ESPE Abstracts

Background: Studies aimed at elucidating the pathophysiology of obesity consistently describe it as a highly heterogeneous disorder at both clinical and molecular level. Despite rare monogenic forms and several regions of susceptibility have been defined, the genetic causes underlying the disease remain largely unknown.

Objective and hypotheses: We aimed to identify novel genetic abnormalities in a cohort of Spanish children with severe non-syndromic early-onset obesity (EOO).

Method: We obtained molecular karyotypes of 157 children with EOO. Large and rare CNVs were validated and segregated in the family. Results were replicated by MLPA in 323 EOO children and 480 controls. Additionally, 26 candidate genes (CNV-related or previously associated with EOO) were studied in both cohorts (480 subjects in each) by Next Generation Sequencing (NGS) using a pooled DNA strategy.

Results: A higher burden of duplication-type CNVs was detected in EOO patients versus controls (OR =1.85, P-value =0.008). Likely pathogenic CNVs included duplications of glutamate receptors (GRIK1, GRM7), the X-linked gastrin-releasing peptide receptor (GRPR) and the NPY genes. By NGS focusing the analysis on rare variants, we identified a missense mutation in NPY, a nonsense mutation in GRIK1, and 5 missense mutations in GRPR in EOO cases, but no mutations in controls. In addition, a significantly higher burden of point mutations was also identified in candidate genes, remarkably MC4R, SIM1, FTO, BDNF NEGR1, PPARG and MC3R; we identified 30 rare variants in patients and 5 in controls (P=0.0001). The difference in the incidence of probable pathogenic variants (15 in patients vs 1 in controls) was also significant (P=0.0005).

Conclusion: Genetic variants highly contributing to the phenotype were identified in up to 12% of patients. Our data reinforce the role of the proopiomelanocortin pathway in the pathophysiology of EOO and bring to light genes that may carry highly penetrant obesogenic allele variants, like PPARG, BDNF, NPY or GRPR.