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

Clinical genetics
plicated: two cousins - brother and sister with symptoms of psychomotoric
retardation and one child with Down syndrome from the other
cousin‘s family. The dysmorphic features were seen from the birth of
this girl. Facial dysmorphism is characterised by the triangular high
forehead with expressed sagital suture, hypertrichosis, wide spaced
eyes, ptosis, down-slanting palpebral fissures, strabismus, broad nasal
root, very short nose with anteverted nares, short grooved philtrum,
triangular mouth, thin upper lip, everted lower lip, high narrow palate,
micrognathia, malformed ears with preauricular sinus on one of sides.
The characteristic skin lesions are typical for chromosomal mosaicism:
they involve streaked, whorled and mottled areas of hypopigmentation
on trunk and limbs. The psychomotor development of our patient is
with severe features of delay: she sat alone only at two years. Clinical
follow-up showed these clinical findings: CT scan showed corpus
callosum agenesis and hydrocephaly, X-ray: abnormal feet position
- equinovarus bilaterally.
Cytogenetic analysis of peripheral blood lymphocytes revealed a mosaic
karyotype 47,XX, +mar/46,XX in girl with dysmorphism of phenotype.
Chromosome analysis was performed from GTG banded metaphases.
The resolution level was 400-500 bands. The exact nature of
the marker chromosome could not be identified in our patient. Parental
karyotypes were normal.
P0097. Disproportional high frequency of CLCN1 mutations
among patients with myotonic dystrophy type 2.
T. Suominen 1 , B. Schoser 2 , O. Raheem 3 , S. Auvinen 4 , R. Krahe 5 , H. Lochmüller
2 , W. Kress 6 , B. Udd 7 ;
1 Neurogenetics, University of Tampere, Tampere, Finland, 2 Friedrich-Baur-Institute,
Ludwig-Maximilians-University Munich, Germany, 3 Department of Pathology,
Pirkanmaa Hospital District, Center for Laboratory Medicine, Tampere,
Finland, 4 Department of Neurology, Central Finland Central Hospital, Jyväskylä,
Finland, 5 Department of Molecular Genetics, University of Texas M. D. Anderson
Cancer Center, Houston, TX, United States, 6 Institute of Human Genetics,
University of Wuerzburg, Germany, 7 Department of Neurology, Tampere University
Hospital, Tampere, Finland.
Background: Myotonic dystrophy type 2 (DM2) is a multiorgan disease
caused by (CCTG)n repeat expansion mutation in ZNF9 gene. Clinical
core features are myotonia, muscle weakness and cataracts. The
phenotype is highly variable ranging from mild to severe forms, which
makes clinical classification difficult. DM2 mutation causes aberrant
splicing of different genes including CLCN1. Mutations in ClC1 chloride
channel gene (CLCN1) cause recessive and rarely dominant myotonia
congenita (MC), characterized by myotonia and muscle hypertrophy.
Objective: to clarify whether co-segregation of frequent recessive
CLC1 mutations may have a modifier effect on the DM2 phenotype.
Methods: CLCN1 mutations R894X, F413C and A531V were analysed
in 200 Finnish and German DM2 patients and 200 controls by TaqMan
Sequence Detection System (ABI) using specific primers for PCR and
fluorescent oligonucleotide probes.
Results: CLCN1 mutations R894X, F413C and A531V in DM2 patients
and controls.
Cohorts R894X hoz R894X hez F413C hez A531V hez total
Finnish DM2 patients
(n=100)
0 3 2 0 5
German DM2 patients
(n=100)
1 4 0 0 5
Finnish controls
(n=100)
0 2 1 0 3
German controls
(n=100)
0 1 0 0 1
Conclusions: In German DM2 patients the frequency of CLC1 co-segregation was
5-fold and in the Finnish DM2 patients almost twofold compared to control population.
The results clearly indicate a considerable contributing effect on the clinical symptoms
and the likelihood of a patient to be diagnosed with DM2. Thus recessive CLCN1
mutations are genetic modifiers in DM2.
P0098. A novel Italian family with ectodermal dysplasiasyndactyly-mental
retardation syndrome
F. Brancati1,2 , G. D’Amato1,2 , R. Mingarelli1 , B. Dallapiccola1,2 ;
1 2 IRCCS CSS Mendel Institute, Rome, Italy, Department of Experimental Medicine
and Pathology, “La Sapienza” University, Rome, Italy.
Ectodermal Dysplasias (EDs) are a heterogeneous group of conditions
presenting with hair, tooth, nails and sweat glands abnormalities. EDs
may be sub-classified into pure forms and syndromic EDs, where ecto-
dermal signs are combined with other anomalies. We studied two sibs,
a 26 year-old man and his 9 year-old sister, born to unrelated healthy
parents showing a distinct phenotype. Hair, eyebrows and eyelashes
were sparse, coarse and brittle with areas of progressive scalp alopecia.
