2009 Vienna - European Society of Human Genetics

Molecular basis of Mendelian disorders
Bethesda, MD, United States, 5 Génétique Médicale, Hôpital de la Croix Rousse,
Lyon, France, 6 Department of Neurology, Hôpital du Haut Lévêque, University
Bordeaux 2, Pessac, France, 7 Department of Neurology, UHMS, Geneva,
Switzerland, 8 Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France,
9 Service de génétique, CHU, Dijon, France, 10 Laboratoire Physiopathologie
des Syndromes Rares Héréditaires, AVENIR-Inserm, EA3949, Université Louis
Pasteur, Strasbourg, France, 11 Department of Molecular Neuroscience, Institute
of Neurology, UCL, London, United Kingdom.
Spinocerebellar ataxia type 15 (SCA15/16) is a recently identified
dominant ataxia caused by mutations in type 1 inositol 1,4,5-triphosphate
receptor (ITPR1). Molecular analysis used micro array to detect
rearrangements as described before (van de Leemput, PLoS Genet
2007) in 76 index cases with autosomal dominant cerebellar ataxia
excluded from polyglutamine expansions. Four index cases (5%) carried
a heterozygous ITPR1 deletion; exact size of the deletions has not
been yet determined.
There were 12 patients in 4 families with a mean age at onset of 35±
15.8 years (n=11; range 18-66); mean disease duration of 15.8± 13
years (n =11; range 1-43). The first symptom was cerebellar gait ataxia
in 10/11; one patient presented with writing difficulties and hand tremor.
All patients developed progressive gait and limb ataxia, with dysarthria
in 9 cases. Disease progression was slow in most, none was wheelchair
bound. Ocular abnormalities included the presence of nystagmus
(n=9), saccadic pursuit (n=5) and intermittent diplopia (n=4). Only one
patient had pyramidal signs. Extrapyramidal signs, cognitive decline or
sensory abnormalities were absent. Cerebral MRI revealed vermian
atrophy in six patients and global cerebellar atrophy in three.
In conclusion SCA 15/16 is rare among French patients with dominant
cerebellar ataxia. The overall phenotype is pure cerebellar ataxia with
slow disease progression.
P12.147
SHH mutations are an uncommon cause of developmental eye
anomalies
S. A. Ugur Iseri 1 , P. Bakrania 1 , A. Wyatt 1 , D. J. Bunyan 2 , W. W. K. Lam 3 , D. R.
Fitzpatrick 4 , D. Robinson 2,5 , N. K. Ragge 1,6,7 ;
1 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford,
United Kingdom, 2 Wessex Regional Genetics Laboratory, Salisbury District
Hospital, Salisbury, Wiltshire, United Kingdom, 3 Department of Clinical Genetics,
Western General Hospital, Edinburgh, United Kingdom, 4 Medical Genetics
Section, MRC Human Genetics Unit, Western General Hospital, Edinburgh,
United Kingdom, 5 National Genetics Reference Laboratory (Wessex), Salisbury
District Hospital, Salisbury, Wiltshire, United Kingdom, 6 Moorfields Eye Hospital
NHS Foundation Trust, London, United Kingdom, 7 Department of Ophthalmology,
Birmingham Children’s Hospital, Birmingham, United Kingdom.
Sonic hedgehog (SHH) gene encodes a key morphogen implicated in
patterning of the ventral neural tube, the anterior-posterior limb axis
and the ventral somites. Mutations in SHH are a cause of holoprosencephaly
(HPE), a disorder in which the developing forebrain fails
to separate correctly into right and left hemispheres. HPE presents a
wide spectrum of clinical severity, ranging from cyclopia, proboscis-like
nasal structure and midfacial clefting in most severe cases to microcephaly,
mild hypotelorism, and eye and tooth anomalies in the milder
ones. Familial cases of HPE are typically inherited in an autosomal
dominant fashion with reduced penetrance and variable expressivity.
In this study, we screened the gene SHH in a cohort of 250 cases with
anophthalmia-microphthalmia and coloboma via chromosome analysis,
dosage analysis with by multiplex ligation-dependent probe amplification
(MLPA), high resolution melting curve analysis and bidirectional
DNA sequencing. These efforts collectively led to identification
of an interstitial deletion on chromosome 7q36.1-q36.3 including the
SHH gene in a girl with microphthalmia in the right eye and coloboma
of the iris and retina in the left eye, a novel 24bp SHH intragenic deletion
in a girl with unilateral microphthalmia, and a missense mutation in
a boy with unilateral microcornea, microphthalmia and iris coloboma.
Our results suggest that the SHH mutations are an uncommon cause
of AM.
P12.148
the involvement of Pi3K signalling pathway in spinal muscular
atrophy risk disease: preliminary molecular data
M. Stavarachi 1 , M. Toma 1 , P. Apostol 1 , D. Cimponeriu 1 , N. Butoianu 2 , N. Panduru
3 , L. Gavrila 1 ;
1 University of Bucharest, Institute of Genetics, Bucharest, Romania, 2 ”Al.Obregia”
Clinical Psychiatry Hospital, Bucharest, Romania, 3 ”N. Paulescu” Institute,
Bucharest, Romania.
Spinal muscular atrophy (SMA) is a genetic condition characterized
by motor neuron apoptosis, followed by progressive muscle weakness
and in many cases by death. It is well known that the disease determining
gene is SMN, but the molecular mechanism is still unclear. The
PI3K signalling pathway has been often reported as being responsible
for the motoneuronal death and can be involved in SMA onset or evolution.
We proposed to evaluate the involvement of PI3KR1 and IGF1R genes
polymorphisms (rs3730089 and rs2229765) in SMA risk disease.
In the study were included 38 SMA patients clinically and molecular
diagnosed, after the informed consent was obtained. The PI3KR1 and
IGF1R genes polymorphisms genotyping was also assessed for 31
control subjects, without neuromuscular problems. Statistical analyses
were therefore performed.
The Hardy-Weinberg equilibrium law was respected for the both polymorphisms.
The odd ratios with 95% confidence intervals estimated
for the risk genotypes, do not revealed statistically significant results.
In the case of PI3KR1 gene, the OR AA = 0.81, 95% CI:0.0487