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

Clinical genetics
P0133. Hidrotic ectodermal dysplasia in a Tunisian family
R. M‘rad 1,2 , F. Maazoul 1 , K. Lilia 1 , E. Chabchoub 1 , M. Chaabouni 1,2 , L. Ben jemaa
1,2 , I. Chelly 1 , I. Ouertani 1 , Z. Marrakchi 3 , H. Chaabouni 1,2 ;
1 Department of human genetics, Charles Nicolle hospital Tunis, Tunisia, 2 Department
of human genetics, Faculty of medicine Tunis, Tunisia, 3 Department of
neonatology, Charles Nicolle hospital Tunis, Tunisia.
Hidrotic ectodermal dysplasia (HED, Clouston syndrome, MIM 129500)
was 1rst described in 1895 and later by Clouston, in families from Quebec.
Although most common in French Canadians, the disorder has
been identified in several ethnic groups. Clouston hidrotic ectodermal
dysplasia (HED) is transmitted as an autosomal dominant condition
with complete penetrance and variable expressivity. The main features
of this rare form of genodermatosis are partial to complete alopecia,
palmoplantar hyperkeratosis, and nail dystrophy. Sweat gland function
in these patients is normal. Recently, mutations in the GJB6 gene
encoding the gap junction protein connexin 30 have been shown to
cause this disorder.
Here we report a girl born to consanguineous parents presenting with
complete alopecia and onychodysplasia without neither oligodentia
nor sweat gland function anomalies. Her father, her paternal uncle and
her paternal aunt are similarly affected. The paternal grandparents are
normal .The comparison with other ectodermal dysplasias is presented
and discussed. The possibility of an autosomal recessive form of
hidrotic ectodermal dysplasia is raised.
P0134. Mutation IVS2-2A>G in SLC2 A (Prestin) gene in two
Estonian families with hearing loss
R. Teek 1,2 , E. Raukas 2 , E. Oitmaa 3 , K. Kruustük 4 , R. Zordania 5 , K. Joost 5 , P.
Gardner 6 , I. Schrijver 7 , M. Kull 1 , K. Õunap 2,8 ;
1 Department of Oto-Rhino-Laryngology, University of Tartu, Tartu, Estonia,
2 United Laboratories, Tartu University Clinics, Tartu, Estonia, 3 Asper Biotech,
Tartu, Estonia, 4 Ear Clinic, Tartu University Clinics, Tartu, Estonia, 5 Tallinn
Children’s Hospital, Tallinn, Estonia, 6 Department of Medicine, Stanford University
Medical Center, Stanford, CA, United States, 7 Department of Pathology and
Pediatrics, Stanford University School of Medicine, Stanford, CA, United States,
8 Department of Pediatrics, University of Tartu, Tartu, Estonia.
Introduction: Prestin is a multipass transmembrane protein of the outer
hair cells of the mammalian cochlea and it was encoded by human
gene SLC26A5. In humans, a single nucleotide change - IVS2-2A>G
in the second intron of SLC26A5 has been reported in association with
hearing loss.
During 2005-2006 we have screened 183 individuals with hereditary
impaired hearing (HIH) by arrayed primer extension method, which
covers 201 mutations in 8 genes (GJB2, Connexin-30, Connexin-31,
Connexin-43, Prestin and Pendrin gene, and 2 mitochondrial genes).
In 3 individuals we found IVS2-2A>G mutation in one allele of Prestin
gene (1.6%).
We report two families with mutation IVS2-2A>G in SLC26A5 (Prestin)
gene. First family: 2 children with severe hearing loss (HL) and genotype
35delG/IVS1+1G>A. Mother has mild HL and mutations 35delG/
V37l; father has normal hearing, mutation IVS1+G>A in GJB2 gene
and IVS2-2A>G in SLC26A5 gene. Second family: mother and daughter
have genotype IVS2-2A>G. Mother has severe HL and 3 years old
daughter has normal hearing.
Conclusions: We found 3 persons with IVS2-2A>G mutation, only in
one of them sensorineural hearing loss was found. However, hearing
loss may still develop of two others. In 1.6% of investigated persons
with HIH IVS2-2A>G mutation in Prestin gene was found. This in the
correlation with previous data: 4% Caucasians and 1.3% Hispanics
carry this mutation (Tang et al. 2005). Our data support the hypothesis
that heterozygosity for the mutation IVS2-2A>G in SLC26A5 gene may
be not be, by itself, sufficient to cause hearing loss.
P0135. Copy number alterations in hereditary spastic paraplegia
genes
C. Beetz 1 , A. Brice 2 , P. Byrne 3 , C. Depienne 2 , A. Durr 2 , A. O. H. Nygren 4 , E.
Reid 5 , L. Schoels 6 , T. Deufel 1 ;
1 Uniklinikum, Jena, Germany, 2 INSERM, Paris, France, 3 University of Dublin,
Dublin, Ireland, 4 MRC-Holland, Amsterdam, The Netherlands, 5 Adenbrooke’s
Hospital, Cambridge, United Kingdom, 6 Uniklinikum, Tübingen, Germany.
