2009 Vienna - European Society of Human Genetics

Concurrent Sessions
c07.5
Prenatal oligo-based arraycGH with custom made focused
design: first experiences
A. Lott, M. Kuhn, H. Gabriel, M. Gencik;
ZMG Osnabrueck, Osnabrueck, Germany.
ArrayCGH is a well implemented diagnostic tool for the detection of
submicroscopic chromosomal imbalances. Postnatal array-CGH is
routinely performed in our lab using whole genome oligonucleotide arrays
(Agilent). Sometimes, if imbalances with uncertain clinical significance
are detected, the interpretation of the results is challenging. This
is particularly crucial in a prenatal setting. To minimize such difficulties,
we decided to design our own focused oligonucleotide microarray using
Agilents eArray tool. Our array design is based on the 44k format
(more than 40.000 oligonucleotides) and restricted on the dense coverage
of about 130 microdeletion/duplication syndromes and subtelomeric
regions combined with a 1Mb whole genome spacing.
In our ongoing process of validation we found very good concordance
of the arrayCGH results with our focused design compared to
the whole genome design. First we used DNA samples derived from
blood of patients with known aberrations and normal male and female
controls. But the interest in prenatal testing of fetuses with abnormal
ultrasound findings is increasing and therefore we successfully tested
the DNA from fetal samples like chorion villi and cultured amniocytes.
If there is no time for culturing, uncultured amniocytes is a challenging
material for use in arrayCGH, since the number of cells in amniotic
fluid in early pregnancies is low. Different methods for DNA isolation,
whole genome amplification and fluorescence labelling were tested to
optimize arrayCGH quality.
Summarized, our results are encouraging to go on with implementing
this focused array design in our lab for pre- and postnatal arrayCGH
diagnostics.
c07.6
trend analysis of invasive prenatal diagnosis before and after
the introduction of a new prenatal screening policy in the
Netherlands.
K. D. Lichtenbelt 1 , B. Z. Alizadeh 2 , P. G. Scheffer 3 , G. C. Page-Christiaens 3 , P.
Stoutenbeek 3 , G. H. Schuring-Blom 4 ;
1 Universitary Medical Center Utrecht, Utrecht, The Netherlands, 2 Complex
Genetics Section, Department of Medical Genetics, University Medical Center
Utrecht, Utrecht, The Netherlands, 3 Department of Perinatology and Gynaecology,
University Medical Center Utrecht, Utrecht, The Netherlands, 4 Department
of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
In 2007 a new prenatal screening-policy for Down’s syndrome was introduced
in the Netherlands. Before 2007 only women of 36 years and
older were offered prenatal screening. According to new legislation,
this was extended to all women, regardless of maternal age. Screening
includes maternal blood markers and fetal nuchal translucency
measurement. We sought to study the effect of the new policy on the
outcome of invasive prenatal diagnosis by chorionic villus sampling
and amniocentesis. Therefore we collected the outcome of conventional
karyotyping of all invasive procedures (n=9931) performed between
January 2000 and December 2008 in the Universitary Medical
Center Utrecht (UMCU). Data were extracted from the cytogenetic
database. A trend analysis was made of the number- and type of invasive
procedures, indications and percentage and type of abnormal
karyotypes. Results show that the contribution of women younger than
36 years rose significantly, from 19,3 % in the years before the new
policy, to 25,3% after 2007. For women younger than 36 years, the
percentage of abnormal karyotypes also increased significantly from
13% to 19%. The percentage of abnormal karyotypes for all maternal
ages increased from 6,5% to 8,8%, mainly due to the increased use of
high performing indications, such as ‘abnormal first trimester screening’
and ‘sonography findings’, as opposed to ‘advanced maternal age’
alone as indication for the invasive diagnostics. This rise was mainly
due to the increased detection of autosomal trisomies. There was no
significant difference in the type of autosomal trisomies detected.
