2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
P02.166
Novel mutation in sEDL gene in three sibling of Russian family
with X-linked spondyloepiphyseal dysplasia tarda
V. P. Fedotov1 , E. A. Bliznetz2 , I. S. Plotko1 , A. V. Korobov1 , A. V. Polyakov2 ;
1 2 VOCDC genetic counseling, Voronezh, Russian Federation, Research Centre
for Medical Genetic, Moscow, Russian Federation.
Spondyloepiphyseal dysplasia tarda (SEDL; MIM 313400) is an Xlinked
recessive osteochondrodysplasia that occurs in approximately
two of every one million people. This progressive skeletal disorder
which manifests in childhood is characterized by disproportionate short
stature with short neck and trunk, barrel chest and absence of systemic
complications. Distinctive radiological signs are platyspondyly with
hump-shaped central and posterior portions, narrow disc spaces, and
mild to moderate epiphyseal dysplasia. The latter usually leads to premature
secondary osteoarthritis often requiring hip arthroplasty. The
disorder is caused by the mutations in SEDL gene located on Xp22.12p22.31.
SEDL encodes a 140 amino acid protein with a putative role in
endoplasmic reticulum (ER)-to-Golgi vesicular transport.
Here we report Russian family case with three affected sibs of five
sibs born in two mother wedlock. Two patients were investigated at the
age of 19 and 26 years and had typical clinical and radiological signs
of SEDL. Onset of the disease was at the age after of 10 with growth
impairment, back pain and waddling gait. Osteoarthritic changes were
present in both hip joints with flattening of the femoral heads. In the patients,
the mutation analysis in SEDL gene was performed, and a novel
hemizygous mutation c.133G>C leading to the amino acid substitution
Ala45Pro was found. This mutation was not identified in healthy
mother and in 88 control chromosomes (in 35 males and 24 females).
P02.167
tAR syndrome case Report
M. Boia 1,2 , V. Belengeanu 1 , E. S. Boia 1,3 , A. Popoiu 1 , D. Iacob 1 , A. Manea 1 , L.
Stoica 4 ;
1 University of Medicine and Pharmacy, Timisoara, Romania, 2 Clinical Emergency
Hospital for Children “Louis Turcanu”; Premature and Neonatology Department;,
Timisoara, Romania, 3 Clinical Emergency Hospital for Children “Louis
Turcanu”, Pediatric Surgery and Orthopedics Department, Timisoara, Romania,
4 Clinical Emergency Hospital for Children “Louis Turcanu”, Timisoara, Romania.
Extremely rare affection in current medical praxis, TAR syndrome represents
an association of malformations that includes almost every tissues
and organs: hematological, cardiac, gastro-intestinal, skeletal.
Material and Method: A case of a newborn was presented, who was
been hospitalized at 10 hours age with a complex malformed syndrome.
Results: The physical examination and the paraclinical investigations
revealed us TAR syndrome. The historical record of the newborn was
not containing any special/unusual elements: newborn female with the
gestational age of 38 weeks, birth weight: 2750 g, natural born in cephalic
presentation, APGAR score: 8/9, green amniotic fluid.
The physical examination was showing: pale tegument, purple items
over the chest, short forearms, simian line, ogival mouth palate, lowimplanted
ears. The cardiologic examination revealed a moderate cardiomegaly
with atrial septal defect and minimal left-right bridge.
The skeletal X-ray confirmed the presence of one malformation: short
forearms with the congenital bilateral radial aplasia.
The head ultrasonography in dynamics showed the presence of this
cystic formations specific for periventricularleucomalacia - cystic form.
A second degree intraventricular haemorrhage was associated.
Thrombocytopenia was severe: initially 14000/mmc until 35-40000/
mmc required several transfusions with thrombocyte concentrate.
The evolution was slow, but favorably under the treatment; the discharge
was done with weekly monitoring of hemogram condition.
Conclusions:
● Specific signs were present, except gastro-intestinal affection - the
patient didn’t present lactose intolerance;
● The severe thrombocytopenia was maintained throughout hospitalization,
but this didn’t aggravate the intraventricular haemorrage (this
particular one had a relatively good evolution).
P02.168
Expression and functional analysis of EFNB mutations in
craniofrontonasal syndrome
R. Makarov 1 , B. Steiner 2 , S. Preisler-Adams 3 , A. Rauch 2 , P. Wieacker 3 , I. Wieland
1 ;
1 Institut für Humangenetik, Magdeburg, Germany, 2 Institut für Medizinische
Genetik, Zürich, Switzerland, 3 Institut für Humangenetik, Münster, Germany.
