2008 Barcelona - European Society of Human Genetics

Concurrent Sessions
limb or thoracic anomalies(ULA or TA) .
Clinical characterization of PS has not been described in literature on a
wide patient series . We have considered the following parameters:
• Describe the disease phenotype in a wide range of patients .
• Verify the current data present in literature
• Classify disesase severity according to clinical features and identify
risk factors according to gender, affected side and other phenotypic
characteristics .
• Definition of associated malformations or syndromes.
• Obtain best methods in management of patients from diagnostic,
therapeutic and prognostic points of view
• Possibility to identify new etiopathogenetic hypotheses (genetic versus
environmental factors) and validate those present in literature
We have studied 122 poland patients (64 M, 48 F) in the period 2003-
2007 .
The management of these patients was based on multidisciplinary approach.
At the first phase of the study all included patients had undergone
Specialistic Counselling (Genetic, Psychologic, Surgical, and
Orthopedic) .
The second phase was based on medical indication and included high
resolution karyotyping or array-CGH . Moreover, the standardization
of pectoral muscle and tendon components by ultrasound is ongoing .
Other investigations included chest X-ray, Echocardiography, Abdominal
ultrasound, and thoracic CT scan .
In collaboration with AISP (Italian Association of Poland Syndrome)
A Spoken presentation on this topic was awarded young researcher
prize at the Italian Socitey of Human Genetics Conference 2007
c11.5
Distal limb deficiency, micrognathia syndrome (OMIM 246560)
and syndromic forms of split hand foot malformation (sHFm) are
caused by chromosome 10q genomic rearrangements
B. I. Dimitrov 1 , T. d. Ravel 1 , C. d. Die-Smulders 2 , A. Toutain 3 , J. R. Vermeesch 1 ,
J. Fryns 1 , K. Devriendt 1 , P. Debeer 1 ;
1 Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium,
2 Department of Clinical Genetics, University Hospital of Maastricht, University
of Maastricht, Maastricht, The Netherlands, 3 Genetic Service, University Hospital
Bretonneau, University of Tours, Tours, France.
As a part of screening for genomic rearrangements in patients with
unexplained syndromic limb defects, arrayCGH was performed in a
cohort of patients with various syndromic limb defects . A 10q24-microduplication
was detected in 6 individuals with distal limb deficiency,
associated with micrognathia, hearing problems and renal hypoplasia .
In addition, in a family with two affected siblings, somatic mosaicism
for the 10q24-microduplication was detected in the apparently healthy
mother .
This chromosomal region has previously been implicated in SHFM .
SHFM3 was mapped to a large interval on chromosome 10q24 . The
corresponding Dactylaplasia mouse model was linked to the syntenic
locus on chromosome 19 . When it was shown that the two existing
Dac alleles result from MusD-insertions upstream of or within Dactylyn
(Fbxw4), this gene seemed a plausible candidate causing SHFM3 .
However, all efforts to identify mutations in this gene failed . Likewise,
no mutations were found in other genes within the linkage area including
FGF8, despite the fact that the observed limb defects resemble
those detected in conditional Fgf8-knockout mice .
However, recently, a 10q24-microduplication was detected in a total
of 15 familial and 4 sporadic SHFM3 cases . In contrast to the present
patients, the previously reported individuals had an isolated form of
SHFM . This difference cannot be explained by a difference in size of
the duplication, since a similar size was present in all individuals .
These findings extend the clinical spectrum of SHFM3. Genetic counseling
should consider the observed somatic mosaicism .
c11.6
Biallelic loss of function of the promyelocytic leukaemia zinc
finger (PLZF) gene causes severe skeletal defects and genital
hypoplasia
B. Horsthemke 1 , S. Fischer 1 , J. Kohlhase 2 , D. Böhm 2 , B. Schweiger 1 , M. Heitmann
1 , D. Wieczorek 1 ;
1 Universitätsklinikum Essen, Essen, Germany, 2 Praxis für Humangenetik, Frei-
burg, Germany.
