2008 Barcelona - European Society of Human Genetics

Clinical genetics
women ranges by population from 8-12% .
Individuals with NF1 have a well-documented increase in the relative
risk of several rare malignancies, including malignant nerve sheath
tumors, childhood myeloid malignancies, neurogenic sarcomas, malignant
CNS tumors, rhabdomyosarcomas, pheochromocytomas and
carcinoid tumors . There has not, however, been a well-documented
increase in the incidence of common adult-onset malignancies such
as colon, breast and prostate, in individuals with NF1 .
Over the past six months in our familial cancer clinic we have encountered
two women with a classical presentation of NF1 who developed
pre-menopausal invasive ductal carcinoma . A literature and database
review initially revealed only anecdotal case reports of breast cancer in
NF1, but a recent publication (Sharif et al ., J MED GENET 44:481-484,
2007) concluded that women with NF1 under age 50 have an approximately
5-fold increased risk of breast cancer . We next proceeded to a
more complete review of publications dealing with mortality and morbidity
in NF1 and now agree with the above authors that women with
NF1 should be offered earlier mammographic screening because of a
moderately-increased risk of pre-menopausal breast cancer . Although
a genotype-phenotype correlation might be suspected, such correlations
have been difficult in NF1 in general and have not been identified
in relation to breast cancer .
P01.196
Neurofibroma by numbers: mutational mechanisms, models and
modifier genes
C. Garcia Linares1 , B. Canet2 , J. Fernandez2 , L. Benito2 , I. Blanco2 , C. Lázaro2 ,
E. Serra Arenas1 ;
1 2 IDIBELL, L’Hospitalet de Llobregat (Barcelona), Spain, Institut Català
d’Oncologia, L’Hospitalet de Llobregat (Barcelona), Spain.
The number of dermal neurofibromas (dNFs) in Neurofibormatosis
type 1 patients is highly variable . It has been shown that there is an
important genetic component in the variation of neurofibroma number
that seems to be consistent with a polygenic effect. Neurofibroma initiates
due to the double inactivation of the NF1 gene . Most (if not all)
somatic NF1 inactivations in dNFs are due to mutation, thus genes
important for DNA repair mechanisms are good candidates as modifier
genes of neurofibroma number variability. We have chosen to study
genes responsible for mitotic recombination as candidate modifiers,
since mitotic recombination is an important mechanism leading to LOH
that accounts for the 20-30% of somatic NF1 inactivations in dNFs . We
are employing different strategies, either directly in humans or using
Saccharomyces cerevisiae as a model, for identifying candidate genes
that will be used in association studies in a well-characterized cohort
of NF1 patients .
P01.197
Mosaic neurofibromatosis type 1 (NF1) in Finland
M. Pöyhönen 1,2 , J. Ruohonen 1 , J. Peltonen 3 , S. Peltonen 4 ;
1 Dept of Medical Genetics, University of Helsinki, Helsinki, Finland, 2 Dept of
Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland, 3 Institute
of Biomedicine, Department of Anatomy, University of Turku, Turku, Finland,
4 Department of Dermatology, University of Turku, Turku, Finland.
Background Neurofibromatoses are hereditary diseases that belong
to the group of phakomatoses . NF1 has distinctive cutaneus features
and NF2 has mainly intracranial lesions . In the segmental or mosaic
type (NF5) the disease features of NF1 are distributed regionally on
the body . There is no previous data on mosaic NF1 in Finland .
methods Patients’ disease features were collected from hospital files.
A large literature search was made and the cases were compared with
the Finnish patients . The objective was to study the incidence of mosaic
NF1 in Finland and the disease features in Finnish patients .
Results Classification of patients unequivocally according to existing
criteria for mosaic NF1 proved difficult. The incidence of mosaic
NF1 in Finland (0,0005%) was lower than that found in other countries
(0,0014%-0,002%), but in areas where the material was the most
comprehensive (Turku and Oulu University Hospital districts) the incidences
(0,0013% and 0,0011% respectively) were very similar to
the other studies . The most common disease feature was the neurofibroma,
which was found in 81% of the Finnish patients and in 76%
of the cases in the literature . The frequence of café-au-lait-spots was
respectively 39% and 35% and that of freckles 26% and 38% . Lisch
nodules, mainly unilateral, presented in 15% of the Finnish patients
and in 8% of the literature cases .
conclusions There is a need for more unified criteria for classifying
mosaic NF1 . The incidence and disease features of mosaic NF1 in
Finland are similar to those found in other countries and in the literature
.
