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

Clinical genetics
growth retardation and associated malformations. If confirmed, these
data may have important implications for directing mutation screening
in CdLS.
P0068. Mutation analysis of the NIPBL and the SMC1L1 gene in
German patients with suspected Cornelia de Lange syndrome.
H. Gabriel 1 , D. Glaeser 2 , A. Dalski 3 , M. Gencik 1 , D. Lohmann 4 , G. Gillessen-
Kaesbach 3 ;
1 Zentrum fuer Medizinische Genetik, Osnabrueck, Germany, 2 Zentrum für
Humangenetik, Georg Mendel Laboratorien, Neu-Ulm, Germany, 3 Institut fuer
Humangenetik, Universitätsklinikum Lübeck, Germany, 4 Institut fuer Humangenetik,
Universitätsklinikum Essen, Germany.
Cornelia-de-Lange-syndrome (CdLS) is a heterogeneous autosomaldominant
disorder characterized by typical facial features, growth retardation,
developmental delay, upper-extremity malformations and a
variety of other abnormalities.
The prevalence of CdLS is estimated to be around 1/10,000. Most
cases are sporadic, although several familial cases are described.
Since 2004 it is known that up to 50% of CdLS cases are caused
by mutations in the NIPBL gene on chromosome 5p13, the human
homolog
of the Drosophila Nipped-B gene. This gene consists of 47 exons and
mutations were found in the entire coding region.
Recently, Musio et al. described an X-linked form of mild CdLS caused
by mutations in the gene SMC1L1 (=SMC1).
Both genes code for proteins, which are part of the cohesin complex
involved in chromosome cohesion.
We investigated the prevalence of NIPBL gen mutations in 108 German
patients with suspected CdLS by DGGE and/or direct sequencing.
Additionally, mutation analysis of the SMC1L1 gene was performed
in all patients tested negative for mutations in the NIPBL gene. We
detect_
ed NIPBL gene mutations in 29 (=27%) of our patients, although previous
studies reported a higher detection rate (ca. 50%). Our lower
detection rate is probably due to patient selection.
Furthermore, the prevalence of SMC1L1 mutations in our cohort will
be discussed.
P0069. Genotype -phenotype analysis of cerebral dysgenesis
associated with TUBA1A mutations
N. Bahi-Buisson 1,2 , K. Poirier 2 , N. Boddaert 1 , Y. Saillour 2 , I. Desguerre 1 , S.
Joriot 3 , S. Manouvrier 3 , M. Barthez 4 , A. Toutain 4 , V. Drouin-Garaud 5 , A. Goldenberg
5 , S. Marret 5 , H. Van Esch 6 , L. Lagae 6 , D. Ville 7 , L. Hertz-Pannier 1 , M.
Moutard 8 , C. Beldjord 9,10 , J. Chelly 2 ;
1 Necker Enfants Malades, APHP, Université Paris V, Paris, France, 2 INSERM
U567, University Paris V, Paris, France, 3 Lille University Hospital, Lille, France,
4 Tours University Hospital, Tours, France, 5 Rouen University Hospital, Rouen,
France, 6 Leuven University Hospital, Leuven, Belgium, 7 Lyon University Hospital,
Lyon, France, 8 Trousseau, APHP, Paris, France, 9 Cochin, APHP, Université
Paris V, Paris, France, 10 INSERM U567, University Paris V, Paris, Austria.
Cortical dysgeneses are, in most cases, associated with profound
neurodevelopmental disability, including severe mental retardation
and epilepsy. Two major genes DCX and LIS1 account for almost 40%
of the cases of agyria-pachygyria, and three additional genes (RELN,
ARX, VLDL receptor) are exceptionally mutated. Recently, mutations
in TUBA1A (NM_006009) gene that encoded for an alpha tubulin that
interacts with doublecortin, have been involved in a large spectrum of
neuronal migration disorders. In order to better define the phenotype,
we retrospectively studied seven unrelated patients with pathogenic
TUBA1A mutations.
Patient and methods : Clinical and imaging assessments were performed
in seven patients, aged from to 2 to 16 years with pathogenic
de novo missense TUBA1A mutations.
Results : Patients exhibited congenital microcephaly (6/7), moderate
(5/7) to severe (2/7) mental retardation, spastic diplegia (6/7). Associated
clinical features were more occasional: facial diplegia (5/7),
oropharyngoglossal dysfunction (4/7), and strabismus (3/7). Epilepsy
was reported in 3/7 but only 2 patients have intractable epilepsy. Brain
MRI revealed dysmorphic basal ganglia with balloon shape (7/7), perisylvian
(5/7) to diffuse pachygyria with a posterior to anterior grading
(2/7), dysmorphic (5/7) or hypotrophic (2/7) corpus callosum, mild (3/7)
to severe (2/7) vermian hypoplasia.
