2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
deletions, the mechanism(s) of deletions remains unanswered . We
characterized the atypical microdeletions using fluorescence in situ
hybridization (FISH), quantitative real-time PCR (qPCR), and Southern
blot hybridization . All the deletion breakpoints in the three cases
were successfully determined at the nucleotide level . Two deletions
are 1 .07 Mb (SoS19) and 1 .23 Mb (SoS109) in size, and another consisted
of two deletions with sizes of 28 kb and 0 .72 Mb, intervened by
an intact 29-kb segment (SoS44) . All deletions were smaller than a
typical 1 .9-Mb common deletion . Alu elements were identified in both
deletion breakpoints in SoS19, one of deletion breakpoints in SoS109,
and both deletion breakpoints of the proximal deletion in SoS44 . Alumediated
NAHR is strongly suggested at least in two of atypical deletions
. Finally, qPCR is a very useful method to determine deletion
breakpoints even in repeat-related regions .
P05.183
sotos syndrome. mutational study in 186 patients
L. Fernández 1,2 , J. del Valle 3,4 , M. del Campo 3,4 , P. Arias 1,2 , L. Magano 1,2 , I.
Incera 1,2 , F. Santos 1,2 , E. Mansilla 1,2 , F. García 1,2 , J. Nevado 1,2 , M. Palomares 1,2 ,
V. Romanelli 1,2 , A. Delicado 1,2 , M. Mori 1,2 , R. Gracia 5 , L. Pérez-Jurado 3,4 , P. Lapunzina
1,2 ;
1 Servicio de Genética Médica y Molecular, Hospital Universitario La Paz,
Madrid, Spain, 2 Centro de Investigación Biomédica en Red de Enfermedades
Raras (CIBERER). ISCIII, Madrid, Spain, 3 Unitat de Genètica, Hospital Vall
d’Hebron, Barcelona, Spain, 4 Centro de Investigación Biomédica en Red de
Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain, 5 Servicio de Endocrinología
Infantil, Hospital Universitario La Paz, Madrid, Spain.
Introduction . Sotos syndrome (SS) is a rare genetic condition characterized
by overgrowth, macrocephaly, large forehead, large hands
and feet, accelerated bone age, typical gestalt, mental retardation of
variable degree and a slight predisposition to develop tumours . This
condition is due to an abnormality of the NSD1 gene caused by deletions
or spontaneous mutations .
Material and methods . From November 2003 to November 2007, we
evaluated 215 patients with presumed diagnosis of SS, referred to the
Spanish Overgrowth Syndrome Registry . The patients were evaluated
in their local hospitals and referred by geneticists, paediatricians, neurologists
and other health professionals . An initial study by microsatellite
genotyping, a MLPA specific for the NSD1 critical region and neighbouring
genes and analysis of the coding regions of NSD1 by dHPLC
and/or bi-directional direct sequencing were made in all of them .
Results . We completed all the studies in 186 out of the 215 patients
referred . One hundred and twelve presented complete clinical data or
a clear phenotype of SS, evaluated by 2 clinical geneticists trained in
SS patients . We found 76 genetic alterations, 17 of them NSD1 deletions
and 59 point mutations; a detection rate of about 68% . Some of
these mutations are novel and others are recurrent .
Comments . The detection rate of mutations in patients with clear clinical-neurobehavioural
phenotype of SS is nearly 70%. Our figures are
similar to that reported in other series. The finding of several recurrent
mutations suggests that there are “hot spots” in NSD1, meaning common
molecular mechanisms responsible for the disease .
P05.184
Identification of the SPG (spastizin) gene, responsible for an
autosomal recessive complicated spastic paraplegia
S. Hanein 1 , E. Martin 1 , A. Boukhris 1,2 , P. Byrne 3 , C. Goizet 1 , A. Hamri 4 , A. Benomar
5 , A. Lossos 6 , P. Denora 1,7 , M. Hutchinson 3 , F. M. Santorelli 7 , C. Mhiri 2 , A.
Brice 1,8 , G. Stevanin 1,8 ;
1 INSERM / UPMC Univ Paris 6, UMR_S679, Paris, France, 2 Habib Bourguiba
Hospital, Sfax, Tunisia, 3 University College, Dublin, Ireland, 4 Benbadis Hospital,
Constantine, Algeria, 5 Specialities Hospital, Rabat, Morocco, 6 Hadassah-Hebrew
University Medical Center, Jerusalem, Israel, 7 IRCCS-Bambino Gesu
Hospital, Rome, Italy, 8 APHP, Dept Genetics Cytogenetics, Pitie-Salpetriere
Hospital, Paris, France.
Hereditary spastic paraplegias (HSPs) are genetically and phenotypically
heterogeneous disorders with various clinical profiles and modes
of transmissions . The SPG15 locus was first reported to account for a
rare form of complicated autosomal recessive spastic paraplegia variably
associated with mental impairment, pigmented maculopathy, dysarthria,
cerebellar signs, distal amyotrophy and thinning of the corpus
callosum, sometimes designated Kjellin syndrome . Here, we report
the refinement of the SPG15 locus to less than 3 Mb on chromosome
14q23-q24 and the identification of 6 different truncating mutations that
were found to segregate with the disease in 8 families with a phenotype
that included, variably, some of the clinical features of Kjellin
syndrome . The SPG15 mRNA was widely distributed in human tissues
and in rat embryos as well. In adult rodent brain, its expression profile
closely resembled that of SPG11, another gene responsible for complicated
HSP. The identification of the SPG15 gene is a starting point
for the elucidation of the mechanisms underlying axonal degeneration
in this complicated form of HSP .
