Introduction Prader-Willi syndrome (PWS) is a rare condition characterized by hypothalamic dysfunction (leading to hyperphagia, abnormal temperature regulation, abnormal pain registration and pituitary hormone deficiencies) and cognitive impairment. PWS is generally believed to be caused by loss of expression of an entire cluster of paternally expressed genes within the PWS region on chromosome 15, due to deletion, uniparental disomy or imprinting center defects. We describe a unique patient with the complete spectrum of PWS features, in whom these regular causes were ruled out. Additional genetic testing revealed a homozygous point mutation in SNRPN (one of the genes located in the PWS region) which was located in a large homozygous region. This patient is unique, because point mutations in a single gene have never been described before as the cause of PWS.

Patients, materials and methods In the index patient, we performed automated sequencing (as part of obesitome diagnostics), methylation testing, Multiplex Ligation-dependent Probe Amplification (MLPA) analysis and SNP array.

Results  In the 46-year-old index patient, genetic diagnose of PWS was initially rejected after regular genetic tests for PWS showed normal results. Since the patient had nearly all phenotypic features corresponding to PWS, we performed additional genetic testing which revealed a homozygous mutation in SNRPN, located in a large homozygous region on chromosome 15. The parents of the patient turned out to be first-degree relatives.

Conclusion: Until now, it was generally accepted that Prader-Willi syndrome could only be caused by functional loss of an entire cluster of genes within the PWS region on chromosome 15q11.2-q13. The unique finding of a homozygous point mutation in a single gene of this region (SNRPN) in a patient with virtually all features of PWS, means a revolutionary change in our knowledge of the pathophysiology of the syndrome.