Conclusions : Albeit each symptom observed in TUBA1A mutated
patients is not specific, our data highlight a potentially specific distinguishable
combination of developmental features that is not seen in
neurodevelopmental disorders resulting from mutations in DCX, LIS1
and ARX. We suggest that this specific neuro-clinical combination
should lead the clinician to the search of TUBA1A mutations.
P0070. Diversity, parental germline origin and phenotypic
spectrum of de novo HRAS missense changes in Costello
syndrome
G. Zampino 1 , F. Pantaleoni 2 , C. Carta 2 , G. Cobellis 3,4 , C. Neri 5,6 , A. Sarkozy 5,6 ,
F. Atzeri 7 , A. Selicorni 7 , K. A. Rauen 8 , R. Weksberg 9 , B. Dallapiccola 5,6 , A. Ballabio
3,4 , B. D. Gelb 10 , G. Neri 1 , M. Tartaglia 2 ;
1 Università Cattolica, Rome, Italy, 2 Istituto Superiore di Sanità, Rome, Italy,
3 Università “Federico II”, Naples, Italy, 4 TIGEM, Naples, Italy, 5 IRCCS-CSS, San
Giovanni Rotondo, Italy, 6 Istituto CSS-Mendel, Rome, Italy, 7 Clinica Pediatrica
De Marchi, Milano, Italy, 8 University of California, San Francisco, CA, United
States, 9 Hospital for Sick Children, Toronto, ON, Canada, 10 Mount Sinai School
of Medicine, New York, NY, United States.
Activating mutations in HRAS have recently been identified as the
molecular cause underlying Costello syndrome (CS). To investigate
further the phenotypic spectrum associated with germline HRAS mutations
and characterize their molecular diversity, subjects with a diagnosis
of CS, Noonan syndrome, cardiofaciocutaneous syndrome or with
a phenotype suggestive of these conditions but without a definitive
diagnosis were screened for the entire coding sequence of the gene. A
de novo heterozygous HRAS change was detected in all the subjects
diagnosed with CS, while no lesion was observed with any of the other
phenotypes. While eight cases shared the recurrent 34G>A change,
a novel 436G>A transition was observed in one individual. The latter
affected residue Ala146, which contributes to GTP/GDP binding, defining
a novel class of activating HRAS lesions that perturb development.
Clinical characterization indicated that Gly12Ser was associated with
a homogeneous phenotype. By analyzing the genomic region flanking
the HRAS mutations, we traced the parental origin of lesions in nine
informative families and demonstrated that de novo mutations were
inherited from the father in all cases. We noted an advanced age at
conception in unaffected fathers transmitting the mutation.
P0071. Crane-Heise syndrome: a further case broadening the
clinical spectrum
M. Holder-Espinasse 1 , L. Devisme 2 , V. Houfflin-Debarge 3 , C. Chafiotte 4 , A.
Dieux-Coeslier 1 , S. Manouvrier-Hanu 1 ;
1 Service de Génétique Clinique, Hôpital Jeanne de Flandre, Lille, France, 2 Service
d’anatomopathologie, Eurasanté, Lille, France, 3 Maternité, Hôpital Jeanne
de Flandre, Lille, France, 4 Service de Radiologie, Hôpital Jeanne de Flandre,
Lille, France.
Crane-Heise syndrome is a rare lethal and autosomal recessive condition
which has been first reported in 1981 in three siblings presenting
with intrauterine growth retardation, a poorly mineralised calvarium,
characteristic facial features comprising cleft lip and palate, hypertelorism,
anteverted nares, low-set and posteriorly rotated ears, vertebral
anomalies and absent clavicles. Since then, to our knowledge,
only one isolated case and two siblings were reported with similar findings.
In 2003, distal phalangeal hypoplasia, mild cardiac and gastrointestinal
anomalies were suggested as additional features. We present
a further case, diagnosed after a termination of pregnancy at 24 weeks’
gestation, very similar to the previously reported ones, and broaden the
clinical spectrum of this entity. On the 20 weeks’gestation ultrasound
scan, a laparoschisis was identified, with poor fetal movements and
polyhydramnios. Fetal chromosomes were normal 46XX. Pathological
examination confirmed the laparoschisis but also revealed facial dysmorphic
features, multiple joint contractures, a cleft palate, and severe
vertebral as well as limb anomalies. Skeletal x-rays showed absent
clavicles, undermineralisation of the skull, micrognathia, and abnormal
phalanges. We discuss the clinical and radiological phenotype of this
rare condition.To our knowledge, no molecular mechanism has been
identified in Crane-Heise syndrome so far.
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