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Del Rey J.,Autonomous University of Barcelona | Santos M.,Autonomous University of Barcelona | Mila M.,Servei de Bioquimica I Genetica Molecular | Fuster C.,Autonomous University of Barcelona
Cytogenetic and Genome Research | Year: 2016

Complex chromosome rearrangements (CCRs) are unusual structural chromosome alterations found in humans, and to date only a few have been characterized molecularly. New mechanisms, such as chromothripsis, have been proposed to explain the presence of the CCRs in cancer cells and in patients with congenital disorders and/or mental retardation. The aim of the present study was the molecular characterization of a constitutional CCR in a girl with multiple congenital disorders and intellectual disability in order to determine the genotype-phenotype relation and to clarify whether the CCR could have been caused by chromosomal catastrophic events. The present CCR was characterized by G-banding, high-resolution CGH, multiplex ligation-dependent probe amplification and subtelomeric 2q-FISH analyses. Preliminary results indicate that the de novo CCR is unbalanced showing a 2q37.3 deletion and 2q34q37.2 partial trisomy. Our patient shows some of the typical traits and intellectual disability described in patients with 2q37 deletion and also in carriers of 2q34q37.2 partial trisomy; thus, the clinical disorders could be explained by additional effects of both chromosome alterations (deletions and duplications). A posterior, sequential FISH study using BAC probes revealed the unexpected presence of at least 17 different reorganizations affecting 2q34q37.2, suggesting the existence of chromosome instability in this region. The present CCR is the first case described in the literature of heterogeneity of unbalanced CCRs affecting a small region of 2q, indicating that the mechanisms involved in constitutional chromosome rearrangement may be more complex than previously thought. © 2016 S. Karger AG, Basel.


Mademont-Soler I.,Hospital Clinic de Barcelona | Peydro C.M.,Servei de Bioquimica I Genetica Molecular | Diaz A.S.,Servei de Bioquimica I Genetica Molecular
Salud(i)Ciencia | Year: 2010

Mental retardation is a frequent disorder related to multiple causes. Among the genetic ones, mental retardation is etiologically heterogeneous and usually linked to syndromic forms. There are still few known genes associated with this phenotype, although for some disorders they are well established. This is the case of neurofibromatosis 1, tuberous sclerosis, and Steinen myotonic dystrophy, which are caused by mutations in NF1, TSC1 and TSC2, and DMPK genes, respectively. All of them are monogenic disorders with an autosomal dominant mode of inheritance. Recent studies have elucidated the pathogenesis of these diseases, suggesting possible therapeutic targets. Another entity responsible for autosomal dominant mental retardation are cryptic imbalances, whose diagnosis is only possible at present with current molecular techniques. In this work we review mental retardation with an autosomal dominant mode of inheritance, with special emphasis on neurofibromatosis 1, tuberous sclerosis and Steinert myotonic dystrophy, and on cryptic imbalances. Copyrigth © Sociedad Iberoamericana de Información Científica (SIIC), 2010.


Mademont-Soler I.,Servei de Bioquimica I Genetica Molecular | Morales C.,Servei de Bioquimica I Genetica Molecular | Morales C.,CIBER ISCIII | Bruguera J.,Fundacio Clinic per a la Recerca Biomedica | And 12 more authors.
Prenatal Diagnosis | Year: 2010

Objective: To evaluate the usefulness of subtelomeric multiplex ligation-dependent probe amplification (MLPA) in both the detection of subtelomeric rearrangements in fetuses with ultrasound abnormalities and normal karyotype, and the characterization of cytogenetically detectable rearrangements. Method: We studied by subtelomeric MLPA 229 pregnancies with ultrasound findings and normal karyotype (Group 1) and five pregnancies with a cytogenetically visible but not microscopically characterizable rearrangement (Group 2). The detected imbalances were confirmed by fluorescence in situ hybridization (FISH) and parents were also studied. Results: In Group 1, two clinically relevant subtelomeric imbalances (14qter deletion and 20pter deletion) and one subtelomeric imbalance of uncertain significance (X/Ypter duplication) were diagnosed, showing a detection rate of cryptic subtelomeric imbalances in these pregnancies of 1.3%. However, only 14qter deletion seems to be clearly associated with the observed prenatal findings. In Group 2, MLPA contributed to the precise description of the chromosome abnormalities. Conclusion: The low detection rate of subtelomeric imbalances and the poor genotype-phenotype correlations in pregnancies with ultrasound abnormalities and normal karyotype suggest that subtelomeric MLPA is not a crucial tool in the prenatal diagnosis of these cases. However, our work provides evidence that MLPA is very useful for the characterization of unbalanced karyotypes. Copyright © 2010 John Wiley & Sons, Ltd.


