2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
P02.036
mutation analysis of Epidermolysis Bullosa in the czech
Republic
B. Jerabkova 1 , H. Buckova 2 , K. Vesely 3 , K. Stehlikova 1 , L. Fajkusova 1 ;
1 University Hospital, Centre of Molecular Biology and Gene Therapy, Brno,
Czech Republic, 2 University Hospital, Department of Pediatric Dermatology of
1st Pediatric Clinic, Brno, Czech Republic, 3 St. Ann´s Hospital, 1st Institute of
Pathological Anatomy, Brno, Czech Republic.
Epidermolysis bullosa (EB) is a rare genetic disease characterized by
extremely fragile skin and recurrent skin blistering after mild or none
mechanical trauma. Traditionally, EB is classified in three major categories
according to the level of dermoepidermal separation at the
basement membrane (BM) zone: i) epidermolysis bullosa simplex
(EBS); ii) dystrophic epidermolysis bullosa (DEB); and iii) junctional
epidermolysis bullosa (JEB).
EB is diagnosed by evaluation of clinical findings, transmission electron
microscopy of skin samples, and immunohistochemical mapping
of protein components of dermal-epidermal junction zone. Moleculargenetic
diagnostics of DEB and EBS was initiated in our laboratory in
2004.
Dystrophic EB (EBD) is caused by mutations in the collagen type VII
(COL7A1) gene, which consists of 118 exons. EB simplex (EBS) is
caused by mutations in the keratin 5 (KRT5) gene (9 exons) and the
keratin 14 (KRT14) gene (8 exons).
DNA from EB patients and their relatives were screened for mutations
in the COL7A1, KRT5 and KRT14 genes. Analysis was performed using
PCR and direct sequencing. We could identify KRT5 or KRT14
dominant mutations in 13 out of 19 EBS families. As regards 27 EBD
probands, we revealed disease causative mutations in 22 patients and
screening of COL7A1 is in progress.
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 MZ CR NR9346-3 and by MSMT
LC06023.
P02.037
Associated malformations in patients with Esophageal atresia
C. G. Stoll, Y. Alembik, B. Dott, M. Roth;
Genetique Medicale, Strasbourg, France.
Esophageal atresia is a common type of congenital malformation.
The etiology of esophageal atresia is unclear and its pathogenesis is
controversial. Because previous reports have inconsistently noted the
type and frequency of malformations associated with esophageal atresia,
we conducted this study in a geographically defined population,
evaluating the birth prevalence of esophageal atresia and associated
malformations ascertained between 1979 and 2003 in 334,262 consecutive
births. Of the 99 patients with esophageal atresia, 46 (46.5%)
had associated malformations. These included patients with chromosomal
abnormalities (8 cases,8.1%); non chromosomal recognized
syndromes including CHARGE syndrome, Fanconi anemia, Fryns syndrome,
and Opitz G/BBB syndrome; associations including VACTERL
(10 patients), and schisis; oculo-auriculo-vertebral spectrum; malformation
complex including sirenomelia, and non syndromic multiple
congenital anomalies (MCA) (21 cases, 21.2%). Malformations of the
cardiovascular system(24.2%), urogenital system (21.2%), digestive
system (21.2%), musculoskeletal system (14.1%), and central nervous
system(7.1%) were the most common other congenital malformations
occurring in patients with esophageal atresia and nonsyndromic MCA.
We observed a striking prevalence of total malformations and specific
patterns of malformations associated with esophageal atresia which
emphasizes the need to evaluate all patients with esophageal atresia
for possible associated malformations. The malformations associated
with esophageal atresia can be often classified into a recognizable
malformation syndrome or pattern (25.3%).
P02.038
Focal dermal hypoplasia: two novel mutations in the PORcN
gene
N. Revencu 1,2 , A. Destrée 3 , B. Bayet 4 , M. Coyette 4 , J. L. Hennecker 5 , M. Vikkula
2 ;
1 Center for Human Genetics, Cliniques universitaires Saint-Luc, Brussels, Belgium,
2 Laboratory of Human Molecular Genetics, de Duve Institute, Brussels,
Belgium, 3 Center for Human Genetics, Institut de Pathologie et de Génétique,
Gosselies, Belgium, 4 Department of Plastic Surgery, Cliniques universitaires
Saint-Luc, Brussels, Belgium, 5 Department of paediatrics, Notre-Dame de
Grâce Hospital, Gosslies, Belgium.