Deletions of 11q23 are associated with mental retardation, craniofacial
dysmorphism, microcephaly and short statue . We present a patient
with similar clinical findings plus absence of thumbs, hypoplasia
of radii and ulnae, additional vertebrae and ribs, retarded bone age
and genital hypoplasia . Using microarray based comparative genomic
hybridization and microsatellite analysis, we identified an ~8 Mbp de
novo deletion on the paternal chromosome 11, which includes the promyelocytic
leukaemia zinc finger (PLZF) gene . In humans PLZF is one
of five partners fused to the retinoic acid receptor alpha in acute promyelocytic
leukaemia . Plzf-deficient mice show severe malformations
of the vertebral and appendicular skeleton and male genital hypoplasia
. Since patients with a deletion of 11q23 do not normally present
with skeletal malformations and genital hypoplasia, we sequenced the
maternal PLZF allele in our patient and identified a missense mutation
(c .1849 A>G), which leads to the substitution of a highly conserved
methionine to valine within the eighth zinc finger motive. The mutation
was inherited from the mother, who does not have skeletal defects . In
vitro reporter gene assays show that the mutation impairs the repressive
function of PLZF. In summary, this is the first report on a germline
mutation of PLZF. Our findings as well as observations in Plzf-deficient
mice demonstrate that PLZF is a key regulator of skeletal and male
germline development . Furthermore, our case highlights the importance
to search for a recessive mutation on the non-deleted allele in
patients with a microdeletion and atypical clinical findings.
c12.1
Mutations in Pericentrin cause microcephalic dwarfism
(seckel syndrome) with defective AtR-dependent DNA damage
signalling
A. P. Jackson 1 , E. Griffith 1 , S. Walker 2 , C. Martin 1 , P. Vagnarelli 3 , T. Stiff 2 , B.
Vernay 1 , N. Al Sanna 4 , A. Saggar 5 , B. Hamel 6 , W. C. Earnshaw 3 , P. A. Jeggo 2 ,
M. O’Driscoll 2 ;
1 MRC Human Genetics Unit, Edinburgh, United Kingdom, 2 Genome Damage
and Stability Centre, University of Sussex, Brighton, United Kingdom, 3 Wellcome
Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United
Kingdom, 4 Pediatric Services Division, Dhahran Health Center, Dhahran, Saudi
Arabia, 5 Southwest Thames Regional Genetics Service, St. George’s Hospital
Medical School, London, United Kingdom, 6 Radboud University Nijmegen Medical
Center, Department of Human Genetics, Nijmegen, Netherlands.
Expansion of the brain is one of the defining characteristics of modern
humans. In microcephalic dwarfism, brain and body size are markedly
reduced to a similar degree to that seen in the recently discovered
Indonesian hominid, Homo Floresiensis . Previously, only a single hypomorphic
mutation in the ATR gene has been found as a cause of this
genetically heterogenous group of disorders .
Here, we report that homozygous truncating mutations in pericentrin
(PCNT) cause microcephalic dwarfism, resulting in its loss from the
centrosome, where it has key functions anchoring both structural and
regulatory proteins. Furthermore, we find that PCNT-mutated patient
cells have defects in ATR-dependent checkpoint signalling, providing
the first evidence linking a structural centrosomal protein with DNA
damage signalling. These findings also suggest that other known microcephaly
genes implicated in either DNA repair responses or centrosomal
function, may act in common developmental pathways determining
brain and body size, pathways potentially important in human
evolution .
c12.2
Polycomb complex shapes the higher order of D4Z4 chromatin
structure during differentiation of normal and FsHD muscle
stem cells
B. Bodega1 , S. Brunelli2,3 , F. Grasser4 , N. Locatelli1 , R. Meneveri2 , A. Marozzi1 ,
S. Mueller4 , E. Battaglioli1 , E. Ginelli1 ;
1Dept. of Biology and Genetics for Medical Sciences, University of Milan, Milan,
Italy, 2Dept. of Experimental Medicine, University of Milan-Bicocca, Monza,
Italy, 3Stem Cell Research Institute (SCRI), DIBIT H San Raffaele, Milan, Italy,
4Dept. of Biology II – Anthropology and Human Genetics, Ludwig Maximilians
University, Munich, Germany.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal
dominant neuromuscolar disorder . FSHD involves a complex cascade
of epigenetic events following contraction of a D4Z4 repeat located on
chromosome 4q35 .2 (FSHD locus) . Previous work has indicated that