EFNB1 gene (OMIM 300035) encodes ephrin-B1 - a member of the
ephrin-receptor ligand family. Together with their receptors (Eph) ephrins
form signalling complexes involved in cell adhesion and migration.
Mutations of EFNB1 cause craniofrontonasal syndrome (CFNS; OMIM
304110). We describe missense mutations c.161C>T (p.P54L) and
c.332C>T (p.T111I), splice-site mutation c.406+2T>C and frameshift
mutation c.614_615delCT that were found in CFNS female patients.
The splice site mutation activates a cryptic splice site resulting in a
smaller transcript. The frameshift mutation causes a premature termination
codon, but escapes nonsense-mediated mRNA decay. No
truncated ephrin-B1 was detected by Western blot analysis in protein
extracts from patient fibroblasts for both of these mutations. Absence
of mutant protein shows that c.406+2T>C and c.614_615delCT probably
have loss-of-function effects. Both missense mutations lead to
an amino acid exchange in the ephrin-B1 extracellular domain. In order
to evaluate the impact of these mutations on signalling and cell
behaviour, NIH 3T3 cells were cotransfected with pEGFP-N3 vector
and pcDNA 3.1 (+) vector containing cDNA of wild-type or mutant type
c.161C>T and c.332C>T EFNB1. Transfected cells were stimulated
with EphB2-Fc/Fc and analysed using fluorescent microscopy. After
stimulation wt- and p.T111I-ephrin-B1 expressing cells formed cell
patches, whereas no patches were observed for p.P54L. Western blot
analysis using anti-ephrin-B1-pTyr(324/329) showed differences concerning
ephrin-B1 phosphorylation and its timing for mutant and wt
protein. This may indicate that other Tyr-residues are more important
for signalling. Alternatively, disrupted signalling through the Eph-B2receptor
contributes to the disease manifestation.
P02.169
EVc1 and EVc2 gene mutations associated to Ellis-van creveld
syndrome
I. Torrente1 , M. C. D’Asdia1 , N. Grifone1 , M. C. Digilio2 , B. Dallapiccola1,3 ;
1IRCCS-CSS, San Giovanni Rotondo and CSS-Mendel Institute, Rome, Italy,
2 3 Medical Genetics, Bambino Gesù Hospital, Rome, Italy, Department of Experimental
Medicine and Pathology, “La Sapienza” University of Rome, Rome, Italy.
Ellis-van Creveld syndrome (EVC, MIM #225500) is a chondral and
ectodermal dysplasia characterized by short ribs, polydactyly, growth
retardation, and ectodermal and heart defects. This rare genetic disease
is inherited as an autosomal recessive trait with variable expression.
In general population the incidence is reported as one per 60000
live births. Mutations of EVC1 and EVC2 genes, located in a head
to head configuration on chromosome 4p16, have been identified as
causative. EVC1 gene has 21 coding exons spanning 120kb of genomic
DNA and gives rise to a 992 amino acid protein. EVC2 gene
has 22 coding exons spanning 150kb of genomic DNA and encodes
a 1,308 amino acid protein. In this study we screened for mutations in
both genes a panel of 33 EvC patients originated from different countries
and collected relative clinical data. The analysis were conducted
by DHPLC and direct sequencing of the PCR products resulting from
amplification of all coding exons. We identified 22 mutations (16 never
described in literature), 16 in EVC1 gene and 6 in EVC2. In EVC1 we
identified 8 splicing, 5 frameshift, 2 missense mutations and a large
deletion spanning almost all exon 13 (82419_82561del). In EVC2 gene
we described 3 frameshift, 1 splicing, 1 missense and 1 nonsense mutations.
Our study expands the spectrum of mutations associated with
EVC syndrome and will contribute to further understanding of the molecular
basis underlying the phenotypic variability of the disease.
P02.170
Alpha thalassemia: sometimes a complex diagnosis
A. Ravani, A. Venturoli, M. Taddei Masieri, B. Dolcini, C. Trabanelli, S. Carturan,
S. Fini, P. Rimessi, F. Gualandi, S. Bigoni, A. Ferlini;
Sezione di Genetica Medica - Università degli Studi, Ferrara, Italy.
We report the case of a couple, coming from Philippines, referred to
our Laboratory during the pregnancy for suspected alpha-thalassemia.We
performed the routine analysis for the 7 most common muta-