Genetic determinants of severe childhood-onset obesity

Childhood obesity is a complex disorder affected by genetic, epigenetic and environmental factors. The genetic background and pathogenesis of severe childhood obesity are incompletely understood. Different strategies have been used to elucidate the genetic factors involved in the development of obesity. Recent research on extreme phenotypes has identified several new obesity-related genes and has indicated that rare highly penetrant genetic variants may be involved in the development of severe childhood obesity. This study aimed to identify disease-causing genetic variants in severe childhood- onset obesity using various genetic approaches. We investigated the contribution of rare copy number variants (CNVs) and the rate and spectrum of rare variants in genes involved in the hypothalamic circuit in patients with severe early-onset obesity. We also searched for rare genetic variants in genes involved in pseudohypoparathyroidism and related disorders in patients with severe childhood obesity. A total number of 92 Finnish patients with severe early-onset obesity participated in this study. Hospital records were evaluated, and the patients were clinically examined. 67 normal-weight subjects were used as controls. Several different genetic methods were used, such as array comparative genomic hybridization (aCGH), Multiplex Ligation-dependent Probe Amplification (MLPA), methylation- sensitive MLPA (MS-MLPA), Sanger sequencing, targeted exome sequencing and whole genome sequencing. Additionally, subcutaneous adipose tissue from body mass index (BMI)-discordant siblings from a Swedish cohort was used for the gene expression analyses of candidate genes from the copy number analysis. We identified an enrichment of rare CNVs in subjects with severe childhood obesity (19%) compared to normal-weight controls (3%). Three of the identified CNVs comprised a known syndromic locus (16p11.2 deletion, 1q21.1 deletion and 22q11.21 duplication), five genes (ACE, EFEMP1, MCTP2, PCM1 and SORCS1) in the CNVs had previously been linked to obesity-related disorders and 10 genes (ACP6, ATR, BAZ2B, EFEMP1, KLF15, MACROD2, MAMLD1, MBD5, PCM1 and SORBS1) showed different expression in subcutaneous adipose tissue from BMI-discordant siblings. In targeted exome sequencing and methylation studies, we did not detect any pathogenic defects in the Gsα-cAMP signaling pathway genes GNAS, PRKAR1A and PDE4D. Using targeted exome sequencing, we identified rare (allele frequency