Submission Details

MAGEL2 (gene is a single exon, maternally imprinted, paternally expressed) variants were first reported in relation to autosomal dominant Schaaf-Yang syndrome (SYS) in 2013 (Schaaf CP et al., PMID: 24076603). Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder that shares multiple clinical features with Prader-Willi syndrome. It usually manifests at birth with muscular hypotonia in all and distal joint contractures in a majority of affected individuals. Gastrointestinal/feeding problems are particularly pronounced in infancy and childhood, but can transition to hyperphagia and obesity in adulthood. All affected individuals show developmental delay, resulting in intellectual disability of variable degree. Other findings may include short stature, seizures, eye anomalies, and hypogonadism. Some patients were originally referred as Chitayat-Hall syndrome but as the molecular mechanism is the same (null variant on the paternal allele), these disease entities were lumped together. 12 variants (nonsense, frameshift) that have been reported in probands in five publications (PMIDs: 24076603, 26365340, 27195816, 33076953, 28281571) are included in this curation. Many more patients with especially recurring c.1996dup/c.1996del variants are reported in the literature (review 2018, PMID: 30302899), but were not scored as the score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be truncating variation on the paternal allele. This gene-disease association is also supported by experimental evidence (two mouse models PMIDs: 17893678, 20876615). In summary, MAGEL2 is definitively associated with autosomal dominant Schaaf-Yang syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification is approved by the Intellectual Disability and Autism Gene Curation Expert Panel on 6/1/2021.