2008 Barcelona - European Society of Human Genetics

Clinical genetics
birth defects is similar to developmental anomalies that are observed in
an animal model with vitamin A or retinoic acid deficiency. We describe
an infant with hypoplastic left heart, right pulmonary artery and lung hypoplasia,
eventration of right hemidiaphragm, complete hypospadias
and absent gonads . The karyotype was normal (46,XY) and FISH for
SRY locus was present . Endocrine evaluations were suggestive of primary
hypogonadism . Low testosterone, AMH (anti mullerian hormone)
and Inhibin B values along with absence of visualized testicular tissue
and Mullerian structures by imaging studies, indicated a defect in early
embryogenesis . Interestingly, the level of plasma free retinol was low,
consistent with severe vitamin A deficiency, supporting the hypothesis
that a defect in vitamin A metabolism may have an etiological role in
this syndrome with multiple congenital anomalies .
P01.343
Perrault syndrome: Report of Four New cases, Review and
Exclusion of candidate Genes
S. Marlin 1,2 , D. Lacombe 3 , L. Jonard 4 , N. Leboulanger 4 , D. Bonneau 5 , C.
Goiset 3 , T. Billette de Villemeur 4 , S. Cabrol 4 , M. Houang 4 , D. Feldmann 4 , F.
Denoyelle 4 ;
1 Hôpital Armand Trousseau, paris, France, 2 INSERM U587, Centre de référence
des surdités génétiques, Paris, France, 3 Hôpital Pellegrin, Bordeaux,
France, 4 Hôpital Armand Trousseau, Paris, France, 5 CHU, Angers, France.
Sensorineural hearing impairment and ovarian dysgenesis are the
main clinical signs of the Perrault syndrome. This syndrome was first
described by Perrault et al in 1951. Since this first report, about 30
cases were described . More recently, some authors have reported
neurologic abnormalities in Perrault syndrome, in particular progressive
cerebellar ataxia and mental retardation . We present here on
three sporadic and two familial new cases of Perrault syndrome . Only
two of them present with neurological defect . We analyse the clinical
features of this five patients and review the published cases in order
to evaluate the frequency of the neurological defect in this syndrome .
Moreover, we exclude GBG2, POLG and FOXL2 as candidate genes
in Perrault syndrome .
P01.344
susceptibility markers for PFAPA disease
R. Gershoni-Baruch 1,2 , E. Dagan 1,3 , K. Ihab 4 , A. Mori 1 , N. Amar 1 , R. Brik 4,2 ;
1 Rambam Health Care Campus, Institute of Human Genetics, Haifa, Israel,
2 The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Institute of
Technology, Haifa, Israel, 3 Department of Nursing, University of Haifa, Haifa,
Israel, 4 Rambam Health Care Campus, Department of Pediatrics, Haifa, Israel.
Periodic fever syndrome (PFAPA) is characterized by aphthous stomatitis,
pharyngitis and cervical adenitis . The periodic fever and autoinflammatory
syndromes constitute a group of diseases characterized
by repeated febrile illnesses associated with various other symptoms .
Except for PFAPA, the genetic basis of each of these diseases is
known . Predominant mutations in MEFV, TNF1A and CARD15/NOD2
were analyzed in 57 children diagnosed with PFAPA .
Children with PFAPA were carefully selected based on clinical signs
and symptoms . All patients were recruited at the Department of Pediatrics,
Meyer Hospital of Children, Rambam-Health Care Campus during
2006-2007 . Parents were invited to include their PFAPA diagnosed
children in the study and to sign inform consent forms as customary .
Clinical information was complemented during physicians-parents encounter
and a blood sample was drawn for molecular testing . PCR and
RFLPs for the predominant mutations in MEFV, TNF1A and CARD15/
NOD2 genes were performed .
The cohort consisted of 57 children with PFAPA [33 (58%) boys; 24
(42%) girls] . The mean age at diagnosis was 30 .64±16 .4 months,
boys were diagnosed earlier than girls (26 .18±13 .83 and 36 .41±18 .32
months, respectively, p=0 .05) . Predominant mutations in the MEFV
genes were found in 16 (28 .1%) children, mutations in TNF1A were
found in 3 (5 .2%) children and mutations in CARD15 also in 3 (5 .2%)
children . The clinical symptoms (e .g . pharangytis, aphthous stomatitis,
abdominal pain and cervical adenitis) were equally manifested
between carriers and non-carriers .
In Israeli children diagnosed with PFAPA a higher frequency of mutations
in MEFV gene were found compared to that observed in the
general population .
