2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
P05.035
supporting the appropriate ordering of genetic laboratory tests
in the UK healthcare workforce
C. Barker, C. Bennett, C. Cooley, P. Farndon;
NHS National Genetics Education and Development Centre, Birmingham,
United Kingdom.
To address an increased need to promote the clinically appropriate
and equitable ordering of genetic laboratory tests in the UK, the NHS
National Genetics Education and Development Centre is working to
raise understanding and knowledge of genetics in the UK healthcare
workforce for non-genetics specialists .
The Centre identified the key knowledge and attitudes required to encourage
appropriate ordering of genetic laboratory tests as part of a
wider project to integrate genetic skills into clinical practice, job planning,
evaluation, education and training . The knowledge and attitudes
identified allow healthcare staff to recognise where genetic tests will
inform clinical management within the limits of their role and where
referral is appropriate . Healthcare staff will also be equipped to recognise
any social, ethical or legal implications in ordering the genetic
laboratory test .
To integrate these skills into clinical practice, the Centre has targeted
health professionals for whom genetics is highly relevant and is working
with these groups and other professional bodies to identify how
genetics affects their clinical practice .
Using this information, the Centre is creating tools allowing healthcare
staff to recognise where genetics impacts on their clinical practice . For
example, relevant case scenarios allow healthcare staff to draw parallels
with their own clinical practice . These tools are further supported
by the Centre through the provision of education and training support
and learning and teaching resources .
It is envisaged that this work will lead to more appropriate and equitable
ordering of genetic tests and ultimately the enhancement of
patient care .
P05.036
Vascular type of Ehlers-Danlos syndrome: Evidences for a
stochastic effect of COL3A1 haploinsufficiency
A. Plancke1 , M. Holder-Espinasse2 , V. Rigau3 , C. Rene1 , M. Taulan1 , B. Catteau2
, R. Sfeir2 , S. Coopman2 , N. Pallares-Ruiz1 , S. Manouvrier-Hanu2 , M.
Claustres1 , P. Khau Van Kien1 ;
1 2 CHU Montpellier/INSERM U827, Montpellier, France, CHRU de Lille, Lille,
France, 3CHU Montpellier, Montpellier, France.
Mutations that confer an unusual pattern of inheritance in a gene
related to a well known genetic disease can sometimes highlight a
particular mechanism useful to correlate genotype to phenotype . Here
we describe a case of recessive Ehlers-Danlos syndrome (EDS) in
a young girl of asymptomatic and related parents (uncle-niece) . She
exhibited: atrophic scars, extensive bruising, joint hypermobility and
died at 12 years-old from an extreme intestinal fragility . According to
the Villefranche nosology, she fulfilled the criteria of EDS vascular type
for laboratory testing . Total sequencing of COL3A1 cDNA (obtain form
skin cultured fibroblasts) identified an homozygous nucleotide duplication
(c .479_480dupT) resulting in a premature termination codon
(p .Val160fsX46) . Studies in genomic DNA showed that this mutation
in exon 5 of the COL3A1 gene was inherited from each parent . As
expected, the expression analysis (RT-PCR, quantitative-PCR, Immunohistochemistry,
WB) showed a strong mRNA decay, which results in
an absence of type III collagen in the proband .
This case, shows that a deficit in collagen III is viable in early childhood
in Man. Here, the expected COL3A1 haploinsufficiency in her
asymptomatic ascendants did not lead to the severe clinical manifestations
of EDS vascular type cause by haploinsufficiency of one allele
as described in the literature . This case provides evidences for a stochastic
effect of COL3A1 haploinsufficiency in Man with (a) modifying
factor(s), which remains to be identified.
P05.037
Early myoclonic encephalopathy caused by a disruption of the
Neuregulin-1 receptor ErbB4
H. Van Esch1 , B. Ceulemans2 , J. Vermeesch1 , K. Devriendt1 , L. Backx1 ;
1 2 Center for Human Genetics, Leuven, Belgium, Rehabilitation and Epilepsy
Centre for Children and Youth, Pulderbos, Belgium.
