Investigation of selected genomic deletions and duplications in a cohort of 338 patients presenting with syndromic obesity by multiplex ligation-dependent probe amplification using synthetic probes

Investigation of selected genomic deletions and duplications in a cohort of 338 patients presenting with syndromic obesity by multiplex ligation-dependent probe amplification using synthetic probes

Author D'Angelo, Carla S. Google Scholar
Varela, Monica C. Google Scholar
Castro, Claudia I. E. de Google Scholar
Kim, Chong A. Google Scholar
Bertola, Debora R. Google Scholar
Lourenco, Charles M. Google Scholar
Perez, Ana Beatriz Alvarez Autor UNIFESP Google Scholar
Koiffmann, Celia P. Google Scholar
Institution Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Abstract Background: Certain rare syndromes with developmental delay or intellectual disability caused by genomic copy number variants (CNVs), either deletions or duplications, are associated with higher rates of obesity. Current strategies to diagnose these syndromes typically rely on phenotype-driven investigation. However, the strong phenotypic overlap between syndromic forms of obesity poses challenges to accurate diagnosis, and many different individual cytogenetic and molecular approaches may be required. Multiplex ligation-dependent probe amplification (MLPA) enables the simultaneous analysis of multiple targeted loci in a single test, and serves as an important screening tool for large cohorts of patients in whom deletions and duplications involving specific loci are suspected. Our aim was to design a synthetic probe set for MLPA analysis to investigate in a cohort of 338 patients with syndromic obesity deletions and duplications in genomic regions that can cause this phenotype.Results: We identified 18 patients harboring copy number imbalances; 18 deletions and 5 duplications. the alterations in ten patients were delineated by chromosomal microarrays, and in the remaining cases by additional MLPA probes incorporated into commercial kits. Nine patients showed deletions in regions of known microdeletion syndromes with obesity as a clinical feature: in 2q37 (4 cases), 9q34 (1 case) and 17p11.2 (4 cases). Four patients harbored CNVs in the DiGeorge syndrome locus at 22q11.2. Two other patients had deletions within the 22q11.2 'distal' locus associated with a variable clinical phenotype and obesity in some individuals. the other three patients had a recurrent CNV of one of three susceptibility loci: at 1q21.1 'distal', 16p11.2 'distal', and 16p11.2 'proximal'.Conclusions: Our study demonstrates the utility of an MLPA-based first line screening test to the evaluation of obese patients presenting with syndromic features. the overall detection rate with the synthetic MLPA probe set was about 5.3% (18 out of 338). Our experience leads us to suggest that MLPA could serve as an effective alternative first line screening test to chromosomal microarrays for diagnosis of syndromic obesity, allowing for a number of loci (e.g., 1p36, 2p25, 2q37, 6q16, 9q34, 11p14, 16p11.2, 17p11.2), known to be clinically relevant for this patient population, to be interrogated simultaneously.
Keywords Obesity
Developmental delay
Copy number variants (CNVs)
Multiplex ligation-dependent probe amplification (MLPA)
Chromosomal microarray analysis (CMA)
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Grant number FAPESP: 09/52523-1
FAPESP: 1998/14254-2
CNPq: 304381/2007-1
Date 2014-10-31
Published in Molecular Cytogenetics. London: Biomed Central Ltd, v. 7, 13 p., 2014.
ISSN 1755-8166 (Sherpa/Romeo, impact factor)
Publisher Biomed Central Ltd
Extent 13
Origin http://dx.doi.org/10.1186/s13039-014-0075-6
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000345793000001
URI http://repositorio.unifesp.br/handle/11600/38348

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