Prader–Willi Syndrome, from Molecular Testing and Clinical Study to Diagnostic Protocols

Abstract

Prader-Willi syndrome (PWS) is a complex and fascinating human disease, whose patophisiological characteristics are still the targets of research in teams that can afford multidisciplinary approaches for seeking the link between the genetic, epigenetic and phenotypic aspects. The genetic complexity of the PWS chromosomal region, 15q11-q13, relies on the multiple clustered imprinted genes, alternative splice variants, gene duplications and variant copies, that control the epigenetic phenomenon of the imprinting itself. These DNA and transcriptome levels are matched by the wide variety of phenotypes that involve multiple organ systems and the complexity of brain functions influenced by the expression of the PWS critical genes. In this review a general description of the clinical diagnostic criteria will be linked with the most recent knowledge described for the structure of the 15 critical chromosomal region and candidate genes, as well as the model mechanisms explaining the interaction of the cisand transgenetic factors and the epigenetic ones during the establishment and maintenance of the imprinting marks that define the parental characteristic contribution to the critical genes expression. This review aims at explaining the criteria of molecular diagnosis and genetic counceling based on the techniques that are currently used and that will be used in the future approaches for the improvement of the diagnosis and treatment schemes. PWS has been initially linked with its main characteristic phenotype, the obesity, and therefore was the first described genetic human obesity syndrome. The main etiology of this disease included: gross hyperphagia, hypogonadism and growth hormone deficiency, indicating hypothalamic dysfunction. A neurodegenerative aspect was also appreciated as a major contributor to the complex PWS phenotype. Recent epidemiological study proved that PWS is a rare disease with an estimated incidence of about 1 in 25 000 births, and a population prevalence of about 1 in 50 000 (Buiting, 2010). An interesting feature linked with the diagnosis and the treatment impact is that this syndrome develops during late development of neonate. Initially, the signs like hypotonia had not suggested a suspicion for PWS, nor the consideration of further clinical and molecular cytogenetic investigations, until