2009 Vienna - European Society of Human Genetics

Concurrent Sessions
results are consistent with recent studies, which indicate that nuclear
position plays a functional role in regulating the expression of some
genes in mammalian cells. Rearrangements may also have implications
on reproductive separation, as we show that reciprocal translocations
not only provide partial isolation for speciation, but also result in
significant changes in transcriptional regulation through alteration of
the relative nuclear position of chromosome territories.
c16.2
5q14.3 microdeletion encompassing MEF C, a gene controlling
excitatory synapse number, is associated with severe mental
retardation, poor eye contact and seizures
A. Goldenberg 1 , M. Holder-Espinasse 2 , S. Jaillard 3,4 , N. Le Meur 1,5 , D. Bonneau
6 , S. Joriot 7 , A. Charollais 8 , H. Journel 9 , S. Auvin 10 , C. Boucher 1 , J. Kerckaert
11 , T. Frébourg 1,12 , V. David 4,13 , S. Manouvrier-Hanu 2 , P. Saugier-Veber 1,12 ,
C. Dubourg 4,13 , J. Andrieux 14 ;
1 Service de Génétique, CHU de Rouen, Rouen, France, 2 Service de Génétique
Clinique, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France, 3 Laboratoire
de Cytogénétique, CHU Pontchaillou, Rennes, France, 4 CNRS UMR 6061, Université
de Rennes 1, IFR 140, Rennes, France, 5 Laboratoire de Cytogénétique,
EFS-Normandie, Bois Guillaume, France, 6 Service de Génétique Médicale,
CHU d’Angers, Angers, France, 7 Service de Neuropédiatrie, Hôpital Roger
Salengro, CHRU de Lille, Lille, France, 8 Service de Médecine Néonatale, CHU
de Rouen, Rouen, France, 9 Service de Génétique Clinique, Centre Hospitalier
Bretagne Atlantique, Vannes, France, 10 Service de Neurologie Pédiatrique,
CHU Robert Debré - APHP, Paris, France, 11 Plateforme de Génomique Fonctionnelle,
Université de Lille II, Lille, France, 12 Inserm U614, IHURBM, Université
de Rouen, Rouen, France, 13 Laboratoire de Génétique Moléculaire, CHU
Pontchaillou, Rennes, France, 14 Laboratoire de Génétique Médicale, Hôpital
Jeanne de Flandre, CHRU de Lille, Lille, France.
Over the last few years, array-CGH has remarkably improved the ability
to detect cryptic unbalanced rearrangements in patients presenting
with syndromic mental retardation. Using oligonucleotide array-CGH,
we identified a 5q14.3 microdeletion in 5 unrelated patients and a
5q14.3 microduplication in one patient. Fluorescence In Situ Hybridization
(FISH) and semi-quantitative PCR further confirmed these de
novo rearrangements. Interestingly, the five patients with the 5q14.3
microdeletion showed striking phenotypic similarities, namely severe
mental retardation, poor visual contact, absent speech, stereotyped
behaviour, facial dysmorphic features, epilepsy and/or cerebral malformations.
The boundaries and sizes of the deletions were different but
the minimal common deleted region encompassed only the MEF2C
gene. This gene, known to act in brain as a neurogenesis effector
which regulates excitatory synapse number, constitutes an excellent
candidate. We suggest therefore that 5q14.3 microdeletion may represent
a novel clinically recognizable condition caused by haploinsufficiency
of the MEF2C gene.
c16.3
19q13.11 deletion syndrome: a novel clinically and biochemically
recognizable genetic condition identified by array-CGH
V. Malan 1,2 , C. Ottolenghi 3,2 , O. Raoul 1,2 , H. V. Firth 4 , B. Chadefaux 3,2 , G. Royer 1 ,
C. Turleau 1,2 , A. Bernheim 5,6 , L. Willatt 4 , A. Munnich 1,2 , M. Vekemans 1,2 , S. Lyonnet
1,2 , V. Cormier-Daire 1,2 , L. Colleaux 1,2 ;
1 Département de Génétique et INSERM U781, Hôpital Necker-Enfants
Malades, Paris, France, 2 Université Paris Descartes, Paris, France, 3 Service
de Biochimie Métabolique, Hôpital Necker-Enfants Malades, Paris, France,
4 Department of Medical Genetics, Addenbrooke’s Hospital, Cambridge, United
Kingdom, 5 CNRS FRE2339 Institut Gustave Roussy, Villejuif, France, 6 Université
Paris Sud, Orsay, France.
Deletions of chromosome 19 have rarely been reported with the exception
of some patients with deletion 19q13.2 and Blackfan-Diamond
syndrome due to haploinsufficiency of the RPS19 gene. The paucity
of observations might result from the difficulty to detect small rearrangements
on this chromosome that lacks a clear banding pattern.
