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.

Hormonal, metabolic and skeletal phenotype of Schaaf-Yang syndrome: a comparison to Prader-Willi syndrome

“…Hypogonadotrophic hypogonadism is also a major feature of PWS,33 and has been previously reported in studies of SYS,2 motivating testing for FSH, LH and testosterone. Although five of nine individuals (three females/two males) showed LH values below the reference ranges provided by the performing laboratory, these five individuals were all young and prepubertal, so a lower-end LH level would be expected.…”

MAGEL2‐related disorders: A study and case series

“…The PWS locus, located on 15q11‐15q13, contains the genes MKRN3 , MAGEL2 , NDN , PWRN1 , NPAP1 , SNURF‐SNRPN , SNORD , IPW , SNORD115 , and SNORD109B . PWS is caused by three separate but related genetic mechanisms, all involving failure of proper paternal gene dosage .…”

“…The similarities between SYS and PWS are well established. In fact, SYS is considered a “Prader‐Willi‐like” syndrome, with overlapping but distinct features . Although Jobling et al suggested overlap between CHS and SYS, to our knowledge no one has systematically compared the three syndromes.…”

Magel2 Gene Mutation and Its Associated Phenotypic Features in A Five-Month-Old Female

“…Our patient also had tightening of the hands and feet, which was concerning for potential arthrogryposis. Her brother also has arthrogryposis, a feature which has been cited in one other case of MAGEL2 mutation [6]. It was noted that she has abnormal eye movements, not characterized as esotropia, which will further complicate her development.…”

“…In addition, two families with lethal arthrogryposis multiplex congenita were found to have truncating mutations in MAGEL2 [5]. MAGEL2 has been most extensively studied in relation to the neurodevelopmental syndromes such as Prader-Willi Syndrome, and to a lesser extent, Schaaf-Yang Syndrome [6]. MAGEL2 is located on the proximal long arm of human chromosome 15 (15q11-q13), within the locus for Prader-Willi Syndrome.…”