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

Clinical genetics
rarely with one of the reasons being underdiagnosis of mild variants.
Our extensive 3-year prospective study (based on the structure of the
Polish Register of Birth Defects) aimed at identifying all new cases of
SLOS in Poland allowed us to detect a four year old boy with a mild
phenotype of SLOS, in whom molecular study of DHCR7 gene demonstrated
a novel mutation.
He was born at 41 weeks of gestation with birth weight 3070 g, OFC -
33,5 cm. Infancy was marked by poor weight gain and recurrent pneumonia.
He walked at 24 months.
At the age of diagnosis he was able to communicate with only few
words and had psychomotor hyperactivity. Weight was ~ 10 centile,
length > 50 centile and OFC < 3 centile. On physical examination subtle
dysmorphic features were noted: bilateral epicanthal folds, blepharoptosis,
short nose with anteverted nares. There was unilateral partial
2 nd and 3 rd toe syndactyly and - within external genitalia - hypospadias
and cryptorchidism. CT of the head revealed hypoplasia of corpus callosum.
Laboratory tests confirmed the clinical diagnosis of SLOS. We found
elevated serum 7-dehydrocholesterol and two missense mutations of
the DHCR7 gene: a novel one mutation c.655T>G (p.Y219D) and a
previously described mutation: c.461C>T (p.T154M), responsible in a
compound heterozygous state for a mild form of SLOS.
The work was supported by grant PBZ-KBN-122/P05/01-10.
P0249. Mutation spectrum and clinical features of SPG4 HSP
C. Depienne1,2 , E. Fedirko2 , B. Bricka2 , E. Denis2 , S. Forlani1 , A. Brice1,2 , A.
Durr1,2 ;
1 2 INSERM U679, Paris, France, Departement de genetique, cytogenetique et
embryologie, Paris, France.
Mutations in SPAST/SPG4, the gene encoding spastin, are the most
frequent cause of autosomal dominant hereditary spastic paraplegia
(AD-HSP). In the context of a systematic routine diagnosis, we investigated
the spectrum of SPG4 mutations and the associated clinical
phenotypes. A large series of 543 patients with either pure or complex
spastic paraplegia, was screneed by denaturing high performance
liquid chromatography (DHPLC) and/or multiplex ligation-dependent
probe amplification (MLPA). We identified 164 (30%) positive families,
133 (25%) of which have substitutions or small deletions/insertions
detected by DHPLC and 31 (6%) which have larger exonic deletions
ranging from one exon to the whole gene, detected by MLPA. The
great majority of the mutations were associated with pure HSP in the
families. However, few families also showed additional features including
cognitive impairment, dementia, mental retardation, peripheral
neuropathy or extra-pyramidal signs. A high proportion of mutations,
especially of missense type, were found in sporadic patients. Phenotype-genotype
correlation showed reduced and age-dependant penetrance,
and we also identified a de novo mutation associated with mosaicism
in one patient. Our findings support the hypothesis of several
mechanisms underlying the penetrance and age at onset variability
including genetic modifiers.
P0250. Delayed speech development with facial asymmetry and
transverse earlobe creases
P. Sarda, L. Pinson, C. Coubes, C. Abadie, P. Blanchet;
Service de Génétique Médicale, Montpellier, France.
Delayed speech is one of the most frequent features in patients with
MCA/MR phenotype. In 1993, Mehes described a Hungarian family
with three patients, a mother and her son and daughter, presenting
delayed speech development, facial asymmetry, strabismus and transverse
earlobe creases (TEC). In 2005, four new unrelated Hungarian
children were reported with similar features.
We describe a new patient, of Spanish and French origins, who presents
a similar phenotype.
The girl was the eutrophic product of a 36 week gestation. No motor
delay was observed but delayed speech marked the development of
the girl. At 4 years autistic behaviour was suspected and psychiatric
therapy was instored. The proposita began to speak at 5 years and her
course was marked by mild mental retardation with anxious behaviour.
At 20 years, weight, height and OFC are in the normal range. The
patient presents facial asymmetry, narrow down-slanting palpebral fissures,
low-set ears with TEC. She has umbilical hernia and hypertrophic
small labia. Skeletal X-rays were normal, cerebral MRI shows
abnormal signal of right putamen. Chromosome studies : metaphase
karyotype, subtelomeric analysis (MLPA), and FISH studies (22q11.2,
11p15) showed no anomaly. Molecular analysis for Beckwith-Wiedemann
syndrome was also normal. This new observation of a patient
with delayed speech development combined with facial asymmetry
and transverse earlobe creases confirms the existence of this new
syndrome. Transverse earlobe creases are a cardinal feature which
is easily found on physical examination. To date, inheritance is not
defined.
