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

Clinical genetics
P0041. The first evidence of a pathogenic insertion in the
NOTCH3 gene causing CADASIL
C. Ungaro1 , F. L. Conforti1 , D. Guidetti2 , M. Muglia1 , A. Patitucci1 , T. Sprovieri1 ,
G. Cenacchi3 , A. Magariello1 , A. L. Gabriele1 , L. Citrigno1 , R. Mazzei1 ;
1Institute of Neurological Sciences, National Research Council, Mangone (CS),
Italy, 2UOC di Neurologia, Ospedale di Guglielmo di Saliceto, Piacenza, Italy,
3Department of Radiological and Istocytopathological Sciences, Section of
Pathology, University of Bologna, Bologna, Italy.
CADASIL is an autosomal dominant disorder leading to cognitive decline
and dementia caused by mutations in NOTCH3 gene. These
highly stereotyped mutations are located within the 22 exons, encoding
for the extracellular domain of the Notch3 receptor, all mutation resulting
either in a gain or loss of a cysteine residue. It has been suggested
that the unpaired cysteine residue might cause aberrant interaction
of the Notch3 receptor with its ligands. Here we report the case of a
patient with clinical and radiological findings consistent with CADASIL
having distinctive GOM deposits in her skin biopsy. We examined the
exons of NOTCH3 gene in this patient and we found a novel NOTCH3
gene mutation consisting in a 3 base pair insertion in the exon 3. This
mutation was not observed in 560 control chromosomes. In the subject
carrying the mutations in exon 3, no mutation was found in the
other exons containing EGF-like repeats (exons 2-23), examined with
both DHPLC analysis and direct sequence. This insertion resulting in
a gain of a cysteine residue together with the neurologic and clinical
phenotype, suggests it is the causative mutation in our patient. The
current findings demonstrate that this insertion of a cysteine residue in
the NOTCH3 gene can cause CADASIL. This is the first evidence of
a pathogenic insertion found in a CADASIL patient, and it is important
to confirm the hypothesis that the change toward an unpaired reactive
cysteine residue within EGF repeat domains is a very critical molecular
event in CADASIL.
P0042. Association of MTHFR gene polymorphism C677T with
dilated cardiomyopathy and severe LV hypertrophy
R. Valiev 1 , A. Pushkareva 2 , R. Khusainova 1 , N. Khusnutdinova 1 , G. Enikeeva 2 ,
G. Arutunov 3 , E. Khusnutdinova 1 ;
1 Institute of biochemistry and genetics, Ufa, Russian Federation, 2 Bashkir State
Medical University, Ufa, Russian Federation, 3 Russian State Medical University,
Moscow, Russian Federation.
Cardiomyopathies are heart-muscle diseases of unknown cause.
There are several theories of cardiomyopathies origin, including autoimmune
hypothesis. In our study we investigated three known genetic
polymorphisms in MTHFR, TNFa and TNFb genes in patients with different
cardiomyopathies and controls (N=200). All patients have been
divided into three groups - dilated cardiomyopathy (ejection fraction 20-
45%, N=83), moderate left ventricular (LV) hypertrophy (wall thickness
less than 1,5 mm, N=79) and severe LV hypertrophy (wall thickness
more than 1,5 mm, N=118). MTHFR, TNFa and TNFb genotypes were
determined by polymerase chain reaction with subsequent restriction
fragment length polymorphism technique. There were no differences
in TNF (alpha and beta) allele frequencies between studied groups
and controls (p>0,05). Significant differences in C677T (MTHFR) allele
frequencies distribution have been found between patients with
dilated cardiomyopathy and controls (chi2 test with Yets’s correction
=5,4; df=1, p=0,024) as well as between severe LV hypertrophy and
controls (chi2 test with Yets’s correction =6,6; df=1, p=0,0109). Genotype
TT of MTHFR polymorphism have been associated with severe
LV hypertrophy development (odds ratio = 3,15; [95% CI 1,04 - 9,86]).
There was no correlation between C677T allele frequencies and patients
with moderate LV hypertrophy. Despite association with other
heart dysfunction diseases, neither TNFa nor TNFb are related with
cardiomyopathy. MTHFR point mutation (cytosine to thymine substitution;
C677T) is a known risk factor for many cardiovascular diseases,
including atherosclerosis, heart attack and peripheral arterial disease.
Our data shows a possible role of C677T polymorphism in development
of dilated cardiomyopathy and severe LV hypertrophy.
P0043. The indications for CATCH22 phenotype FISH analysis
should be widened
K. Õunap 1,2 , K. Kuuse 1 , T. Ilus 1 , K. Muru 1 , R. Zordania 3 , K. Joost 3 , T. Reimand 1 ;
1 Medical Genetics Center, United Laboratories, Tartu University Hospital, Tartu,
Estonia, 2 Department of Pediatrics, University of Tartu, Tartu, Estonia, 3 Tallinn
Children’s Hospital, Tallinn, Estonia.
