Referral diagnosis of Prader-Willi syndrome and Angelman syndrome based on methylation-specific polymerase chain reaction

Abstract

Background and purpose: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are associated with distinct phenotypes that include mental retardation. Both PWS and AS are caused by loss of function of genes located in chromosome 15q11-q13, an area subject to genomic imprinting. Methylation-specific polymerase chain reaction (M-PCR), based on parent of origin specific DNA methylation at the promoter region of the small nuclear ribonucleoprotein polypeptide N gene (SNRPN), can provide accurate and rapid diagnosis for nearly all PWS patients while it is less accurate for AS patients. We report the development of a referral system for molecular diagnosis of PWS and AS based on M-PCR.

Methods: Pediatric geneticists, psychiatrists, or neurologists were asked to evaluate phenotypes of patients with PWS or AS and complete a questionnaire designed according to the consensus criteria to diagnose these conditions. Molecular analysis based on M-PCR was performed for patients with a score of at least two.

Results: A total of 108 patients with suspected PWS and 20 patients with suspected AS were referred for diagnostic testing. PWS was diagnosed in 26 of these patients and AS in two. Among the major diagnostic criteria for PWS, excessive weight gain, developmental delay, and hyperphagia were more prevalent in older patients (> or = 1 yr) than in younger patients. Cerebral hypotonia and developmental delay were significantly more prevalent in older PWS patients than in non-PWS patients.

Conclusion: M-PCR is a cost-effective method for the diagnosis of PWS and AS. The limitations of current scoring systems and the low cost of M-PCR suggest that routine molecular screening is justified for patients suspected of having PWS.