P0251. Analysis of the SMN and NAIP genes in Brazilian Spinal
Muscular Atrophy Patients
V. G. Ramos 1 , A. P. Araújo 2 , P. H. Cabello 1 ;
1 Oswaldo Cruz Institute - IOC (FIOCRUZ), Rio de Janeiro, Brazil, 2 Instituto de
Puericultura e Pediatria Martagão Gesteira da Universidade Federal do Rio de
Janeiro, Rio de Janeiro, Brazil.
Spinal muscular atrophies (SMAs) are inherited motor neuron degenerative
disorders that cause progressive muscular weakness, with
high mortality. Three types of SMA were studied, type I, which is the
most severe form, type II or intermediate form, and type III. There are
two genes linked to SMA: the survival motor neuron (SMN) and neuronal
apoptosis inhibitory protein (NAIP). This work has the objective
of showing it is possible to make an efficient molecular diagnosis of
the SMAs by studying genotypic composition of SMN and NAIP genes
in individuals suspected clinically as SMA patients. Nested PCR was
used for both exons 7 and 8 of SMN gene, frequently deleted in SMA
patients, followed by enzymatic digestion and 12% poliacrilamide gel
electrophoresis. For exons 5 and 6 of NAIP gene, PCR was performed
followed by 2% agarose gel. In all groups but SMA patients, no deletions
were observed neither in exons 7 and 8 of SMN gene, nor in
exons 5 and 6 of NAIP gene. This study showed a high frequency
of deletions in SMA patients (88%), and 32% in NAIP gene. It was
not possible to avoid SMA diagnosis, even in those patients without
deletions. DNA study represents an efficient confirmatory test for SMA
patients, demanding a non-invasive sample.
P0252. A rare autosomal recessive skeletal dysplasia: Spondylometa-epiphyseal
dysplasia, short limb- abnormal calcification
type
B. Tüysüz, S. Başaran Yılmaz;
Istanbul University, Cerrahpasa Medical School, Medical Genetics, İstanbul,
Turkey.
A boy 1-month-old boy was referred to our department because of
considered achondroplasia on prenatal USG. The parents are first
cousins. He had one healthy older brother. His weigth and heigth were
3. centile and his head circumference was between 2 and 50 centile.
Clinical findings consist on short limbs with small hands, narrow
chest, flat face, hypertelorism, broad nasal bridge with wide nostils,
hypertelorism, microretrognathia and wide open anterior fontanelle
(6X5 cm). Radiological investigations showed severe platyspondyly,
very short ribs, short tubular bones with irregular and flared metaphyses,
flared iliac wings with convex inferior iliac magrin. The patient was
followed-up until he was 2 years old. His height is very short (61 cm)
and he had language and social development were compatible with 2
years of age but gross motor skill was delayed at that age. Re-evaluation
of radiologic finding revealed premature calcification on costal
cartilages and femoral epiphyses . We diagnosed Spondylo-metaepiphyseal
dysplasia (SMED), short limb-abnormal calcification type.
This condition is a very rare autosomal recessive inheritance disorders
characreristic by platyspondyly, short limbs with short hands, short
ribs, meta-epiphyseal irregularity and cartilage calcification. Shorting
of the tubuler bones, platyspondyly, meta-epiphyseal irregularity and
cartilage calcification are also seen in chondrodysplasia punctata, recessive
type but severe platyspondyly, short hands and ribs associated
with SMED, short limb- abnormal calcification type.
P0253. Mutations in TBX1 genocopy the 22q11.2 deletion and
duplication syndromes: a new susceptibility factor for mental
retardation
D. Heine-Suñer 1 , L. Torres-Juan 1 , X. Busquets 1 , M. Morla 1 , N. Govea 1 , M. Bernues
1 , C. Vidal-Pou 1 , F. Garcia-Algas 1 , M. de la Fuente 1 , A. Perez-Granero 1 , M.
Juan 2 , A. Tubau 2 , J. Rosell 1 ;
1 Hospital Universitari Son Dureta, Palma de Mallorca, Spain, 2 Hospital Fun-
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