The tyrosine kinase receptor ErbB4 (erythroblastic leukemia viral oncogene
homolog 4) plays a crucial role in numerous neurobiological
processes in the developing and adult brain . One of the most important
and well-studied ligands of ErbB4 is Neuregulin-1 (NRG1) and it
was shown that NRG1-ErbB4 signaling is essential for neurobiological
processes like neurogenesis, migration, synaptic plasticity and differentiation
of neurons and glia . Moreover, recent molecular genetics
studies implicate ErbB4 in the pathophysiology of schizophrenia . However,
the phenotypic consequences of haploinsufficiency of ErbB4 are
not known, since no coding mutations have been identified until now.
Here, we present a patient with early myoclonic encephalopathy and
profound psychomotor delay with a de novo reciprocal translocation
t(2;6)(q34;p25 .3), disrupting the ErbB4 gene . This patient represents
the first case of haploinsufficiency for one of the ErbB family members
of tyrosine kinase receptors .
P05.038
mutation analysis of epidermolysis bullosa in the czech
Republic
B. Jerabkova 1,2 , L. Fajkusova 1,2 , H. Buckova 3,2,4 , K. Vesely 5,6 , R. Gaillyova 7,2 ;
1 Centre of Molecular Biology and Gene Therapy, Faculty Hospital Brno, Brno,
Czech Republic, 2 Masaryk University Brno, Brno, Czech Republic, 3 Department
of Pediatric Dermatology of 1st Pediatric Clinic, Faculty Hospital Brno, Brno,
Czech Republic, 4 Institute of Medical Postgraduate Studies Prague, Prague,
Czech Republic, 5 1st Institute of Pathological Anatomy, St. Ann´s Hospital,
Brno, Czech Republic, 6 Medical Faculty of Masaryk University Brno, Brno,
Czech Republic, 7 Department of Clinical Genetics, Faculty Hospital Brno, Brno,
Czech Republic.
Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous
group of heritable skin disorders . It is characterised by skin blistering
and mucous membrane . EB has been divided into three major
categories based on the level of blister formation in dermal-epidermal
junction zone .
EB is diagnosed by evaluation of clinical findings, by transmission
electron microscopic examination of a skin biopsy and immunohistochemical
mapping of protein components of dermal-epidermal junction
zone from a skin biopsy . Molecular-genetic diagnostics of EB was initiated
in 2004 .
Dystrophic EB (EBD) is caused by mutations in the collagen type VII
(COL7A1), which consists of 118 exons . EB simplex (EBS) is caused
by mutations in the keratin 5 (KRT5), which consists of 9 exons and
keratin 14 (KRT14), which consists of 8 exons .
DNA from EB patients and their relatives were screened for mutations
in COL7A1, KRT5 and KRT14 genes . Analysis was performed using
PCR, denaturing high performance liquid chromatography, high resolution
melting analysis and direct sequencing . We could identify KRT5
or KRT14 dominant mutations in 11 out of 18 EBS families . As regards
27 EBD probands, we revealed disease causative mutations in 16 patients
and screening of COL7A1 is in progress . Prenatal diagnosis of
one pregnancy in family with occurrence of EBS predicted the fetus
being normal and subsequently a healthy child was born .
Determination of EB at the level of DNA has important implication for
final confirmation of diagnosis, possibility of genetic counselling and
early prenatal diagnosis .
This work was supported by IGA MH NR9346-3 .
P05.039
Erythropoietic protoporphyria in a czech family caused by a new
84G>A (W28X) mutation in the ferrochelatase gene
J. Prochazkova1 , J. Sperl2 , S. M. Farrag1 , L. Barnincova1 , J. Spicak2 , P. Martasek1
;
1 2 1st School of Medicine, Charles University, Prague, Czech Republic, Institute
for Clinical and Experimental Medicine, Prague, Czech Republic.
Erythropoietic protoporphyria (EPP) is a disorder with autosomal dominant
inheritance caused by partial deficiency of ferrochelatase (FECH).
Ferrochelatase is the ultimate enzyme of heme biosynthesis . EPP is
characterized by excess accumulation of protoporphyrin, particularly