Hereditary spastic paraplegia (HSP) is a neurodegenerative condition
causing progressive leg spasticity and weakness. SPG4 (SPAST
gene, spastin protein) is the major HSP locus; there is large hetero-
geneity underlying the remaining ~60% of cases. We have previously
shown for SPG4 that large genomic deletions represent a surprisingly
frequent class of disease-causing alterations. We subsequently widened
pertinent analyses to (i) investigate the very extend of SPAST
deletions and (ii) screen for copy number aberrations in other HSP
genes.
In 18/18 cases investigated so far, deletion of SPAST exon 1 is accompanied
by deletion of the promotor. This finding establishes a loss
of function mechanisms, i.e. haploinsufficiency, as underlying at least
some cases of SPG4 HSP. We also identified copy number aberrations
in SPG3A, SPG6, SPG7, and SPG31. As not all of these are associated
with an HSP phenotype, haploinsufficiency is of no relevance for
the corresponding HSP genes. This information impacts on the strategies
for choosing appropriate cellular and animal disease models as
well as on molecular therapeutic considerations. Current efforts therefore
aim at uncovering the disease-association of copy number alterations
in the complete spectrum of known HSP genes.
P0136. Hermansky-Pudlak syndrome: report of two portuguese
families
C. Dias 1 , J. Silva 1 , S. Morais 2 , E. Oliveira 3 , E. Silva 4 , S. Gonçalves 5 , J. Barbot 6 ,
M. Sousa 3 , M. Reis Lima 1 ;
1 Genetics Clinic, Instituto de Genética Médica, Porto, Portugal, 2 Haematology
Department, Hospital Geral de Santo António, Porto, Portugal, 3 Cell Biology
Lab, Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal, 4 Ophtalmology
Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal,
5 Ophtalmology Department, Hospital de Crianças Maria Pia, Porto, Portugal,
6 Haematology Department, Hospital de Crianças Maria Pia, Porto, Portugal.
Hermansky-Pudlak Syndrome (HPS) [MIM#203300] is a genetically
heterogeneous autossomic recessive disorder, characterized
by oculocutaneous albinism (OCA) and platelet dysfunction, caused
by defects in lysosome-related organelles. Eight human subtypes of
HPS have been described. Patients show hypopigmentation of hair
and skin. Ocular findings include nystagmus, iris transillumination,
hypopigmentation of retina and decreased visual acuity. They have
prolonged bleeding with easy bruising. Severe bleeding diathesis is
more frequent in subtypes 1 and 4. Patients may also have pulmonary
fibrosis in the third and fourth decades. Granulomatous colitis is highly
variable. Electron microscopic examination of platelets shows absent
or greatly decreased number of platelet dense granules.
We present two unrelated families with a clinical and electron microscopic
diagnosis of Hermansky-Pudlak syndrome. The first family, with
consanguineous first cousin parents, has two affected children: the eldest
daughter has clinical features of HPS along with epilepsy and mild
mental retardation; the youngest son has identical clinical features but
with normal development.
In the second family, parents are non-consanguineous and their only
son is affected. He was initially diagnosed as having OCA. When easy
bruising was noticed, the investigation of platelet function revealed abnormalities.
Patients were submitted to platelet function tests and electron microscopic
evaluation of platelets. The clinical presentation of HPS is reviewed,
as well as differential diagnosis. Though this condition is more
frequent in Puerto Rican patients it has been described in many other
parts of the world.
P0137. The syndrome comprising myopathy with excess of
muscle spindles, hypertrophic cardiomyopathy, and Noonan-like
phenotype is caused by mutations in HRAS; The severe end of
Costello syndrome
I. van der Burgt1 , W. Kupsky2 , S. Katechis3 , A. Nadroo3 , C. Kratz4 , H. ter Laak5 ,
E. Sistermans5 , M. Zenker6 ;
1University Medical Centre St Radboud, 6500 HB Nijmegen, The Netherlands,
2 3 Wayne State University, Detroit, MI, United States, New York Methodist Hospital,
New York, NY, United States, 4University of Freiburg, Freiburg, Germany,
5 6 University Medical Centre St Radboud, Nijmegen, The Netherlands, University
of Erlangen-Nuremberg, Erlangen, Germany.
In the recent time, great progress has been achieved in the understanding
of the molecular basis of Noonan syndrome (NS; OMIM
163950), Cardio-Facio-Cutaneous syndrome (CFC; OMIM 115150),
and Costello syndrome (CS; OMIM 218040). These disorders represent
distinct entities wich share a common pattern of congenital
anomalies. They are all caused by mutations in genes involved in the