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

Abstract

BackgroundCertain 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.ResultsWe 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’.ConclusionsOur 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.

Genome-wide copy number variation analysis identifies novel candidate loci associated with pediatric obesity

“…Female proband 6-0197-03 (BMI +3.30 SD) with typical development carries a 730 kb duplication of unknown inheritance within the 22q11DS locus (2.44 Mb) encompassing 12 genes ( Supplementary Figure 1). We prioritized this CNV as potentially clinically relevant as obesity has been reported in individuals with 22q11.21 deletion and duplication syndromes (ISCA: 37446) [26]. One study investigating the clinical features of adults with 22q11DS found obesity to be a prevalent phenotype [27].…”

Clinical Characteristics and Genotype–Phenotype Correlation in Children with KMT2E Gene-Related Neurodevelopmental Disorders: Report of Two New Cases and Review of Published Literature

“…10 The more severe phenotype in individuals with 7q22.2-22.3 microdeletions might be because the same region harbors additional genes such as SRPK2, RINT1, and LHFPL3, which are expressed in the central nervous system and play a role in regulating cell cycle. [15][16][17] Till date, at least eight monogenic disorders have been described that impair the regulation of H3K4 methylation and present with neurodevelopmental syndromes. Out of these, Wiedemann-Steiner's syndrome (KMT2A mutation with intellectual disability, short stature, hairy elbows, dysmorphic features, autism), childhood-onset dystonia-28 (KMT2B mutation with dystonia, developmental delay, short stature), Kleefstra syndrome 2 (KMT2C mutation with intellectual disability, autism, epilepsy, short stature, dysmorphic features, hypotonia) and Kabuki syndrome1 (KMT2D mutation with intellectual disability, short stature, dysmorphic features, multiple congenital anomalies, hirsutism) are considered part of the KMT2 gene family of neurodevelopmental disorders.…”

Reviewed and updated Algorithm for Genetic Characterization of Syndromic Obesity Phenotypes

“…Other chromosome regions and alterations detected by whole-genome array hybridization have also been clinically related to causing or predisposing an individual to syndromic obesity. Examples include microdeletions in the 1p21.3 region, 2p25.3 deletions, 6q14.1q15 and 11p14.1 interstitial deletions, deletions that involve the 6q22, 12q subtelomeric deletions, microdeletions affecting the 17q24.2 region, and duplications of 19q [ 21 ]. Furthermore, deletions of 6q16, 1p36, 2q37 and 9q34 have also been linked to obesity [ 58 ].…”