The 22q11.2 microdeletion is one of the most common human microdeletion
syndromes. It is usually diagnosed by FISH analysis using TU-
PLE1 probe at 22q11.2 and N85A3 clone control probe at 22q13.3.
This study includes 335 patients investigated for CATCH22 microdeletion
by FISH analysis during 2000-2007. In 19 patients abnormal finding
was found (6%). Fifteen patients had classical 22q11.2 microdeletion
(79%), in 4 cases other abnormalities were found (21%). Two
had 22q11.2 microduplication, one had 22q13.3 deletion and in one
22q13.3 duplication was diagnosed.
In patients with 22q11.2 deletion the indications for FISH investigation
were classical: heart anomaly with different additional problems; 3 had
typical facial phenotype with cleft palate or immunological problems
only. In the patient with 22q13.3 deletion (developmental delay and
muscular hypotonia) the main indication for FISH analysis was the
cleft palate in his mother. Similarly, a patient with 22q13.3 duplication
(developmental delay and abnormal face) had heart anomaly in one
sister. Two patients with 22q11.2 duplication in one family had minor
facial abnormalities and failure to thrive, and were investigated only
because referral doctor was a cardiologist. None of four patients with
other abnormalities found had cardiac anomaly.
In summary: among the cases with abnormal CATCH22 FISH results
we found in 21% other abnormality than classical 22q11.2 microdeletion.
The indication for FISH analysis in these cases was rather superficial.
This shows that the indications should be widened for CATCH22
FISH analysis: developmental delay only (+/- dysmorphic face, muscular
hypotonia or failure to thrive).
P0044. Caudal duplication syndrome with unilateral hypoplasia
of the pelvis and lower limb and ventriculo-septal heart defect
K. Becker 1 , K. Howard 1 , D. Klazinga 2 , C. Hall 3 ;
1 North Wales Clinical Genetics Service, Glan Clwyd Hospital, Bodelwyddan,
Rhyl, United Kingdom, 2 Department of Obstetrics and Gynaecology, Glan Clwyd
Hospital, Bodelwyddan, Rhyl, United Kingdom, 3 Department of Radiology,
Great Ormond Street Hospital For Sick Children, London, United Kingdom.
Dominguez et al. (1993) reported six cases with caudal duplication
syndrome and reviewed eight reports from the literature. Kroes et al.
(2002) reported another two cases, including discordant monozygotic
twins. The phenotypic spectrum encompasses gastrointestinal anomalies
(intestinal duplication including double appendix, anal duplication,
small bowel atresia or webs, intestinal malrotation, imperforate
anus, omphalocele, esophageal cysts), genitourinary tract anomalies
(duplication of external genitalia, vagina, bladder, urethras, cervix and
uterus, single pelvic or malrotated kidney) and abnormalities of the
spinal cord. We report a 22 year old female with caudal duplication
syndrome, who in addition to intestinal duplication, imperforate anus, a
dydelphic uterus and a single kidney also had a VSD and hypoplasia of
the left pelvis, leg, labia majora and left side of a duplicated vagina.
P0045. Forget the classic CDG phenotype; a broad spectrum of
congenital anomalies in CDG type II
E. Morava 1 , R. Zeevaert 2 , M. Guillard 1 , D. Lefeber 1 , R. Wevers 1 ;
1 UMC Nijmegen, Nijmegen, The Netherlands, 2 UMC Leuven, Leuven, Belgium.
CDG type Ia, the most common form of Congenital Disorders of Glycosylation
presents with characteristic symptoms of hypotonia, strabismus,
arachnodactyly, cerebellar hypoplasia, abnormal lipid distribution
and gastrointestinal, endocrine and coagulation abnormalities.
Patients with CDG type II, diagnosed with a glycosylation disorder due
to Golgi dysfunction and abnormal transferrin isoelectric focusing in
blood, have very different clinical features. Mutations in COG7, coding
for one of the 8 subunits of the Conserved Oligomeric Golgi complex,
lead to a new clinical syndrome of growth retardation, severe progressive
microcephaly, adducted thumbs, gastrointestinal pseudo-obstruction,
cardiac anomalies, wrinkled skin and episodes of extreme hyperthermia.
Features in COG1 deficient patients include hypotonia, developmental
delay, ventricular hypertrophy/cardiac dysfunction and a
rhizomelic short stature. The single patient described so far with COG8
mutation showed a phenotype similar to that in mitochondrial disease.
Other defects affecting the biosynthesis of both N- and O- linked glycosylation
with hyposialylation include a new subtype of autosomal
recessive cutis laxa syndrome with neonatal cutis laxa, microcephaly
with large fontanel, hypotonia and failure to thrive. Despite the clinical
and biochemical diagnosis in an increasing number of patients with