c08.1
Nicolaides-Baraitser syndrome - Delineation of the Phenotype
S. B. Sousa 1,2 , O. A. Abdul-Rahman 3 , A. Bottani 4 , V. Cormier-Daire 5 , A. Fryer 6 ,
G. Gillessen-Kaesbach 7 , D. Horn 8 , D. Josifova 9 , A. Kuechler 10 , M. Lees 1 , K.
MacDermot 11 , A. Magee 12 , F. Morice-Picard 13 , E. Rosser 1 , A. Sarkar 11 , N. Shannon
14 , I. Stolte-Dijkstra 15 , A. Verloes 16 , E. Wakeling 11 , L. Wilson 1 , R. C. M. Hennekam
1,17 ;
1 Department of Clinical Genetics, Great Ormond Street Hospital for Children,
London, United Kingdom, 2 Serviço de Genética Médica, Hospital Pediátrico de
Coimbra, Coimbra, Portugal, 3 Division of Medical Genetics, Department of Pediatrics,
University of Mississippi Medical Center, Jackson, MS, United States,
4 Department of Genetic Medicine, Geneva University Hospitals, Geneva, Switzerland,
5 Département de Génétique, Hôpital Necker-Enfants Malades, Paris,
France, 6 Royal Liverpool Children’s Hospital, Liverpool, United Kingdom, 7 Institut
für Humangenetik Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck,
Germany, 8 Institut für Medizinische Genetik, Humboldt-Universität, Berlin, Germany,
9 Clinical Genetics Department, Guy’s Hospital, London, United Kingdom,
10 Institute of Human Genetics, University Hospital, Essen, Germany, 11 North
West Thames Regional Genetics Service, Kennedy Galton Center, London,
United Kingdom, 12 Regional Genetics Service, Belfast City Hospital, Belfast,
United Kingdom, 13 Medical Genetics Unit, CHU de Bordeaux, Bordeaux,
France, 14 Clinical Genetics Service, City Hospital, Nottingham, United Kingdom,
15 Department of Genetics, University Medical Center Groningen, Groningen,
The Netherlands, 16 Department of Clinical Genetics, Robert Debré University
Hospital, Paris, France, 17 Clinical and Molecular Genetics Unit, Institute of Child
Health, UCL, London, United Kingdom.
Nicolaides-Baraitser syndrome is a mental retardation-multiple congenital
anomalies syndrome, reported for the first time in 1993, and
since then in only four cases. We aimed to delineate the phenotype
and natural history better and were able to gather eighteen hitherto
undescribed patients through a multi-centric collaborative study. In addition,
we gathered follow-up data of the earlier reported cases, including
long-term follow-up of the original patient.
Nicolaides-Baraitser syndrome was found to be a distinct and well recognizable
entity with limited clinical variability. Main clinical features
are severe mental retardation, limited or absent speech, seizures,
short stature, sparse hair, typical facial characteristics, brachydactyly,
prominent finger joints and broad distal phalanges. Some of the features
can be progressive with time. There is no important gender difference
in occurrence, frequency and severity of the syndrome, and
all cases have thus far been sporadic. Consanguinity is not increased.
Micro-array analysis in 14 of the patients gave normal results. There is
no clue to the cause, except possibly the progressive nature.
The entity has always been considered a very rare condition, but the
present series gathered over a short period of time may indicate it
to be underrecognized. The present detailed phenotype analysis may
help recognizing further patients. Further research to detect the cause
is in progress.
c08.2
severe Non-Lethal Recessive type Viii Oi: clinical, Histological
and Radiographic Features
J. C. Marini 1 , W. Chang 1 , F. H. Glorieux 2 , T. E. Hefferan 3 , F. Rauch 2 , M.
Abukhaled 1 , P. A. Smith 4 , D. Eyre 5 ;
1 NICHD, NIH, Bethesda, MD, United States, 2 Shriners Hospital for Children,
McGill Univ, Montreal, QC, Canada, 3 Mayo Clinic, Rochester, MN, United
States, 4 Shriners Hospital for Children, Chicago, IL, United States, 5 Univ Washington,
Seattle, WA, United States.
Type VIII osteogenesis imperfecta is a recently defined recessive lethal/severe
OI caused by null mutations in LEPRE1 encoding collagen
prolyl 3-hydroxylase I. We present here the first complete description
of two non-lethal cases of type VIII OI, 17 and 10 yr old boys with
null mutations in both alleles of LEPRE1. Both probands were SGA
term babies. They have extreme growth deficiency, white sclerae and
normal dentin. Their extremities are rhizomelic with popcorn epiphyses.
They have severe scoliosis with multiple vertebral compressions;
DEXA L1-L4 z-scores were -6.3 and -5.8. Their dermal collagen fibrils
have same average diameter as matched controls, but greater diameter
variability and multiple border irregularities. On mass spectrometry,
the level of Type I collagen Pro986 3-hydroxylation was