Background: Variants in the melanocortin-4 receptor (MC4R) gene are the most frequent cause of monogenic obesity. The relevance of MC4R variations with respect to clinical phenotype and biochemical function remains controversial. Methods: We sequenced the MC4R gene in 510 overweight/obese children. The clinical phenotype was assessed in a case-control setting matched for age, gender, puberty and body mass index. Identified MC4R variants were functionally characterized in vitro. Results: The frequency of MC4R variants was 5.3%, with functionally relevant mutations (D⁹⁰N, V¹⁰³I/S¹²⁷L, R¹⁶⁵W, G¹⁸¹D) occurring in 1.2% (confidence interval 0.26–2.15) of our sample. 4.1% were carriers of variants (Y³⁵Y, V¹⁰³I, T¹¹²M, M²⁰⁰V, I²⁵¹L) with preserved receptor function in vitro. We did not detect large heterozygous deletions by multiple-ligand probe amplification assay. There were no differences in anthropometric or metabolic parameters between children with loss-of-function mutations and noncarriers. Carriers of the V¹⁰³I or I²⁵¹L variant had higher high-density lipoprotein cholesterol and HbA1c levels than matched noncarriers of MC4R variants. Conclusions: In our data set of childhood obesity in central Germany, we identified functionally relevant mutations in the MC4R gene in only 1.2% of the children. There were no major significant phenotypic differences between obese children with and without MC4R mutations. Hence, the diagnosis of genetically caused obesity due to MC4R mutation should be made with caution.

ObjectiveRecent genome-wide association studies identified novel candidate genes for fasting and 2 h blood glucose and insulin levels in adults. We investigated the role of four of these loci (ADCY5, GIPR, GCKR and VPS13C) in early impairment of glucose and insulin metabolism in children.Research Design and MethodsWe genotyped four variants (rs2877716; rs1260326; rs10423928; rs17271305) in 638 Caucasian children with detailed metabolic testing including an oGTT and assessed associations with measures of glucose and insulin metabolism (including fasting blood glucose, insulin levels and insulin sensitivity/secretion indices) by linear regression analyses adjusted for age, sex, BMI-SDS and pubertal stage.ResultsThe major allele (C) of rs2877716 (ADCY5) was nominally associated with decreased fasting plasma insulin (P = 0.008), peak insulin (P = 0.009) and increased QUICKI (P = 0.016) and Matsuda insulin sensitivity index (P = 0.013). rs17271305 (VPS13C) was nominally associated with 2 h blood glucose (P = 0.009), but not with any of the insulin or insulin sensitivity parameters. We found no association of the GIPR and GCKR variants with parameters of glucose and insulin metabolism. None of the variants correlated with anthropometric traits such as height, WHR or BMI-SDS, which excluded potential underlying associations with obesity.ConclusionsOur data on obese children indicate effects of genetic variation within ADCY5 in early impairment of insulin metabolism and VPS13C in early impairment of blood glucose homeostasis.

In our modest sample of severely obese children, we were unable to find CNVs in well-established monogenic obesity genes. Nevertheless, we found an association of rs3734354 in SIM1 with obesity of early-onset type in children, although not with obesity-related traits.