2008 Barcelona - European Society of Human Genetics

Cytogenetics
cise etiological diagnosis, an adequate genetic counseling, avoiding
recurrence of the disease, epigenetic therapies and an optimal management
of these diseases . These objectives are doubled by the interest
concerning rare diseases in generally and the opened research
wants to be a beginning in the multidisciplinary approach of rare diseases
in Romania .
We are proposing to contact some teams of European researchers
with certain results in the study of PWS/AS to cooperate, with the purpose
of deciphering the mechanisms involved in these diseases .
P02.060
Genomic and epigenetic abnormalities in silver-Russell
syndrome patients
I. Cuscó 1 , L. Fernández 2 , O. Villa 1 , L. Rodríguez-Revenga 3 , M. Palomares 2 , M.
Rosales 1 , J. del Valle 1 , S. García-Miñaur 4 , F. Santos 2 , M. Milà 3 , P. Lapunzina 2 ,
L. A. Pérez-Jurado 1,4 ;
1 Unitat de Genètica, Universitat Pompeu Fabra, U-735 CIBERER, Barcelona,
Spain, 2 Servicio de Genética, Hospital Universitario La Paz, U-753 CIBERER,
Madrid, Spain, 3 Servei de Bioquimica i Genètica Molecular, Hospital Clínic, U-
726 CIBERER, Barcelona, Spain, 4 Programa de Medicina Molecular i Genètica,
Hospital Vall d’Hebron, Barcelona, Spain.
Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized
by severe intrauterine and post-natal growth retardation,
characteristic dysmorphic facial features and occasional asymmetry .
The SRS incidence is ~1-30/100000 live-births with most cases being
sporadic . Maternal uniparental disomy of chromosome 7 and maternal
duplications or epimutations of the 11p15 region have been reported
accounting for ~35-40% of cases . Several chromosomal abnormalities,
affecting chromosomes 1, 15, 17 and X, have also been found in
patients with SRS .
In order to define the molecular cause of the disease and to establish
a diagnostic protocol, we have screened a collection of 46 patients
with a clinical diagnosis of SRS with a “step by step” strategy . Cytogenetic
abnormalities were found in three cases (r(15), sSMC(7),
Xq26-q28dup). A metilation sensitive (MS) MLPA assay targeting five
imprinted regions (11p15, 7q31,15q12,14q32,20q13) detected epigenetic
abnormalities in 4 cases, 2 with maternal UPD (verified by microsatellites)
and 2 with H19 locus hypometilation (verified by F-COBRA).
Screening for copy number variants was performed by MLPA (19 candidate
loci), and aCGH in the still negative cases . De novo putatively
pathogenic rearrangements were found in 5 additional cases (15q26
deletion, 15q26del+11q24dup, 7q36dup+ 10q, 12p13dup and 1 with
4q13 .3 del) . Our approach was able to detect the molecular basis of
12/46 (26%) SRS patients, further confirming the syndrome heterogeneity
and suggesting novel candidate loci for the disorder . Although
epigenetic abnormalities at 11p15 are less frequent in our series, the
use of targeted MS-MLPA and aCGH appears to be indicated in the
workup of these patients .
P02.061
mutations in sLc9A6 are present in about 4% of males with an
Angelman syndrome-like phenotype
C. E. Schwartz1 , J. Barwick2 , R. Patel2 , A. Archie2 , B. Schutt2 , J. Garbern2 , R.
Schroer1 , M. J. Friez1 ;
1 2 Greenwood Genetic Center, Greenwood, SC, United States, Wayne State
University, Detroit, MI, United States.
Recently, Gilfillan et al (ASHG, in press) reported that mutations in the
SLC9A6 gene cause X-linked mental retardation (XLMR) with epilepsy
and ataxia . Additionally, for many of the patients, the phenotype resembled
that associated with Angelman syndrome . With this association
between gene and phenotype, we wished to determine the degree
of involvement of SLC9A6 mutations in patients with clinical findings
suggestive of Angelman syndrome who had normal diagnostic testing
. We tested 30 males submitted to rule out Angelman syndrome
who had normal methylation studies and identified 1 mutation (3.3%).
Additionally, 65 males with normal UBE3A sequencing were screened
and 3 mutations (4.6%) were identified. Lastly, based on the phenotype,
20 families enrolled in our XLMR project were tested and 2 mutations
(10%) were found . All of the mutations were truncating mutations .
