2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
P02.053
Genotype-Phenotype correlations in Best Vitelliform macular
Dystrophy
G. Querques 1,2 , J. Zerbib 3 , R. Santacroce 4 , M. Margaglione 5,6 , J. Rozet 7 , D.
Martinelli 8 , N. Delle Noci 1 , G. Soubrane 3 , E. Souied 3 ;
1 Department of Ophthalmology - University of Foggia, Foggia, Italy, 2 Department
of Ophthalmology,University Paris XII, Paris, France, 3 Department of Ophthalmology
- University Paris XII, Paris, France, 4 Genetica Medica- University
of Foggia, Foggia, Italy, 5 Genetica Medica - University of Foggia, Foggia, Italy,
6 Unita’ di Emostasi e Trombosi,I.R.C.C.S. “Casa Sollievo della Sofferenza”, San
Giovanni Rotondo- Foggia, Italy, 7 Department of Genetics, Necker Hospital,
University Paris V, Paris, France, 8 Department of Hygiene, Policlinico di Bari,
University of Bari, Bari, Italy.
The Best disease has an autosomal dominant pattern of inheritance
with very highly variable expressivity. Our purpose was to determine
the genotype-phenotype correlation in Best VMD patients with heterozygous
or homozygous mutations in the VMD2/BEST1 gene. Best
VMD patients and relatives that presented consecutively at the Créteil
University Eye Clinic and at the Foggia University Eye Clinic were included
in this prospective study. They were evaluated prospectively regarding
age, age at onset, best-corrected visual acuity (BCVA), fundus
autofluorescence (FAF), fluorescein angiography (FA), optical coherence
tomography (OCT), electro-oculography (EOG).
All 11 exons of VMD2/BEST1 were amplified by PCR and mutation
analysis was carried out by sequencing these PCR products. All exons
were screened in all probands. We identified 9 different VMD2 mutations
(2 novel), in 7 unrelated families and 3 isolated cases (9 heterozygous,
and 1 homozygous). Patients presented with various stages
of the disease, from absence of clinically detectable lesions / previtelliform
lesions to and-stage lesions. The patients age ranged between
3 and 75 years. Age at onset varied between 2 and 67 years. BCVA
ranged between 20/20 and 20/200. Even with the same mutation, the
age at onset and the disease progression was highly variable interfamilially
and intrafamilially. No association existed between the specific
nature of VMD2/BEST1 mutations and expressivity, as regards age,
age at onset, BCVA, and stage of the disease as evaluated by FAF,
FA, OCT (p>.05).The type of VMD2/BEST1 mutations were not associated
with the severity of the phenotype in the Best VMD patients
determined.
P02.054
Identification of the common NEMO rearrangement in Korean
patients with incontinentia pigmenti
M. J. Song 1 , E. A. Park 2 , J. H. Chae 3 , C. S. Ki 1 ;
1 Samsung Medical Center, Seoul, Republic of Korea, 2 Ewha Womans University,
Seoul, Republic of Korea, 3 Seoul National University Hospital, Seoul,
Republic of Korea.
Incontinentia pigmenti (IP) is a rare X-linked dominant disorder characterized
by highly variable abnormalities of the skin, hair, nails, teeth,
eyes, and central nervous system. Mutation of NEMO/IKBKG gene in
Xq28 is believed to play a role in pathogenesis and it occurs mostly
in female patients due to its fatality in male in utero. Although many
patients have been reported worldwide, there are no genetically confirmed
patients in Korea. In the present study, we performed a genetic
analysis on the NEMO gene in four Korean female patients clinically
diagnosed with IP. All the patients had typical clinical manifestations
of IP including abnormal skin pigmentation, nail and dysplasia. Deletion
of exons 4 to 10 in NEMO gene, the most common mutation in IP
patients, was detected in all the patients by the long-range polymerase
chain reaction (PCR) test. This method enabled us to discriminate between
NEMO gene and pseudogene (ΔNEMO) rearrangement. Therefore,
a PCR-based analysis of the NEMO gene is useful to establish
the definitive diagnosis of IP for a timely treatment to improve patient
prognosis. Furthermore, all the patients showed completely skewed
patterns of X-inactivation, indicating cells carrying the mutant X as the
pathogenicity of the disease. To the best of our knowledge, this is the
first report of genetically confirmed cases of IP in Korea. More investigations
are needed to identify genotype-phenotype correlations and
ethnicity-specific genetic background of IP.