Using array-based comparative genomic hybridization (array-CGH)
we identified three distinct but overlapping interstitial 19q13.11 deletions,
defining a minimal critical region of 2.87 Mb, associated with
a clinically recognizable syndrome. The three patients share several
major features including: pre and postnatal growth retardation with
slender habitus, severe postnatal feeding difficulties, microcephaly,
hypospadias, signs of ectodermal dysplasia and cutis aplasia over
the posterior occiput. Among the deleted genes, the human prolidase
(PEPD) gene is of particular interest. It is involved in a rare autosomal
recessive disorder of the connective tissue. Biochemical assays
showed reduced prolidase activity in our patients. Their dermatological
anomalies, including cutis aplasia of the scalp and thin skin, might
thus be accounted for by PEPD haploinsufficiency. We suggest that
del 19q13.11 represents a novel clinically recognizable microdeletion
syndrome caused by haploinsufficiency of dosage sensitive genes in
the 19q13.11 region. Moreover, as a complement to the specific clinical
features, prolidase activity in erythrocytes may provide a simple
diagnostic marker for this new genomic disorder.
c16.4
Parental origin and possible mechanisms of formation of de
novo balanced reciprocal translocations
A. Spreiz 1 , M. Höckner 1 , S. Demuth 2 , A. Dufke 3 , V. Kalscheuer 4 , M. Rieger 5 ,
O. Rittinger 6 , I. Rost 7 , S. Singer 3 , A. Tzschach 4 , E. Wiedersberg 8 , M. Erdel 1 , C.
Fauth 1 , J. Zschocke 1 , G. Utermann 1 , D. Kotzot 1 ;
1 Division for Clinical Genetics, Innsbruck, Austria, 2 Praxis für Humangenetik,
Erfurt, Germany, 3 Institute for Human Genetics, Medical Genetics, Tübingen,
Germany, 4 Max Planck Institute for Molecular Genetics, Berlin, Germany,
5 Heckscher Klinik, Rottmannshöhe, Germany, 6 Section Clinical Genetics,
Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg,
Austria, 7 Zentrum für Humangenetik und Laboratoriumsmedizin, Martinsried,
Germany, 8 Humangenetische Beratungsstelle, HELIOS Kliniken Schwerin
GmbH, Schwerin, Germany.
Balanced reciprocal translocations are found in approx. 1 : 400 newborns.
Most of them are inherited from one parent. De novo formation
is a rare event and accompanied by various anomalies if there is a
microrearrangement closed to one or both breakpoints. From associated
deletions or duplications, the involvement of the Y chromosome,
or cytogenetic polymorphisms a preferentially formation in paternal
meiosis was assumed but so far not proven directly.
Here, we report on the parental origin and possible mechanisms
of formation of de novo cytogenetically balanced reciprocal translocations
in two healthy probands and seven patients affected
by multiple congenital anomalies. Two of them have been recorded
previously. The karyotypes are 46,XY,t(4;5)(q21.1;p15.33),
46,XX,t(2;3)(q33;q23), 46,XY,t(6;14)(q15;q24), 46,XX,t(2;8)(p13~15;q
22), 46,XX,t(2;5)(p21;q11.2), 46,XX,t(2;13)(p13;q12), 46,XY,t(7;11)(q1
1.21;p11.2), 46,XX,t(2;7)(q23;p21), and 46,XX,t(2;4)(p16;q35).
For each chromosome of interest, microdissected derivative chromosomes
and their normal homologs were pooled separately for investigation,
which included whole genome amplification (GenomePlex Single
Cell Kit®, Sigma-Aldrich, Vienna, Austria), microsatellite mediated
haplotype analysis, and visualisation of the products by silver staining
subsequent to a 6% polyacrylamide/urea gel electrophoresis.
Involvement of paternal chromosomes was found in all seven cases investigated
so far. Our results confirm the assumed preferentially paternal
origin of de novo reciprocal translocations for the first time by direct
investigation of the chromosomes involved. In addition, the conformity
for either maternal or paternal origin for all derivative chromosomes
and their normal homologs makes a meiotic formation more likely than
a postzygotic formation.
c16.5
22q13.3 deletion syndrome is a multigenic disorder, with
SHANK as the major pathogenic gene
M. Zollino 1 , M. E. Grimaldi 1 , L. Boccuto 1,2 , C. Schwartz 2 , D. Battaglia 3 , E. Mercuri
3 , F. Guzzetta 3 , G. Marangi 1 , D. Orteschi 1 , D. Buccella 1 , M. Lauri 1 , P. Visconti
4 , G. Gobbi 4 , G. Neri 1 , F. Gurrieri 1 ;
1 Istituto di Genetica Medica Università Cattolica Sacro Cuore, Roma, Italy,
2 Greenwood Genetic Center, Greenwood, SC, United States, 3 Neuropsichiatria
Infantile Università Cattolica Sacro Cuore, Roma, Italy, 4 Neuropsichiatria Infantile
Ospedale Maggiore Bologna, Bologna, Italy.
The 22q13.3 deletion syndrome consists of hypotonia, mental retardation
with delayed or absent speech, normal or accelerated growth, autistic-like
behaviour and few dysmorphic features. This condition was
recently inferred to be a single gene (SHANK3) disorder.
We analysed a total of 32 patients presenting with clinical manifestations
consistent with this condition, by means of a-CGH, FISH with
cosmids n66c4 and n85a3 containing SHANK3 and sequence analysis
of SHANK3. Loss-of-function mutations limited to SHANK3 were detected
in three patients (9%). They were c.3895delG (p.Glu1299fs)dn,