Focal dermal hypoplasia (FDH) or Goltz syndrome (OMIM 305600)
is an X-linked dominant disorder characterized by patchy hypoplastic
skin and digital, ocular, bony and dental anomalies. Recently, mutations
in the PORCN gene, a putative regulator of Wnt signalling were
demonstrated to cause sporadic and familial FDH cases.
We report on here the clinical presentation and the molecular studies
in two unrelated girls with sporadic FDH: an 8-month-old Algerian girl
(patient 1) and a 6-year-old Belgian girl (patient 2). Both had: normal
head circumference at birth and developed progressive microcephaly
with no developmental delay, patchy, hyper-pigmented or red atrophic
skin lesion, abnormal extremities with syndactyly, +/- ectrodactyly,
dysplastic nails, sparse and brittle hair with patchy alopecia, iris and
chorioretinal coloboma.
Sequencing of the 14 coding exons and the exon-intron boundaries of
the longest human splice variant of the PORCN gene (isoform D; NM_
203475.1) revealed novel heterozygous mutations in both children.
Patient 1 had a de novo duplication of 11 nucleotides in exon 8 causing
a frame-shift and a premature termination codon (c.762_772dup-
CAACTATTTTG ). Patient 2 had an A to G substitution which alters the
ATG start codon (c.1A>G). The PORCN transcript does not have any
ATG upstream of the start codon and the next in-frame ATG is in position
72. Thus, both mutations are expected to cause loss-of-function.
This study expands the number of PORCN mutations in the FDH patients
to 28. The clinical description contributes to the delineation of the
FDH phenotype associated with PORCN mutations.
P02.039
Female-to-female transmission of Frasier syndrome : Lessons
for genetic counseling
K. Dahan 1 , N. Godefroid 2 , M. Jadoul 2 , O. Devuyst 2 , Y. Pirson 2 ;
1 Centre for Human Genetics, Université Catholique de Louvain, Brussels,
Belgium, 2 Department of Nephrology, University Hospital St Luc, Brussels,
Belgium.
Frasier syndrome is defined by the association of focal segmental
glomerulosclerosis (FSGS), male pseudohermaphroditism with streak
gonads and risk to develop gonadoblastoma. There have been some
recent reports that observed Frasier site mutations in genetically female
(46XX) patients. These females seemed to have normal genital
development. We present a female-to-female transmission of a Frasier
intronic mutation affecting splicing of the primary transcript of Wilms
tumour suppressor gene (WT1). The index patient developped an isolated
proteinuria from the age of 3 years with normal renal function at
age 5. No urogenital involvement and wilm’s tumour were observed
throughout the 2 years follow-up. Her karyotype performed at age 5
with informed consent was normal 46,XX. The mother originated from
Belgium had proteinuria at age of 8 years and progressed into endstage
renal disease at age 17. Renal histology showed FSGS. She became
pregnant when she was 22 years and was delivered at 35 weeks
of gestation from a baby girl of 1800g. The occurrence of proteinuria in
our proband combined with the medical history of her mother prompted
us to perform genetic analysis which revealed the same Frasier
intronic mutation in both mother and daughter.
Conclusion: these data illustrate that 46,XX patients affected by WT1
mutations in the Frasier site have a conserved ovarian function and
then, emphasizes the importance of genetic counseling in all female
patients presenting a steroid-resistant FSGS. Furthermore, early genetic
work-up allowed us to avoid a renal biopsy and an useless immunosuppressive
therapy in our proband.
P02.040
Progranulin gene mutations are infrequent cause of
frontotemporal lobar degeneration (FtLD) in Polish population
M. Berdynski 1 , M. Kuzma-Kozakiewicz 2 , B. Gajewska 3 , H. Kwieciński 2 , C. Zekanowski
1 ;
1 Department of Neurodegenerative Disorders, Mossakowski Medical Research
Centre, Warsaw, Poland, 2 Department of Neurology, Medical University of
Warsaw, Warsaw, Poland, 3 Department of Biochemistry, Medical University of