2008 Barcelona - European Society of Human Genetics

Concurrent Sessions
ESHG CONCURRENT SESSIONS
c01.1
clinical and molecular characteristics of 1qter syndrome:
Delineating a critical region for corpus callosum agenesis/
hypogenesis
B. W. M. van Bon 1 , D. A. Koolen 1 , R. Borgatti 2 , A. Magee 3 , S. Garcia-Minaur 4 ,
L. Rooms 5 , W. Reardon 6 , M. Zollino 7 , M. C. Bonaglia 2 , M. De Gregori 8 , F.
Novara 8 , R. Grasso 2 , R. Ciccone 8 , H. A. van Duyvenvoorde 9 , R. Guerrini 10 , E.
Fazzi 11 , S. G. Kant 9 , C. L. Marcelis 1 , R. Pfundt 1 , N. de Leeuw 1 , B. C. Hamel 1 , H.
G. Brunner 1 , F. Kooy 5 , O. Zuffardi 8 , B. B. A. de Vries 1 ;
1 Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands,
2 IRCCS Eugenio Medea La Nostra Famiglia, Lecco, Italy, 3 Northern Ireland
Regional Genetics Service, Belfast, Ireland, 4 South East of Scotland Clinical
Genetic Service, Edinburgh, United Kingdom, 5 University of Antwerp, Antwerp,
Belgium, 6 National Centre for Medical Genetics, Dublin, Ireland, 7 Università
Cattolica Sacro Cuore, Roma, Italy, 8 Università di Pavia, Pavia, Italy, 9 Leiden
University Medical Centre, Leiden, The Netherlands, 10 Azienda Ospedaliero-
Universitaria A. Meyer, Firenze, Italy, 11 IRCCS C. Mondino Institute, Pavia, Italy.
Patients with a microscopically visible deletion of the distal part of the
long arm of chromosome 1 have a recognisable phenotype, including
mental retardation, microcephaly, growth retardation, a distinct facial
appearance and various midline defects including corpus callosum
abnormalities, cardiac, gastro-oesophageal and urogenital defects as
well as various central nervous system anomalies .
So far, only 8 cases with a pure submicroscopic deletion of distal 1q
have been clinically described . In general, patients with a submicroscopic
deletion have a similar phenotype, suggesting that the main
phenotype of these patients is caused by haploinsufficiency of genes
in this region .
In the present study we describe the clinical presentation of 13 new
patients with a submicroscopic deletion of chromosome 1q43q44, of
which 9 were interstitial, and report on the molecular characterisation
of the deletion size .
The clinical presentation of these patients has clear similarities with
previously reported cases with a terminal 1q deletion . Corpus callosum
abnormalities were present in ten of our patients . The AKT3 gene has
been reported as an important candidate gene causing this abnormality
. However, through detailed molecular analysis of the deletion size in
our patient cohort, we were able to delineate the critical region for corpus
callosum abnormalites to a 360 kb genomic segment which contains
four possible candidate genes, but excluding the AKT3 gene .
c01.2
submicroscopic duplications of the hydroxysteroid
dehydrogenase HSD B 0 and the E3 ubiquitin ligase HUWE
are associated with mental retardation
G. Froyen 1 , M. Corbett 2 , J. Vandewalle 1 , I. Jarvela 3 , O. Lawrence 4 , M. Bauters 1 ,
H. Van Esch 5 , J. Chelly 6 , D. Sanlaville 7 , H. van Bokhoven 8 , H. Ropers 9 , F. Laumonnier
10 , C. E. Schwartz 11 , F. Abidi 11 , P. S. Tarpey 12 , A. Whibley 13 , F. L. Raymond
13 , M. R. Stratton 12 , J. Fryns 5 , M. Peippo 14 , M. Partington 15 , A. Hackett 15 , P.
Marynen 1 , G. Turner 15 , J. Gécz 2 ;
1 VIB, University of Leuven, Leuven, Belgium, 2 Women’s and Children’s Hospital,
Adelaide, Australia, 3 Helsinki University Central Hospital, Helsinki, Finland,
4 John Hunter Hospital, Newcastle, Australia, 5 University Hospital Leuven,
Leuven, Belgium, 6 Université Paris Descartes, Paris, France, 7 Necker Enfants
Malades Hospital, Paris, France, 8 University Medical Centre, Nijmegen, The
Netherlands, 9 Max Planck Institute for Molecular Genetics, Berlin, Germany,
10 Centre Hospitalier Universitaire Bretonneau, Tours, France, 11 JC Self Research
Institute of Human Genetics, Greenwood, SC, United States, 12 The
Wellcome Trust Sanger Institute, Hinxton, United Kingdom, 13 Cambridge Institute
of Medical Research, Cambridge, United Kingdom, 14 The Family Federation
of Finland, Helsinki, Finland, 15 The GOLD service Hunter Genetics University
of Newcastle, Newcastle, Australia.
