2008 Barcelona - European Society of Human Genetics

Cytogenetics
mosomal rearrangement could theoretically be performed by region
specific FISH, array-CGH detected 15 rearrangements in 44 patients,
with a high detection rate (34,09%), allowing to propose a new critical
region for a complex syndromic PEHO-like phenotype .
P02.017
Defining a new checklist of sensitive clinical signs in mental
retardation, useful to select patients for array-cGH and to
validate array-cGH results
M. Zollino 1 , G. Marangi 1 , D. Orteschi 1 , R. Lecce 1 , M. Murdolo 1 , M. E. Grimaldi 1 ,
A. Orrico 2 , O. Zuffardi 3 , G. Neri 1 ;
1 Institute of Medical Genetics, Università Cattolica del Sacro Cuore, Roma,
Italy, 2 Clinical Genetics, UOC Molecular Medicine, Azienda Ospedaliera Universitaria
Senese, Siena, Italy, 3 Biologia Generale e Genetica Medica, University
of Pavia, Pavia, Italy.
Cryptic chromosomal rearrangements are responsible of about 1-25%
of cases of idiopathic mental retardation .
We studied 325 subjects with mental retardation/developmental delay
by the means of subtelomeric FISH (300 patients) and array-CGH
analysis (70 patients) using BAC-array with an average resolution of
1 Mb .
Cryptic chromosomal rearrangements were detected in 29 cases (10%)
by subtelomeric FISH . A total of 70 patients with normal telomeres underwent
array-CGH, that disclosed an interstitial cryptic abnormality
in 17 (24%) . Adapting this percentage to all cases with normal telomeres,
detection rate for cryptic chromosome abnormality was 30% in
the present cohort of patients . It represents the highest detection rate
of cryptic chromosome abnormalities in idiopathic mental retardation
reported so far by molecular karyotyping .
Detailed clinical analysis of all positive cases and of 50 negative
patients allowed us to develop a new checklist of the clinical signs
sensitive for chromosomal abnormalities . It includes 5 categories: 1)
postnatal growth abnormalities, 2) disproportion between growth parameters,
3) minor facial anomalies, 4) hands and feet abnormalities
and 5) major malformations . A 0-2 score was assigned to each categories,
with a maximum of 10 . Cut-off value resulted to be 4 in our
series . Interestingly, familial MR and IUGR were not sensitive signs .
Genotype-phenotype correlations represent a great problem during array-CGH
analysis .
We propose this checklist as an useful tool for clinical validation of the
chromosomal unbalances detected by array-CGH .
P02.018
Identification of cryptic chromosomal rearrangements in
patients with multiple anomaly syndromes and mental
retardation using oligo-based array-cGH
V. Vranova 1,2 , P. Kuglik 1,2 , I. Slamova 2 , E. Zrnova 1 , A. Oltova 2 , R. Gaillyova 2 ;
1 Masaryk University, Institute of Experimental Biology, Department of Genetics
and Molecular Biology, Brno, Czech Republic, 2 University Hospital Brno, Department
of Medical Genetics, Brno, Czech Republic.
Chromosomal abnormalities are the major cause of mental retardation
(MR), growth and developmental delay and dysmorphic features .
Many of these imbalances are caused by submicroscopic deletions
or duplications not detected by conventional cytogenetic methods . Array-CGH
is an innovative high-resolution technology that detects and
maps submicroscopic DNA copy number alterations, improving the diagnostic
detection rate of subtle copy number changes .
From 67 patients with mental disability, congenital anomalies, dysmorphic
features and unknown underlying cause investigated by G-banding,
FISH, SKY and high-resolution CGH (HR-CGH) were chosen 4
that were also screened using 60-mer oligonucletide-based array-CGH
(Agilent). Two interstitial and two terminal imbalances were identified.
In patient 1 and 2, both with normal karyotype, de novo interstitial deletion
was found at 6q15 and 11q13, respectively . Both abnormalities
arose de novo and were previously detected using HR-CGH . Array-
CGH studies not only confirmed these aberrations but specified their
position and size. In patient 3 with no cytogenetic finding, array-CGH
revealed deletion of terminal part of 1p include 1p36 . The deletion was
de novo and was confirmed by FISH and MLPA methods. The last
patient had karyotype 46,XY,der(4p), but no evident cytogenetic imbalance
. Using array-CGH, not only deletion of telomeric region of 4p,
but additional duplication of terminal part of 8p was revealed . Both
imbalances were also detected by MLPA, but duplication at 8p was
negative by FISH .
