal defect, polidactyly,
abnormal male external genitals; CNS
- dilated ventricles (1)
microcephaly (13); heart defect (11); cleft pal-
20, 30 (n=3),
ate (6); renal anomaly (5); GI tract defect (4);
35 (n=2), 40,
CNS malformation (3); cataract (1); polidactyly
50, 55 (n=4), 60
(10); syndactyly other than 2/3 toe (1); abnor-
(n=2), 65
mal external genitals: male (9/11), female (2/4)
20 (n=2), 30
(n=2), 40
microcephaly, hart defect, 2/3 and 4/5 toe
syndactyly, cleft palate, enlarged clitoris (2/2)
microcephaly, cleft palate, hart defect, polidactyly,
abnormal male external genitals
microcephaly, abnormal male external genitals
(4); pyloric stenosis (2); cleft palate, heart
defect, cataract (1)
TM1/CT 2 5, 5 microcephaly, slight 2/3 toe syndactyly
TM7/1L 2 10, 15
TM7/TM7 3 15, 20, 30
microcephaly, cryptorchidism, hypospadias (2);
2/3 toe syndactyly (1)
microcephaly, cleft palate (2); heart and renal
defect, cryptorchidism, CNS - dilated ventricles
(1)
We hope that our study will give new insights into the genetics of Smith-Lemli-Opitz
syndrome.
This work was supported in part by grants 2P05E06727 and PBZ-KBN 122/P05/01-
10.
P0248. Smith-Lemli-Opitz syndrome - novel mutation with a mild
phenotype
M. Krajewska-Walasek 1 , L. Korniszewski 2 , E. Ciara 1 , E. Malunowicz 1 , A. Jezela-Stanek
1 , M. Gajdulewicz 1 , K. Spodar 1 , E. Popowska 1 , A. Materna-Kiryluk 3 ,
K. H. Chrzanowska 1 , A. Latos-Bielenska 3 ;
1 The Children’s Memorial Health Institute, Warsaw, Poland, 2 Genetic Counselling
Unit, Institute of Physiology and Pathology of Hearing, Warsaw, Poland,
3 University of Medical Sciences, Poznan, Poland.
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder
of cholesterol biosynthesis, caused by mutations in DHCR7gene.
Although its phenotype is well characterized, SLOS is recognized