P05.185
mutation spectrum and phenotype description in a large series
of patients with autosomal recessive spastic paraplegia type 11
(sPG11)
H. Azzedine 1,2 , A. Durr 3,4 , P. Denora 3,5 , A. Boukhris 3,4,6 , M. Tazir 7 , I. Lerer 8 , J.
Vale 9 , A. Hamri 10 , C. Goizet 3,11 , M. Anheim 12 , C. Tallaksen 13 , M. Tada 14 , G. Garrigues
15 , C. Verny 1 , V. Meiner 8 , S. Forlani 3 , D. Bonneau 1 , C. Tranchant 12 , A. Lossos
8 , F. M. Santorelli 16 , P. Coutinho 17 , C. Mhiri 6 , A. Brice 3,4 , G. Stevanin 3,4 ;
1 Centre National de Référence pour les maladies Neurogénétiques, Angers,
France, 2 INSERM / UMR_S679, Paris, France, 3 INSERM / UPMC UMR_S679,
Paris, France, 4 Département de Génétique et Cytogénétique - CHU Pitié-
Salpêtrière, Paris, France, 5 Bambino Gesù Children’s Hospital, Rome, Italy,
6 Hôpital Habib Bourguiba, Sfax, Tunisia, 7 Hôpital Mustapha, Algiers, Algeria,
8 Hadassah-Hebrew University Medical Center, Jerusalem, Israel, 9 Hospital De
Egas Moniz, Lisboa, Portugal, 10 Hôpital Benbadis, Constantine, Algeria, 11 Hôpital
Pellegrin, Bordeaux, France, 12 Hôpital Civil, Strasbourg, France, 13 Ullevål
University Hospital, Oslo, Norway, 14 Niigata University, Niigata, Japan, 15 CHU
de Montpellier, Montpellier, France, 16 Bambino Gesù Children’s Hospital, Roma,
Italy, 17 Hospital S. Sebastiao, Santa Maria da Feira, Portugal.
Hereditary spastic paraplegias (HSP) are neurodegenerative disorders
mainly characterized by lower limb spasticity associated, in complicated
forms, with additional neurological signs. Recently, we identified the
SPG11, as the responsible gene for a complex autosomal recessive
(AR) HSP . We have analyzed 76 index ARHSP patients for mutations
in the SPG11 gene . We found 22 mutations segregating in 13 (30%)
families and 7 (21%) isolated cases . Two mutations where recurrent
suggesting founder effects . Nineteen mutations were novel . The highest
frequency of patients with SPG11 mutations (41%) was found in
HSP patients presenting with a thin corpus callosum (TCC); however,
these mutations were rare in patients with mental impairment without
TCC (4.5%). Disease onset occurred during the first to the third decade
mainly by problems with gait and/or mental retardation . Overall,
the phenotype of the 38 examined SPG11 patients was severe . After
a mean disease duration of 14 .9 ± 6 .6 years (range: 2-35), 53% of patients
used a wheelchair or were bedridden . At the time of examination,
in addition to mental retardation, 80% of the patients showed cognitive
decline with executive dysfunction . The phenotype also frequently
included lower motor neuron degeneration (81%) with wasting (53%) .
Slight ocular cerebellar signs were also noted in patients with long
disease durations . In addition to TCC (95%), brain MRI revealed white
matter alterations (69%) and cortical atrophy (81%), which worsened
with disease duration . Our study reveals the high frequency of SPG11
mutations in patients with HSP associating TCC and cognitive impairment
and also extends the associated phenotype .
P05.186
sPG4 mutations and phenotype of hereditary spastic paraplegia
in Estonia
R. Tamm 1,2 , M. Braschinsky 3 , E. Raukas 2,4 , S. Lüüs 3 , K. Gross-Paju 5 , C. Boillot 6 ,
F. Canzian 7 , A. Metspalu 4,8 , S. Haldre 3 ;
1 IMCB, University of Tartu, Tartu, Estonia, 2 Department of Genetics, United
Laboratories, Tartu University Clinics, Tartu, Estonia, 3 Neurological department,
Tartu University Clinics, Tartu, Estonia, 4 Estonian Biocenter, Tartu, Estonia,
5 Neurological department, West Tallinn Central Hospital, Tallinn, Estonia, 6 International
Agency for Research on Cancer, Lyon, France, 7 German Cancer
Research Center (DKFZ), Heidelberg, Germany, 8 University of Tartu, Tartu,
Estonia.
Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous
disorder, which is classified clinically into “pure” (pHSP)
and “complex” (cHSP) forms . Great inter- and intrafamilial variations
are very typical . Autosomal dominant hereditary spastic paraplegia
(AD-HSP) is the most common form due to the mutations in the spastin
gene (SPG4) . The aim of this study was to describe phenotype
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