We conclude that oligonucleotide based array-CGH can be used as
excellent diagnostic tool for genome-wide screening and identification
of cryptic chromosomal imbalances not evident by routine cytogenetic
analysis .
P02.019
High resolution Agilent 244K oligoarray CGH analysis for
screening of patients with congenital eye malformations
I. Balikova, T. de Ravel, K. Devriendt, J. Fryns, J. R. Vermeesch;
Center for Human Genetics, Leuven, Belgium.
Hereditary diseases of the eyes are a frequent cause for blindness in
early childhood with complex etiology . The exact frequency of chromosomal
deletions and duplications causing congenital eye abnormalities
is unknown . Summarising results from conventional karyotyping
showed that around 1/8 segmental chromosomal duplications and 1/6
deletions are associated with eye malformations . Considering the high
frequency of microscopically visible imbalances associated with eye
disorders we hypothesize that patients with idiopathic eye anomalies
may carry submicroscopic imbalances .
Compared with conventional cytogenetics methods - karyotyping and
fluorescent in situ hybridization [FISH], array Comparative Genomic
Hybridization [array CGH] provides the advantage of full genome scan
with significantly higher resolution to detect deletions or duplications.
Agilent 244K oligoarrays allow to perform a genomic screen with a
theoretical resolution higher than 50kb .
We screened patients with congenital eye malformations and associated
abnormalities and their both parents on 244K array . The project
aims to identify novel genes involved in the development of the eye
and to improve the diagnosis in these patients . We will present results
from the analyses .
P02.020
inherited not polymorphic cNV in mental retardation patients:
implications in clinical practice
E. Katzaki, M. A. Mencarelli, F. T. Papa, R. Caselli, V. Uliana, M. Pollazzon, K.
Sampieri, I. Longo, F. Ariani, I. Meloni, F. Mari, A. Renieri;
Medical Genetics, Siena, Italy.
Mental retardation is a common disorder, affecting 1-3% of the population
. In spite of all diagnostic tools available, the etiology can still not be
established in half of the cases .The introduction of array-CGH analysis
has improved the identification of novel genomic disorders. However,
this high-resolution new technique open novel diagnostic challenges
when inherited private CNVs of unclear clinical significance are found.
The analysis of 84 patients with mild to severe mental retardation associated
to facial dysmorphisms and/or congenital anomalies revealed
10 private CNVs inherited from an healthy parent . Three were deletions
(7q31, 14q21 .1, Xq25) and 7 duplications (12p11 .22, 12q31 .31,
13q31 .1, 17q12, Xp22 .31, Xq28) ranging between 0 .1 and 3 .8 Mb .
Three small rearrangements were gene desert . The remaining 7 had a
mean gene content of 5 (ranging from 1 to 18) . None of the rearranged
genes is known to be imprinted . Three disease-genes were found
in three different cases: KAL1 in dupXp22 .31, STS gene in another
dupXp22 .31 and TCF2 gene in dup17q12 . The patient carrying the last
duplication presents, among others, sex reversal, Peters’ anomaly and
renal cysts and the duplication is located 4Mb apart of the HSD17B1
gene, coding a key enzyme of testosterone biosynthesis . We suggest
that at least in this case low penetrance instead of no pathogenesis,
should be taken into account. We discuss on the final interpretation
that should be given in the clinical practice and the opportunity to report
such rearrangements in the family reports .
P02.021
Description of two new cases of microdeletions detected by
array-cGH in carriers of apparently cytogenetically balanced
chromosome rearrangements associated with phenotypic
abnormalities
I. Mademont-Soler 1 , C. Morales 2 , L. Armengol 3 , E. Margarit 2,4 , A. Soler 2,4 , X.
Estivill 3 , A. Sánchez 2,4 ;
1 CIBERER, Barcelona, Spain, 2 Servei de Bioquímica i Genètica Molecular,
Hospital Clínic, Barcelona, Spain, 3 CRG, Barcelona, Spain, 4 IDIBAPS, Barce-