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

Clinical genetics
P0072. Cranioectodermal dysplasia (Sensenbrenner’s
syndrome): Report of two siblings
A. Latos-Bielenska 1 , J. Walczak-Sztulpa 2 , M. Szczepańska 1 , M. Krawczyński 1 ,
J. Zachwieja 1 , A. W. Kuss 2 , H. H. Ropers 2 , D. Zwolińska 3 , A. Tzschach 2 ;
1 University of Medical Sciences in Poznan, Poznan, Poland, 2 Max Planck Institute
for Molecular Genetics, Berlin, Germany, 3 University of Medical Sciences in
Wrocław, Wrocław, Poland.
Cranioectodermal dysplasia (CED, Sensenbrenner’s syndrome, OMIM
218330) is a rare disorder characterized by dolichocephaly, rhizomelic
dwarfism, dental and nail dysplasia, sparse hair and renal problems.
Among about 20 cases reported to date, most are sporadic, but few
familial cases suggest autosomal recessive inheritance. So far, the
underlying genetic defect is unknown, and linkage analyses were not
possible due to the limited number of patients and small family sizes.
Here, we report on a 5-year-old girl and her 1-year-old brother with cranioectodermal
dysplasia. Their healthy parents (16- and 25-year-old at
the birth of the first child) are remotely consanguineous which supports
the assumption of autosomal recessive inheritance. Clinical features
included short stature with rhizomelic shortening of limbs, brachydactyly,
narrow chest, craniosynostosis, dolichocephaly, full cheeks, telecanthus,
broad nasal bridge, small and widely spaced teeth, dysplastic
auricles and fine, sparse hair, bilateral inguinal hernia and hyperelastic
skin. Psychomotor development is normal. Both children suffer from
tubulointerstitial nephropathy with more severe features in the brother.
We present detailed clinical features of the patients in comparison to
previously reported cases, as well as prenatal features of the syndrome
detected on ultrasound examinations.
P0073. Spectrum of HLXB9 gene mutations in Currarino
syndrome and genotype-phenotype correlation
C. Crétolle1 , D. Sanlaville2 , M. Zérah1 , C. Fékété1 , A. Munnich1 , S. Lyonnet1 ;
1 2 Hôpital Necker-Enfants Malades, PARIS, France, Hôpital Hôtel-Dieu, LYON,
France.
Currarino syndrome (CS) (OMIM 176450) is a rare congenital disease
described in 1981 as an association of three main features: typical
sacral malformation (sickled-shape sacrum or total sacral agenesis
below S2), hindgut anomaly and pre-sacral tumor. Moreover, neurological
defects, namely tethered cord and/or lipoma of the conus, are
also frequent and has to be search for as they may lead to severe
complications if not treated.
CS is ascribed in half of cases to heterozygous mutations of the HLXB9
gene (OMIM 142994) located at 7q36, with an autosomal dominant
mode of inheritance. HLXB9 gene encodes the HB9 protein, a 403
amino acid transcription factor that interacts with DNA through a highly
evolutionarily conserved homeodomain, involved in embryological development.
Thus far, 41 different heterozygous mutations have been
described in clinically typical CS patients, mostly in familial cases (90
% of cases).
In this work, we describe 23 novel mutations in 26 mutated patients
of a 50 index patients’ series harbouring clinical CS (22 males and 28
females). Mutations concerned 19/20 familial forms and 7/30 sporadic
cases. Sex predominance was not observed. Truncating mutations
(frameshift or non-sens) represents 56.4 % of cases, suggesting that
haploinsufficiency is the basis of CS. No obvious genotype-phenotype
correlation could be identified. A genetic heterogeneity is suspected as
at least 16 from the 24/50 not mutated patients harboured subtle phenotypic
variations, and other genes probably account for cases with no
mutation of the HLXB9 gene.
P0074. Clinical and Molecular study of 17 patients with Cutis
Laxa
S. Hadj-Rabia1 , M. Devillers2 , C. Bodemer2 , H. Megarbané2 , J. Pauchard2 , C.
Blanchet-Bardon2 , P. Sommer2 , J. Fischer2 ;
1 2 Dermatology, Paris, France, *Cutis laxa Network, contact: p.sommer@ibcp.fr
or mdevillers@afm.genethon.fr, Evry, France.
Among different disorders with elastic fibres deficiencies, cutis laxa
(CL) comprises a clinically and genetically heterogeneous group of
acquired and genetic disorders characterized by loose, sagging and
inelastic skin. Mutations in at least two genes, elastin (ELN) and fibulin5
(FBLN5), are known to be causative for CL.