P01.345
Analysis of the cAG repeat and A467t and W748s POLG
mutations in iranian patients With multiple sclerosis
H. Soltanzadeh 1 , M. Ataei 2 , M. Shaf 2 , M. Houshmand 2 , M. Nabavi 3 , K. Parivar 4 ,
M. Ariany 5 , M. H. Sanati 2 ;
1 Young researchers club. Science and Research of Islamic Azad University.
National Institute for Genetic Engineering and Biotechnology, Tehran, Islamic
Republic of Iran, 2 National Institute for Genetic Engineering and Biotechnology,
Tehran, Islamic Republic of Iran, 3 Shahed university, Tehran, Islamic Republic
of Iran, 4 Science and Research Islamic Azad University, Tehran, Islamic Republic
of Iran, 5 Special Medical center, Tehran, Islamic Republic of Iran.
Multiple sclerosis (MS) is an autoimmune multifactorial disease that
usually develops in susceptible young adults . A possible involvement
of mitochondria in MS has been postulated because of a higher rate
transmission of the disease from mother to child than from father to
child . Also association between Leber’s Hereditary Optic Neuropathy
a mitochondrial disease and MS is another evidence . Fatigue is a common
problem of the MS patients which is relted to the energy production
difficulty by the mitochondria. To investigate further the relationship
between MS and mitochondria we analysed the gene encoding
for polymerase G (POLG) . Among the nearly 50 disease mutations in
the gene for the catalytic subunit of POLG, The A467T mutant enzyme
possesses only 4% of wild-type DNA polymerase activity .
Polymerase gene (pol G) is a two-subunit complex consisting of a
140-kDa catalytic and a 55-kDa accessory subunit (p55the Nterminalcatalytic
subunit contains a trinucleotide CAG repeat encoding a polyglutamine
tract near the amino-terminus of the protein . Expansions
of similar polyglutamine-encoding CAG microsatellite repeats in other
genes are known to cause neurodegenerative disorders .
Total genomic DNA was extracted from 60 idiopathic Ms Patients and
40 controls . Primers were designed to amplify the 4 hot exones and
CAG repeat length of the gene following by sequencing . The distribution
of the POLG CAG repeat length in the control samples matched
the distribution reported for control samples by others . The analysis
of our sample shows no difference between the CAG repeat length
distribution of control and ms disease samples analysis of exon 7, 8, 9,
and13 of POLG gene from 60 DNA samples of MS patients showed no
mutation . However this does not exclude the association of the gene
in MS but it needs more investigation . Also it is necessary to test the
other exones of the gene .
P01.346
TCF deletions in Pitt-Hopkins syndrome
I. Giurgea1,2,3 , C. Missirian4 , S. Whalen1,2,3 , T. Fredriksen1,2,3 , T. Gaillon1,2,3 , J.
Rankin5 , M. Mathieu-Dramard6 , G. Morin6 , D. Martin-Coignard7 , B. Chabrol8 ,
J. Arfi9 , F. Giuliano10 , J. Lambert10 , L. Villard11 , N. Philip12,9 , M. Goossens1,2,3 , A.
Moncla12,9 ;
1INSERM U841, IMRB, département de génétique, Equipe 11, Créteil, France,
2 3 Université Paris 12, Faculté de Médecine, IFR10, Créteil, France, AP-HP,
Groupe Hospitalier Henri Mondor-Albert Chenevier, Service de biochimie et
génétique, Créteil, France, 42Département de Génétique Médicale, Hôpital
des enfants de la Timone, Marseille, France, 5Department of Clinical Genetics,
Royal Devon and Exeter NHS Foundation Trust (Heavitree), Exeter, United Kingdom,
6Département de Génétique Médicale, CHU d’Amiens - Nord, Amiens,
France, 7Département de Génétique Médicale, CH du Mans, Le Mans, France,
8Service de Neuropédiatrie, Hôpital des enfants de la Timone, Marseille, France,
9Unité INSERM U491 « Génétique Médicale & Développement », Faculté
de Médecine La Timone, Marseille, France, 10Service de Génétique, Hôpital
L’Archet 2, Nice, France, 11Faculté de Médecine La Timone, Marseille, France,
12Département de Génétique Médicale, Hôpital des enfants de la Timone, Marseille,
France.
Background: Pitt-Hopkins syndrome (PHS) is a syndromic mental retardation
disorder marked by hyperventilation episodes and characteristic
dysmorphism (large beaked nose, wide mouth, fleshy lips, and
clubbed fingertips). PHS has been shown to be caused by de novo
heterozygous mutations of the TCF4 gene, located in 18q21 . To expand
the phenotypic spectrum of mutations and deletions of the TCF4
gene, we studied 30 hitherto unexplored patients whose phenotype
overlapped with PHS .
Methods: The TCF4 gene was analysed by QMF-PCR, followed by
sequencing . Large deletions were characterised by CGH array . All patients
were karyotyped .
Results: In three patients, 18q21 .1-q22 .2 deletions were revealed by