The older patient showed axillary and pubic hypotrichosis and
mildly dystrophic nails. Oral findings included multiple frenula, small,
wide-spaced teeth with peg-shaped and conical crowns. Spontaneous
sweating was normal. There were also broad nasal bridge, short
philtrum with anteverted nares, and small ears with thickened, overfolded
helices. The older brother showed 2-3 toes syndactyly and underwent
surgical correction of 2-3 and 3-4 cutaneous syndactyly at the
hands, while his sister had 3-4 hands syndactyly and toes 2-3 and 4-5.
An abnormal pattern of palmar flexion creases was present in both
sibs, with bilateral four-finger lines in the male. The oldest patient had
also mild mental retardation (MR) and unilateral conductive deafness.
These subjects add to the 7 previously reported (one family with 4 affected
sibs and 3 sporadic cases) presenting the association of hidrotic
ectodermal dysplasia, cutaneous syndactyly and variable mental retardation
and ease the delineation of an autosomal recessive (AR) EDsyndactyly-MR
syndrome. Differential diagnosis, among AR syndromic
EDs, include Zlotogora-Orun syndrome, consisting of ectodermal dysplasia,
syndactyly, mental retardation in addition to cleft lip/palate.
P0099. Lessons from two families affected with borderline
forms of Vascular Elhers-Danlos syndrome: Genetic testing is
necessary!
A. Plancke1 , N. Ruiz-Pallares1 , I. Quere2 , H. Plauchu3 , M. Claustres1 , P. Khau
van Kien1 ;
1 2 CHU Montpellier/INSERM U827, Montpellier, France, CHU Montpellier, Montpellier,
France, 3Hospices Civils de Lyon, Lyon, France.
Vascular Elhers-Danlos syndrome (V-EDS) is a rare dominantly inherited
disorder cause by mutations in the type III procollagen gene
(COL3A1). The diagnosis is particularly difficult to establish and a
marked intra/inter-familial phenotypic variability occurs with frequent
sub-clinical manifestations revealed by genetic testing and familial investigations.
In view to help to the diagnosis work-up, the Villefranche
criteria define the indications of laboratory testing that in practice only
provides diagnosis certainty.
We had the opportunity to study two unrelated young women with a V-
EDS suspicion and a strong familial history of Familial Thoracic Aortic
Aneurysm and/or Aortic Dissection (TAA/AD). Attentive familial investigation
also suggested the possibility of V-EDS manifestations. Thus,
we performed a first screening of the COL3A1 gene from skin cultured
fibroblast. We identified heterozygous transversion in each probant:
c.1835G>A and c.2357G>T. Both mutations are predicted to result in a
glycine substitution (p.Gly612Asp and p.Gly786Val). Theses missenses
alter an obligatory glycine residue of the Gly-X-Y tripe-helix repeated
domain of the type III procollagen. The mutations were confirmed at
the genomic level and mutation-based familial investigation allowed to
clarify affected-status in relatives with ambiguous phenotype.
In conclusion, V-EDS must be carefully evaluated at a familial level.
Suggestive familial history such TAAD/AD, sudden death but also
other events may reinforce the V-EDS suspicion and genetic testing is
crucial for diagnosis certainty, efficient familial screening, risk assessment
and preventive follow-up.
P0100. Adult onset forms of eIF2B related disorders: diagnostic
value of MRI and molecular analysis
P. Labauge 1 , F. Niel 2,3 , L. Horzinski 2 , M. Petit 3 , C. Confavreux 4 , D. Rodriguez 5 ,
C. Goizet 6 , S. Vukusic 4 , F. Maugière 4 , F. Bouhour 4 , G. Casterlnovo 1 , A. Fogli 2,3 ,
O. Boespflug-Tanguy 2,7 ;
1 CHU Carmeau, service Neurologie, NIMES, France, 2 INSERM UMR 384,
Clermont ferrand, France, 3 CHU de Clermont Ferrand, service de Biochimie
Médicale, Clermont ferrand, France, 4 Hospices civils de Lyon, Service de
Neurologie A, Hôpital Neurologique, Lyon, France, 5 Assistance publique-Hopitaux
de Paris, service de neuropédiatrie, Hopital Armand Trousseau, Paris,
France, 6 CHU Pellegrin, Service de Neurologie, BORDEAUX, France, 7 CHU de
Clermont Ferrand, service de génétique Médicale, Clermont ferrand, France.
Mutations in the five subunits of the eIF2B translation initiation factor
have been reported in a heterogeneous group of autosomal recessive
leukodystrophies characterized by a CSF-like aspect of the
white matter (vanishing white matter)on magnetic resonance imaging
(MRI), leading to the concept of eIF2B related disorders. The key role