Fifteen patients from four families presented: herniae (inguinal n=7,
umbilical n=1), pulmonary emphysema (n=5), ankle laxity (n=2), mitral
insufficiency (n=1), aorta dilatation (n=1), pulmonary arterial hypertension
(n=1), vaginal prolapse (n=1), dysuria (n=3). Skin presented as
inelastic on the face with inguinal folds during infancy (n=4), thick folds
on the face during the third decade (n=5), and loose skin on the neck
after 40 years (n=7). three deletions of 1 bp (n=13) and one deletion of
15bp (n=2) were detected in ELN gene.
A 11y old boy and his 8 y old sister, presented both with loose skin,
bilateral inguinal hernia and hoarse voice, right ventricle dilatation
(n=1), pulmonary emphysema (n=1). Homozygous missense mutation
in FBLN5 was identified.
CL is a systemic disorder with dermatologic, pulmonary and cardiovascular
features. Patients with mutations in FBNL5 all present a severe
phenotype, whereas intrafamilial clinical heterogeneity is observed in
families with mutations in ELN.
Skin involvement evolves over time: thick folds during infancy, wrinkled
chin during third decade and loose skin after 40 years.
Patients affected by CL should undergo systematic exploration of clinical
features, but should also take advantage of molecular analysis to
confirm the genetic basis of their phenotype.
P0075. Identification of two Alu insertions in the CFTR gene
E. Masson1 , M. Audrézet1 , M. Macek2 , O. Raguénès1 , B. Fercot1 , J. Chen3 , C.
Férec1 ;
1 2 CHU-INSERM U613, Brest, France, Institute of Biology and Medical Genetics,
Prague, Czech Republic, 3EFS–Bretagne, Brest, France.
LINE-1 (long interspersed element-1) or L1-mediated retrotransposition
is a potent force in human genome evolution and an occasional
cause of human genetic disease. Since the first report of two de novo
L1 insertions in the F8 gene causing hemophilia A, more than 50 L1mediated
retrotranspositional events have been identified as causing
human genetic disease.
On the basis of the observation that both L1 elements and Alu sequences
are abundant in the human genome, the increasing number
of genomic rearrangements reported in the CFTR gene, and the fairly
large size of the CFTR gene, we surmised that some previously unresolved
CF chromosomes might carry hitherto undetected L1-mediated
retrotranspositional insertions.
This study report the identification of two simple Alu insertions using
quantitative high-performance liquid chromatography (QHPLC), technique
previously employed to delineate the boundaries of large genomic
deletions in the CFTR gene.
The first one, identified in a 24-year-old French girl, carrying F508del
on the other chromosome, correspond to a 103 pb antisense insertion
in exon 16 containing an Alu sequence of 46pb and a poly(A) tail of
57pb. The second one, identified in a 28-year-old Czech man, correspond
to a 337pb sense insertion of an Alu sequence of 281 pb and a
poly(A) tail of 56 pb. Both mutations are presumed to lead to aberrant
splicing.
The identification of these two simple Alu insertions in the CFTR gene
revealed a previously unknown mutational mechanism responsible for
CF and also represents an important addition to the already diverse
spectrum of CFTR gene mutations.
P0076. Attempts to explain why Cystic Fibrosis is of lower
prevalence in the Greek-Cypriot population
N. Stavrou1 , K. Voskarides1 , V. Neokleous2 , C. Deltas1,2 ;
1Department of Biological Sciences, University of Cyprus, Lefkosia, Cyprus,
2The Cyprus Institute of Neurology and Genetics, Lefkosia, Cyprus.
Cystic fibrosis (CF) is one of the most frequent autosomal recessive
diseases in Europe. In Cyprus, the prevalence appears lower compared
to the rest of European populations (carrier frequency 1/44).
An exception is a village in which 1:14 individuals is carrier of mutation
F508del probably because of a founder effect. We hypothesised
that undiagnosed mild cases on the island may give an erroneous impression
of lower prevalence while mild mutations may be responsible
for cases of male sterility.Mild mutations R117C and L346P were not
found in 200 Greek-Cypriot samples, concluding that their frequency is
lower that 0.25%. Variant M348K was found in two individuals in heterozygosity,
giving allele frequency of 0.5%. Two other polymorphisms
next to each other in intron 8 are: a TG repeat with known alleles of 11,
12 or 13 repeats and a stretch of 5, 7 or 9 thymines. We designed a
new approach for detecting the disease allele 5T, that includes nested
2