ESPE Abstracts

Deletions at 16p11.2 have been reported to be associated with obesity, intellectual disability and various malformations. There are variations in phenotypes associated with deletions of different sizes in this region. Some deletions encompass the SH2B1 gene encoding an adaptor protein involved in leptin and insulin signalling which is believed to be causal for the early-onset obesity of these patients who in addition show a developmental delay (see patient 1). Deletions at 16p11.2 not affecting SH2B1 are also frequently associated with obesity: the recurrent microdeletion of ~593 kb is in addition associated with developmental delay, intellectual disability, and/or autism spectrum disorder (see patient 2). In addition, there are patients with even larger deletions not affecting SH2B1 partly overlapping with the recurrent microdeletion (see patient 3). So far, it is unknown which genes in those deletions not affecting SH2B1 are responsible for the obesity. Patient 1 is a 10-year old girl with developmental delay, aggressive behaviour, ADHD and muscular hypotonia. Early-onset obesity started at the age of 3 years with steadily increasing BMI up to 30.3 kg/m² (+2.8 SDS) at the age of 10 years. In this patient a de novo ~232 kb deletion (hg19 chr16: 28.819-29.051 Mb) was found, affecting SH2B1. Patient 2 is a 15-year old boy with psychomotor retardation, hypothyroidism and reflux nephrophathy. Extreme early-onset obesity started at the age of 2 years with increasing BMI to 54.4 kg/m² (+3.65 S.D.S.) at the age of 14. In this patient a ~598 kb deletion at position hg19 chr16: 29.580–30.177 Mb was detected (without affecting SH2B1). His parents have not been analysed. Patient 3 is a 18-year old boy with developmental delay, mild abnormalities of the heart and a pylorus hypertrophy. Early-onset obesity started at the age of 4 years resulting in a BMI of 47.6 kg/m² (+3.8 SDS) at the age of 18. In this patient a de novo ~1.138 Mb deletion at position hg 19 chr16: 28.996-30.134 Mb was detected (without SH2B1 deletion). In order to extend the spectrum of the associated phenotype, we added 3 more patients with different deletions at 16p11.2 and early-onset obesity to the small group of published cases. Further investigations of the deleted genes are necessary to gain a better understanding of the potential mechanism of weight regulation.