2008 Barcelona - European Society of Human Genetics

Concurrent Sessions
c06.3
clinical features of maternal uniparental disomy 14 are also
present in patients with an epimutation and a deletion of the
imprinted DLK/GTL gene cluster
G. Gillessen-Kaesbach 1 , D. Kamber 2 , J. I. Martin-Subero 3 , W. Lieb 1 , P. Terhal 4 ,
B. Albrecht 2 , E. Rossier 5 , D. Rita 6 , S. Das 7 , S. Purmann 1 , S. Groß 2 , C. Lich 2 , R.
Siebert 8 , B. Horsthemke 2 , K. Buiting 2 ;
1 Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany, 2 Institut
für Humangenetik, Universitätsklinikum Essen, Essen, Germany, 3 Institut für
Humangenetik, Christian Albrecht Universität Kiel, Kiel, Germany, 4 Department
of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands,
5 Institut für Humangenetik, Universitätsklinikum Tübingen, Tübingen,
Germany, 6 The Park Site Center, Park Ridge, Illinois, IL, United States, 7 Department
Of Human Genetics, University of Chicago, Chicago, IL, United States,
8 Institut für Humangenetik, Christian Albrecht Universität Kiel, Kiel, Germany.
Maternal uniparental disomy 14 [upd(14)mat] is associated with a recognizable
phenotype that includes pre- and postnatal growth retardation,
neonatal hypotonia, feeding problems and precocious puberty .
Chromosome 14 contains an imprinted gene cluster, which is regulated
by a differentially methylated region (IG-DMR) between DLK1 and
GTL2 . Here we report on six patients with clinical features of maternal
upd(14)mat who show a typical methylation pattern at the IG-DMR and
the GTL2 promoter region, but biparental inheritance for chromosome
14. In five of the patients loss of paternal methylation appears to be
a primary epimutation, whereas the other patient has a paternally derived
deletion of ~1 Mb that includes the imprinted DLK-GTL2 gene
cluster. These findings demonstrate that the upd(14)mat phenotype is
caused by altered expression of genes within this cluster .
c06.4
capillary malformation - Arteriovenous malformation: clinical
and molecular aspects
N. Revencu 1,2 , L. M. Boon 1,3 , J. B. Mulliken 4 , O. Enjolras 5 , M. Cordisco 6 , P. E.
Burrows 4 , P. Clapuyt 7 , F. Hammer 7 , J. Dubois 8 , E. Baselga 9 , D. Chitayat 10 , M.
Vikkula 1 ;
1 de Duve Institute, Brussels, Belgium, 2 Center for Human Genetics, Cliniques
universitaires Saint Luc, Brussels, Belgium, 3 Vascular Anomalies Centre, Division
of Plastic Surgery, Cliniques universitaires Saint Luc, Brussels, Belgium,
4 Vascular Anomalies Center, Children’s Hospital, Boston, MA, United States,
5 Centre Multidisciplinaire des Angiomes de l’enfant, Hôpital d’enfants Armand-
Trousseau, Paris, France, 6 Department of Pediatric Dermatology, Hospital de
Pediatria Dr. J.P. Garrahan, Buenos Aires, Argentina, 7 Department of Radiology,
Cliniques universitaires Saint Luc, Brussels, Belgium, 8 Department of
Medical Imaging, Sainte-Justine Mother-Child University Hospital, Montreal,
QC, Canada, 9 Hospital de la Santa Creu I Sant Pau, Barcelona, Spain, 10 Medical
Genetics Program Mount Sinai Hospital, Toronto, ON, Canada.
Background: Mutations in RASA1 were documented in 6 families (39
individuals) with autosomal dominant multifocal capillary malformations
(CMs) . Nine individuals had an associated arteriovenous malformation/fistula
(AVM/AVF). One patient had Parkes Weber syndrome
(PKWS), a disorder considered to be sporadic and non-genetic .
Methods: We collected clinical information and DNA samples for 61
probands (from 21 centers) and their families with a phenotype similar
to that observed in the original study: 56 had multifocal CMs, and 35
also a fast-flow vascular anomaly: 19 AVM/AVF and 16 PKWS; 5 had
PKWS without multifocal CMs . RASA1 was screened by DHPLC followed
by sequencing .
Results: We identified 42 distinct mutations in 44/61 probands: 16/19
with AVM/AVF, 13/16 with PKWS, 15/21 with multifocal CMs only, and
0/5 with PKWS without multifocal CMs . RASA1 mutation was also
found in 57 relatives . Overall, 17 individuals with a RASA1 mutation
had an AVM/AVF: 8 were intracranial, 2 of which were vein of Galen
aneurysmal malformations . Moreover, 7 patients had either a benign
or a malignant tumor, 3 of which are known to occur in neurofibromatosis
type 1 or 2 . Penetrance of RASA1 mutations was 98% and de novo
occurrence was 32% .