Mademont-Soler I.,Servei de Bioquimica I Genetica Molecular | Morales C.,Servei de Bioquimica I Genetica Molecular | Morales C.,CIBER ISCIII | Soler A.,Servei de Bioquimica I Genetica Molecular | And 12 more authors.
Gene | Year: 2012

Congenital heart defects (CHD) represent the most common birth defects, so they are not a rare finding when performing routine ultrasound examinations during pregnancy. Once chromosome abnormalities have been excluded in a fetus with a CHD, chromosome 22q11.2 deletion is usually investigated by FISH, as it is the most frequent microdeletion syndrome and is generally associated with cardiac malformations. If 22q11.2 microdeletion is ruled out, the etiology of the CHD remains generally unexplained, making familial genetic counseling difficult. To evaluate the usefulness of Multiplex Ligation-dependent Probe Amplification (MLPA) kits designed for the study of 22q11.2 and other genomic regions previously associated with syndromic CHD, we performed MLPA in 55 pregnancies with fetuses presenting CHD, normal karyotype and negative FISH results for 22q11.2 microdeletion, which constitutes the largest prenatal series reported. Definitive MLPA results were obtained in 50 pregnancies, and in this setting such MLPA kits did not detect any imbalance. On the other hand, to compare FISH and MLPA techniques for the study of 22q11.2 microdeletions, we performed MLPA in 4 pregnancies known to have 22q11.2 deletions (by FISH). All four 22q11.2 microdeletions were also detected by MLPA, which corroborates that it is a reliable technique for the diagnosis and characterization of 22q11.2 deletions. Finally, we evaluated the possibility of replacing conventional FISH by MLPA for the prenatal diagnosis of CHD, comparing the diagnostic potential, results delivery times, repetition and failure rates and cost of both techniques, and concluded that FISH should still be the technique of choice for the prenatal diagnosis of fetuses with CHD. © 2012 Elsevier B.V.


Mademont-Soler I.,Servei de Bioquimica I Genetica Molecular | Morales C.,Servei de Bioquimica I Genetica Molecular | Morales C.,CIBER ISCIII | Soler A.,Servei de Bioquimica I Genetica Molecular | And 12 more authors.
Ultrasound in Obstetrics and Gynecology | Year: 2013

Objectives To assess the frequency of karyotype abnormalities and chromosome 22q11.2 deletion syndrome among fetuses with abnormal cardiac ultrasound findings, and to evaluate the clinical value of chromosomal microarray-based analysis (CMA) in the study of such pregnancies. Methods First, we carried out retrospective analysis of karyotype abnormalities and 22q11.2 deletion syndrome cases diagnosed between January 2009 and December 2011 in our center among fetuses with abnormal cardiac ultrasound findings (n = 276). Second, CMA was performed in 51 of the fetuses with such findings, normal karyotype and negative or no 22q11.2 deletion syndrome study, and in the only fetus with a heart defect and an apparently balanced de novo chromosomal rearrangement. Results Out of the 276 pregnancies with abnormal cardiac ultrasound findings, karyotyping revealed a chromosomal abnormality in 44 (15.9%). Of fetuses with normal karyotype in which 22q11.2 deletion syndrome studies were performed, 6.4% (5/78) had this microdeletion syndrome. Among fetuses with abnormal cardiac findings, normal karyotype and negative or no 22q11.2 deletion syndrome study that underwent CMA, the detection rate of pathogenic copy number variants not detected by conventional cytogenetics was 2.0% (1/51), and no variants of uncertain clinical significance were found. In the fetus with a heart defect and an apparently balanced de novo chromosomal rearrangement, CMA revealed that the rearrangement was not truly balanced. Conclusions In the assessment of genetic abnormalities in pregnancies with abnormal cardiac ultrasound findings, the diagnostic yield may be increased by 2% if CMA is used as a complementary tool to conventional cytogenetics. Our results suggest that CMA could be a good alternative to karyotyping in these pregnancies. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.

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