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

Molecular Cytogenetics

Celia P Koiffmann¹  Ana Beatriz A Perez²  Charles M Lourenço³  Débora R Bertola⁴  Chong A Kim⁴  Cláudia IE de Castro¹  Monica C Varela¹  Carla S D¿Angelo¹ 

[1] Human Genome and Stem Cell Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil;Department of Morphology, Medical Genetics Center, Federal University of Sao Paulo, Sao Paulo, Brazil;Neurogenetics Unit, Department of Medical Genetics, School of Medicine, University of Sao Paulo, Ribeirao Preto, Brazil;Genetics Unit, Department of Pediatrics, Children Institute, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil

关键词: Chromosomal microarray analysis (CMA);    Multiplex ligation-dependent probe amplification (MLPA);    Copy number variants (CNVs);    Developmental delay;    Obesity;   

Others  :  1149563
DOI  :  10.1186/s13039-014-0075-6

 received in 2014-05-23, accepted in 2014-10-19,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 D'Angelo et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 2.

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