Conclusions: Multifocal CM is the hallmark of RASA1 mutation . These
patients often have extra- or intracranial AVM/AVF. This study confirms
the original association designated capillary malformation-arteriovenous
malformation (CM-AVM) . In addition, PKWS, as well as vein of
Galen aneurysmal malformation are genetic diseases, part of the CM-
AVM spectrum. Specific neural tumors also may be linked to RASA1.
c06.5
A novel, autosomal dominant, Pseudoxanthoma Elasticum-like
phenotype in a five-generation family
P. D. Turnpenny 1 , O. M. Vanakker 2 , L. Costrop 2 , A. de Paepe 2 , L. Schurgers 3 ,
R. Florijn 4 , F. M. Pope 5 , M. James 6 , S. Tomkins 6 , P. Newman 7 , S. Ellard 8 , E.
Young 8 , M. L. P. Robert 1 ;
1 Peninsula Clinical Genetic Service, Exeter, United Kingdom, 2 Center for Medical
Genetics, Ghent University, Ghent, Belgium, 3 VitaK & CARIM, University
of Maastricht, Maastricht, The Netherlands, 4 The Netherlands Ophthalmic Research
Institute, Amsterdam, The Netherlands, 5 Northwick Park Health Institute,
London, United Kingdom, 6 South Western Regional Genetics Service, Bristol,
United Kingdom, 7 Dept Histology, Royal Devon & Exeter Hospital, Exeter,
United Kingdom, 8 Molecular Genetics, Royal Devon & Exeter Hospital, Exeter,
United Kingdom.
Pseudoxanthoma elasticum (PXE) is an autosomal recessive (AR)
progressive disorder of elastic fibres characterised by dermal, ocular
and vascular lesions, due to mutations in ABCC6, an ATP-binding
cassette transporter, in ~80% of cases . Autosomal dominant (AD)
inheritance is very rare and usually due to pseudodominance (Plomp
et al . 2004) . We studied 17 individuals from a 5-generation family with
PXE-like skin manifestations . Many subjects also suffer premature
claudication pain and ischaemic heart disease but they do not have
typical PXE ophthalmic signs . Electron microscopy analysis of skin
was normal except in one patient who had fragmentation and clumping
of elastic fibres with no evidence of calcification. Sequencing of
ABCC6 was negative and linkage to this locus excluded . Vanakker et
al (2007) reported GGCX mutations in 3 families with an AR PXE-like
phenotype and vitamin K-dependent coagulopathy . Our family has no
history of abnormal bleeding, clotting assays were normal in one affected
individual, and sequencing of GGCX and VKORC1 was normal .
Immunohistochemistry of lesional skin tissue showed disturbance in
the gamma-carboxylation of vitamin K-dependent mineralization inhibitors,
particularly matrix gla protein (MGP) . This suggests involvement
of a related pathway as in the PXE-like phenotype of Vanakker et al
(2007) . Genome-wide linkage results, and candidate gene sequencing,
are awaited . This 5-generation family with a PXE-like phenotype
demonstrates unequivocal AD inheritance . We believe this is a previously
unreported clinical and genetic entity, the pathogenesis of which
may provide new information on the molecular pathways involved in
PXE and related disorders .
c06.6
clinical phenotypes and outcome of 101 LmNA gene mutation
carriers
N. Marziliano1 , M. Pasotti1 , M. Grasso1 , A. Pilotto1 , E. Serafini1 , B. De Giorgio1 ,
M. Diegoli2 , A. Brega3 , E. Arbustini1 ;
1 2 Fondazione IRCCS Policlinico San Matteo, PAVIA, Italy, University of Pavia,
PAVIA, Italy, 3University of Milan, MILANO, Italy.
Background . Lamin A/C (LMNA) gene mutations cause a variety of
phenotypes . In the cardiologic setting, patients diagnosed with idiopathic
dilated cardiomyopathy (DCM) plus atrio-ventricular block (AVB)
constitute the majority of reported cases .
Methods . This was a longitudinal retrospective study conducted in 32
consecutive families in which LMNA gene defects were identified in the
probands, sharing DCM (n=31) and ARVD (n=1) phenotype .
Results . Of the 171 family members, 101 were carriers of LMNA gene
mutations . 65 of 101 (64 .5%) were phenotypically affected while 36
were only genotypically affected, including 5 with preclinical signs . The
65 patients had DCM with AVB (n=44), DCM with Ventricular Tachycardia/Fibrillation
(VT/VF) (n=12), DCM with AVB and Emery-Dreifuss
Muscle Dystrophy type 2 (EDMD2) (n=6), AVB plus EDMD2 (n=2) and
ARVD (n=1) . The disease was proven to be familial autosomal dominant
(AD) in 23 of the 32 families; likely familial AD in 6 and associated
with a de novo mutation in 3 . During a median follow-up of 57 .4 months
(interquartile range 26-115 months) we observed 54 events in 47 DCM
patients (7 had a later event excluded from the analysis) whereas no
event was observed among the 36 non-affected carriers . The events
were related to heart failur
Conclusions . DCMs caused by LMNA gene defects are highly penetrant,
adult-onset, malignant diseases characterized by high rate of HF
and life-threatening arrhythmias predicted by NYHA class, competitive
sport activity and type of mutation . We also found a LMNA gene defect
associated with an ARVD clinical phenotype .