P01.198
Analysis of the NF gene in a cohort of 118 unselected NF1
patients using direct cDNA sequencing complemented with
mLPA analysis
B. Campos1 , J. Gardenyes1 , O. Abad1 , P. Fábregas1 , S. Bernal2 , V. Volpini1 ;
1 2 IDIBELL, L’Hospitalet de Llobregat, Spain, Hospital de la Santa Creu i Sant
Pau, Barcelona, Spain.
Neurofibromatosis type 1 (NF1) [MIM 162200] is a common dominant
autosomal disorder, affecting 1 in 3500 individuals . The disease is
caused by mutations in the NF1 gene at 17q11 .2, in which has been
identified a wide range of molecular abnormalities. In the last years
it has made clear the need for a reliable and sensitive genetic test
for the NF1 gene to help resolve diagnostic dilemmas in patients not
fulfilling clinical criteria as those defined by The National Institutes of
Health (NIH) .
We screened for mutations a panel of 118 unrelated patients suspected
of having NF1, using direct cDNA sequencing complemented
with multiplex ligation-dependent probe amplification (MLPA) analysis.
Possible disease causing mutations were identified in 82 (69%) cases.
These comprised 74 different sequence alterations, of which 46 were
novel. Among the 82 changes identified, we observed 26 (32%) frameshift
mutations, 21 (26%) nonsense mutations, 15 (18%) splice errors
and 6 (7%) missense mutations . Furthermore, using MLPA approach
we found 14 mutations (17%): 8 total gene deletions, 4 multiexon deletions
and 2 multiexon duplications .
Out of the 118 cases referred, there were 84 patients with reliable clinical
data, of whom 53 satisfied the NIH diagnostic criteria. Within this
better defined cohort of NF1 patients, mutations were identified in 47
individuals (89%) . Interestingly, 10 out of 24 (42%) patients who satisfied
only one NIH criteria carried a mutation.
Our results show that direct cDNA sequencing together with MLPA
analysis provide a sensitive and specific method for the rapid identification
of NF1 mutations .
P01.199
Genetic diagnosis of Neurofibromatosis 1 in 62 Spanish patients
and determination of the mutational spectrum of the NF1 gene in
our population
J. Garcia-Planells1,2 , M. Molero1 , M. Bellón1 , M. Torres-Puente1 , M. Perez-
Alonso1,2 ;
1 2 Sistemas Genomicos, Valencia, Spain, Instituto Valenciano de Genética,
IVGEN, Valencia, Spain.
Neurofibromatosis 1 (NF1) is a multisistemic disease characterized by
the presence of multiple cafe au lait spots, freckling, neurofibromas
and iris Lisch nodules . NF1 is caused by mutations in the NF1 gene,
more than 500 different mutations been identified and many of them
are private . A half of mutations are de novo and the mutational heterogeneity
of NF1 gene is high: point mutations (27%), splicing mutations
(20%), small deletion or insertion (47%) and large deletions or rearrangements
(8%) . The aims of this work are: i) to achieve a genetic
diagnosis in patients with clinical criteria of NF1, ii) to evaluate the
RNA sequencing of the NF1 gene as a diagnostic methodology for
Neurofibromatosis 1, iii) to determinate the mutational spectrum of the
NF1 gene in our series . Here we report our three years results and
experience with genetic diagnosis of NF1 . We have achieved a genetic
diagnosis in 75 patients and 42 mutations not reported previously have
been identified. RNA sequencing of the NF1 gene is the methodology
gold standard for the genetic diagnosis of Neurofibromatosis 1,
because it allows to identify point mutations, splicing mutations and
duplications or deletions, including these affecting to one or a only a
few exons . The mutational spectrum of the NF1 gene obtained in our
population provides an interesting epidemiologic and pathogenic information
. A high expertise and experience must be required for the interpretation
of nucleotide changes identified in the sequencing of genes
with a high rate of de novo mutations