P02.055
A very early juvenile Huntington disease revealed by cerebellar
ataxia in a 2 years old boy
L. Guyant-Marechal 1 , A. Goldenberg 1 , C. Hervé 2 , L. Delhaye 2 , M. Brasseur-
Daudruy 2 , V. Drouin-Garraud 1 , P. Saugier-Veber 1 , T. Frebourg 1 , D. Hannequin 1 ,
D. Devys 3 ;
1 Inserm and Rouen University Hospital, Rouen, France, 2 Rouen University
Hospital, Rouen, France, 3 Strasbourg University Hospital, Strasbourg, France.
Juvenile Huntington disease (JHD) is a rare clinical entity characterized
by an age of onset of Huntington disease (HD) younger than 20.
JHD accounts for 1% to 10% of the HD cases. In 80% to 90% of cases,
transmission of JHD is paternal. Patients with JHD have usually more
than 60 CAG repeats within the IT15 gene. We report on the case of
the 4 th child of unrelated parents. He was seen at the age of 23 months
for absence of unaided walk and delayed speech. His development
was considered as normal until 15 months of age, when an insufficient
weight gain was noted and motor delay appeared. Clinical examination
showed truncal hypotonia, postural and intentional tremor, lower limbs
rigidity and ataxia. Cerebral MRI showed cerebellar atrophy. Extensive
chromosomal and metabolic screening was normal. Six months later,
his father, 47 years old, was seen for a 4 years history of progressive
dementia with severe behavioural disturbance and chorea. MRI
was normal. DNA analysis revealed a 43 CAG expansion of the IT15
gene in the father and a very large expansion (more than 100 CAG)
in the child. This unusual case shows that very early onset JHD due
to large CAG expansions should be considered in case of motor skills
delay associated to cerebellar atrophy. In addition, this observation
highlights the diagnosis pitfall of JHD in young children especially if the
diagnosis is not yet established in the parents.
P02.056
congenital heart defects in Kabuki syndrome
M. C. Panzaru, C. Rusu, M. Volosciuc, E. Braha, L. Butnariu, M. Covic;
Medical Genetics Centre, Iasi, Romania.
Kabuki syndrome (KS) is a congenital mental retardation syndrome
with additional features, including distinctive facial features, dermatoglyphic
abnormalities and short stature. Some cases associate heart
defects. Most cases are sporadic. The underlying genetic mechanism
remains unknown.
We have analysed the prevalence and types of congenital cardiac defects
in 20 children with Kabuki syndrome recorded in the files of Iasi
Medical Genetics Center . There were 7 girls and 13 boys, diagnosed
at a median age of 4.9 years (ranges from 0.2 to 13 years). ). The
diagnosis was based on the presence of the characteristic features of
the disorder. Cardiac defects were present in 9 children (45%) - atrial
septal defect (35%), coarctation of the aorta, aortic stenosis, bicuspid
aortic valve (5%) and dextroposition (5%). The prevalence of heart defects
was higher in boys (53,8%) than in girls (28,5%). Complex heart
defects were present only in males. In the literature aortic coarctation,
atrial septal defect and ventricular septal defect are the most frequent
congenital heart defects associated with Kabuki syndrome. The comparison
of our data and the literature data will be presented in detail.
In conclusion we present a study of 20 cases with Kabuki make-up
syndrome, 45% of them having heart defects. Cardiac defects are
commonly associated to KS and males are more frequently and severely
affected than females. Patient’s prognosis depends on the presence/
absence of cardiac defects, renal failure and severity of mental
retardation.
P02.057
Kabuki make-up syndrome in two tunisian girls with
consanguinity and background of mental disability
N. B. Abdelmoula1 , I. T. Sahnoun2 , R. Louati1 , S. Kammoun2 , T. Rebai1 ;
1 2 Medical University, Sfax, Tunisia, Department of Cardiology, CHU Hedi
Chaker, Sfax, Tunisia.
Kabuki makeup syndrome (KS) is characterized by distinct facial
anomalies, mental retardation, congenital heart defect (CHD), and
skeletal malformations.
In the present study, we report two Tunisian girls, who fulfilled clinical
criteria of KS syndrome, diagnosed in the course of our genetic testing
strategy of CHD at the medical university of Sfax.
Patient 1 is a 9-year-old girl who had partial atrioventricular canal
defect and patient 2 is a 17-year-old girl who had double outlet right