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Background  Inactivating mutations of the hypothalamic transcription factor singleminded1 (SIM1) have been shown as a cause of early-onset severe obesity. However, to date, the contribution of  SIM1  mutations to the obesity phenotype has only been studied in a few populations. In this study, we screened the functional regions of  SIM1  in severely obese children of Slovak and Moravian descent to determine if genetic variants within  SIM1  may influence the development of obesity in these populations.    Methods  The  SIM1  promoter region, exons and exon-intron boundaries were sequenced in 126 unrelated obese children and adolescents (2–18 years of age) and 41 adult lean controls of Slovak and Moravian origin. Inclusion criteria for the children and adolescents were a body mass index standard deviation score higher than 2 SD for an appropriate age and sex, and obesity onset at less than 5 years of age. The clinical phenotypes of the  SIM1  variant carriers were compared with clinical phenotypes of 4  MC4R  variant carriers and with 27 unrelated  SIM1  and  MC4R  mutation negative obese controls that were matched for age and gender.    Results  Seven previously described  SIM1  variants and one novel heterozygous variant p.D134N were identified. The novel variant was predicted to be pathogenic by 7  in silico  software analyses and is located at a highly conserved position of the SIM1 protein. The p.D134N variant was found in an 18 year old female proband (BMI 44.2kg/m 2 ; +7.5 SD), and in 3 obese family members. Regardless of early onset severe obesity, the proband and her brother (age 16 years) did not fulfill the criteria of metabolic syndrome. Moreover, the variant carriers had significantly lower preferences for high sugar ( p  = 0.02) and low fat, low carbohydrate, high protein ( p  = 0.02) foods compared to the obese controls.    Conclusions  We have identified a novel  SIM1  variant, p.D134N, in 4 obese individuals from a single pedigree which is also associated with lower preference for certain foods.

Genetic analysis of single-minded 1 gene in early-onset severely obese children and adolescents