Submicroscopic copy number imbalances contribute significantly to
the genetic etiology of human disease . We report on a novel microduplication
hot spot at Xp11.22 identified in 6 unrelated families with
predominantly nonsyndromic XLMR . All duplications are unique and
segregate with the disease, including the large families MRX17 and
MRX31 . Our FISH data are strongly suggestive for tandem duplication
events with their sizes ranging from 0 .4 to 1 .0 Mb with a minimal, commonly
duplicated region that contains three genes: RIBC1, HSD17B10
and HUWE1 . RIBC1 could be excluded based on its absence of ex-
pression in the brain and since it escapes X-inactivation in females .
For the other genes, expression array and quantitative PCR analysis
in patient cell lines compared to controls showed a significant up-regulation
of HSD17B10 and HUWE1 as well as several important genes
in their molecular pathways . Loss-of-function mutations of HSD17B10
have previously been associated with progressive neurological disease
and XLMR . The E3 ubiquitin ligase HUWE1 has been implicated
in TP53-associated regulation of the neuronal cell cycle . We also detected
segregating sequence changes of highly conserved residues in
HUWE1 in three XLMR families, which are possibly associated with the
phenotype . Mutations in HSD17B10 have previously been reported to
be associated with XLMR and a progressive neurological disorder . Our
findings demonstrate that an increased gene dosage of HSD17B10,
HUWE1, or both contribute to the etiology of XLMR, and suggest that
point mutations in both genes are associated with this disease too .
c01.3
clinical outcome and molecular investigation of Pitt-Hopkins
syndrome: a series of 9 patients
L. de Pontual, Y. Mathieu, M. Rio, A. Munnich, S. Lyonnet, J. Amiel;
INSERM U-781, Department of Genetics, Necker Hospital, Paris, France, Paris,
France.
Pitt-Hopkins syndrome (PHS) is a syndromic encephalopathy characterised
by severe psychomotor delay, epilepsy, daily bouts of diurnal
hyperventilation starting in infancy, and distinctive facial features . A
systematic 1Mb resolution genome wide BAC array identified a 1.8 Mb
de novo microdeletion on chromosome 18q21 .1 in 1 case . We subsequently
identified de novo heterozygous mutations of TCF4 gene in 8
additional PHS cases. These findings provide the first evidence of a
human disorder related to class I basic helix-loop-helix transcription
factor (also known as E-proteins) defects . Our data support that haploinsufficiency
is the most likely disease-causing mechanism, while a
dominant-negative effect is an alternative hypothesis currently being
tested for missense mutations occurring in the basic domain . Expression
analysis of the TCF4 gene during human embryonic development
will also be presented .
Bouts of hyperventilation and epilepsy, although distinctive, are not
fully penetrant . Several clinical features will be underscored as possible
diagnostic clues in particular the facial gestalt, dysautonomia and
subtle immunoglobulin deficiency. EEG and brain MRI may also give
valuable clues that will be discussed . Patients diagnosed with PHS
display a broad spectrum of dysautonomic features that will be detailed
. These data may also shed new light on the normal processes
underlying autonomic nervous system development and maintenance
of an appropriate ventilatory neuronal circuitry .
c01.4
Expanding the clinical phenotype of tetrasomy 18p
C. D. Sebold 1 , E. Roeder 1,2 , B. T. Soileau 1 , A. Malik 1 , D. Neigut 2 , K. Hernandez
3 , M. Thomas 3 , B. Perry 4 , P. Fox 5 , M. Semrud-Clikeman 6 , B. Butcher 6 , S.
Smith 7 , L. O’Donnell 1 , K. Richards 8 , K. Reinker 9 , R. Tragus 1 , D. E. Hale 1 , J. D.
Cody 1 ;
1 Chromosome 18 Clinical Research Center, San Antonio, TX, United States,
2 Christus Santa Rosa Children’s Hospital, San Antonio, TX, United States, 3 University
Health System, San Antonio, TX, United States, 4 Ear Medical Group,
San Antonio, TX, United States, 5 UTHSCSA Research Imaging Center, San
Antonio, TX, United States, 6 University of Texas at Austin, Austin, TX, United
States, 7 University of Texas at Austin, San Antonio, TX, United States, 8 Wilford
Hall Medical Center, San Antonio, TX, United States, 9 University of Texas
Health Science Center at San Antonio, San Antonio, TX, United States.
Background. Thus far, the phenotype of tetrasomy 18p has been primarily
delineated by a series of published case series and case reports
. Findings reported in more than 25% of these cases include neonatal
feeding problems, growth retardation, microcephaly, strabismus,
abnormalities in muscle tone, scoliosis/kyphosis, and variants on MRI .
Developmental delays and mental retardation are also universally
present . Methods. To further refine the phenotype and natural history
of tetrasomy 18p, we reviewed the medical history and records of 34
individuals with tetrasomy 18p . In addition, 20 individuals with tetrasomy
18p were clinically evaluated at our center . These individuals had
multiple evaluations, including endocrinology, ophthalmology, neuropsychology,
orthopedics, ENT, and genetics . They also underwent an
MRI as well as a hearing test . Results. As a result of these analyses,