Abstract
Genetic studies in patients with severe early-onset obesity have provided insights into the molecular and physiological pathways that regulate body weight in humans. We report a 19-year-old male with hyperphagia and severe obesity, mild learning difficulties and hypogonadism, in whom diagnostic tests for Prader-Willi syndrome (PWS) had been negative. We carried out detailed clinical and metabolic phenotyping of this patient and investigated the genetic basis of this obesity syndrome using Agilent 185 k array comparative genomic hybridization (aCGH) and Affymetrix 6.0 genotyping arrays. The identified deletion was validated using multiplex ligation-dependent probe amplification and long-range PCR, followed by breakpoint sequencing which enabled precise localization of the deletion. We identified a approximately 187 kb microdeletion at chromosome 15q11-13 that encompasses non-coding small nucleolar RNAs (including HBII-85 snoRNAs) which were not expressed in peripheral lymphocytes from the patient. Characterization of the clinical phenotype revealed increased ad libitum food intake, normal basal metabolic rate when adjusted for fat-free mass, partial hypogonadotropic hypogonadism and growth failure. We have identified a novel deletion on chromosome 15q11-13 in an individual with hyperphagia, obesity, hypogonadism and other features associated with PWS, which is normally caused by deficiency of several paternally expressed imprinted transcripts within chromosome 15q11-13, a region that includes multiple protein-coding genes as well as several non-coding snoRNAs. These findings provide direct evidence for the role of a particular family of non-coding RNAs, the HBII-85 snoRNA cluster, in human energy homeostasis, growth and reproduction.