Prader-Willi Syndrome and Schaaf-Yang Syndrome: Neurodevelopmental Diseases Intersecting at the MAGEL2 Gene

Abstract

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by neonatal hypotonia, developmental delay/intellectual disability, and characteristic feeding behaviors with failure to thrive during infancy; followed by hyperphagia and excessive weight gain later in childhood. Individuals with PWS also manifest complex behavioral phenotypes. Approximately 25% meet criteria for autism spectrum disorder (ASD). PWS is caused by the absence of paternally expressed, maternally silenced genes at chromosome 15q11-q13. MAGEL2 is one of five protein-coding genes in the PWS-critical domain. Truncating point mutations of the paternal allele of MAGEL2 cause Schaaf-Yang syndrome, which has significant phenotypic overlap with PWS, but is also clinically distinct; based on the presence of joint contractures, and a particularly high prevalence of autism spectrum disorder (up to 75% of affected individuals). The clinical and molecular overlap between PWS and Schaaf-Yang syndrome, but also their distinguishing features provide insight into the pathogenetic mechanisms underlying both disorders.

Keywords: MAGEL2; Prader-Willi syndrome; Schaaf-Yang syndrome; USP7; neurodevelopmental disorders.

Figure 1

Prader-Willi syndrome and Schaaf-Yang syndrome share common overlapping symptoms, yet have important distinct features. While none of the symptoms listed in this figure may be exclusive to any one condition, the figure attempts to highlight those features that have particularly high prevalence in the respective disorders. Only phenotypes of >50% prevalence for the respective disorder are listed. ¹, defined by gene deletions in the 15q11-q13 chromosomal region; ², defined by truncating point mutations of the MAGEL2 gene.

Figure 2

Prader-Willi syndrome, Schaaf-Yang syndrome, and USP7-associated disorder represent a spectrum of neurodevelopmental disorders. Shared and distinct clinical features are illustrated. While none of the symptoms listed may be exclusive to any one condition, the figure attempts to highlight those features that have a high (>50%) prevalence in the respective disorders. ¹, disorder defined by gene deletions in the 15q11-q13 chromosomal region; ², disorder defined by truncating point mutations of the MAGEL2 gene; ³, disorder defined by a deletion or truncating point mutation of the USP7 gene.