Taken together, our results would indicate: 1) SLC9A6 mutations may
account for about 4% of males with a phenotype resembling Angelman
syndrome and 2) SLC9A6 mutations may account for about 10% of
males with XLMR associated with epilepsy and ataxia . Thus, SLC9A6
testing should be considered in any male with a phenotype resembling
Angelman syndrome particularly if an X-linked pattern of inheritance
is suspected .
P02.062
mutations in SLC A cause microcephaly, epilepsy, and severe
mental retardation with abnormal postures.
F. Raymond 1 , A. Whibley 1 , C. Freeman 1 , J. Clayton-Smith 2 , H. Archer 3 , A.
Clarke 3 , M. Bitner-Glindzicz 4 , R. Smith 5 , P. Tarpey 5 , M. Stratton 5 , A. Futreal 5 , I.
GOLD 1 ;
1 Cambridge Institute for Medical Research, Cambridge, United Kingdom, 2 Regional
Genetics Service, St. Mary’s Hospital, Manchester, United Kingdom,
3 Medical Genetics, University of Wales, Cardiff, United Kingdom, 4 Institute of
Child Health, University of London, London, United Kingdom, 5 Sanger Institute,
Hinxton, Cambridge, United Kingdom.
We have recently reported pathogenic mutations in SLC9A6 in 4
families with a characteristic phenotype of severe to profound mental
retardation in association with microcephaly, epilepsy and abnormal
postures . The differential diagnosis included Angelman syndrome in
all cases but the pedigree structure suggested an X-linked mode of
inheritance in 3 of the families .
There is considerable clinical overlap between Angelman syndrome,
West syndrome and atypical Rett syndrome and thus we selected
an additional 30 male patients from these categories and performed
sequence analysis of SLC9A6 to identify causative mutations having
excluded the known causes of disease in each group i .e . UBE3A, ARX
and MECP2 . We also screened >200 males from families with X-linked
mental retardation .
We report a deletion within SLC9A6 in a pair of brothers with severe
mental retardation where the mutation is likely to be pathogenic . We
also report 2 sequence variants in families with X-linked mental retardation
where the pathogenicity is less clear . These are a missense
mutation which is likely to be a rare SNP and a splice site mutation
(IVS12+4A>G) where the expression of SLC9A6 mRNA in lymphocytes
is unaltered . We did not identify further pathogenic mutations
in the samples from males with Angelman, West or atypical Rett syndrome
cohorts suggesting that the etiology of these conditions remains
heterogenous and further genes are likely to cause these overlapping
phenotypes .
P02.063
A valuation of facial dysmorphism in diagnostics of 22q11.2
microdeletion syndrome in countries with lower average income
G. M. Cuturilo1 , I. Jovanovic1 , S. Grkovic1 , M. Djukic1 , V. Parezanovic1 , G.
Vukomanovic1 , M. Stevanovic2 , D. Drakulic2 ;
1 2 University Children’s Hospital, Belgrade, Serbia, Institute of molecular genetics
and genetic engineering, Belgrade, Serbia.
Most authors consider both specific and non-specific facial dysmorphism
as an important diagnostic criterion for 22q11 .2 microdeletion
syndrome . As a consequence, FISH analysis should be required frequently
. While in most European countries this fact does not represent
a significant problem, in those with lower average income such wide
coverage is still unavailable .
The aim of this study was to compare a significance of specific and
non-specific facial dysmorphism in diagnostics of 22q11.2 microdeletion
syndrome .
We analyzed 34 patients that underwent FISH for 22q11 .2 microdeletion
in our hospital in the last three years . Among nine newborn infants
diagnosed as positive, eight had some kind of facial dysmorphism .
Seven had non-specific dysmorphism (88%), while only one had specific
dysmorphism (12%). All six children older then one month and
diagnosed as positive, had facial dysmorphism . Two of them had nonspecific
dysmorphism (33%) and four had specific facial dysmorphism
(67%) .
In conclusion, it is clear that facial dysmorphism becomes more and
more specific with age. In the situation of seriously limited availability
of FISH testing, some narrowing of indications possibly could be
achieved in group of patients older then one month (or better, older
then one year) by considering only a specific facial dysmorphism as
a diagnostic criterion . However, individual approach to the patient and
careful clinical assessment are necessary, as it is clear that non-specific
facial dysmorphism also has an important role in clinical diagnosis
of 22q11 .2 microdeletion syndrome .