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MAGEL2, a maternally imprinted gene on 15q11-13, is causally implicated in Schaaf-Yang syndrome, an autosomal dominant neurodevelopmental disorder characterized by neonatal hypotonia, feeding difficulties, respiratory dysfunction, joint contractures, and autism spectrum features. Pathogenic variants cluster as truncating mutations on the paternal allele, with c.1996dupC (p.Gln666ProfsTer) arising as a recurrent hotspot and other nonsense or frameshift changes distributed throughout the coding sequence. Loss of MAGEL2 function disrupts retrograde transport and RNA metabolism, leading to a spectrum of Prader-Willi-like and unique Schaaf-Yang phenotypes.
Extensive case series and cohort studies have identified over 130 unrelated probands with truncating MAGEL2 variants, including 18 new individuals from 14 families ([PMID:27195816]) and 78 international patients ([PMID:30302899]), with an additional 127 described in a neonatal genome project ([PMID:37404980]). In two multiplex pedigrees—five siblings with c.1996dupC ([PMID:32021601]) and three related cases ([PMID:27195816])—eight affected relatives showed complete segregation of the paternal allele variant, supporting pathogenicity. A single missense variant, p.Ala538Glu, has been reported but remains of uncertain significance outside a truncating-variant context.
All pathogenic variants are predicted to truncate the MAGEL2 protein, abrogating its MAGE homology domain. Variant classes include nonsense (e.g., c.1912C>T (p.Gln638Ter)), frameshift insertions/deletions (notably c.1996dupC), splice-site disruptions, and rare missense changes. The recurrent c.1996dupC accounts for over 30% of alleles and demonstrates a founder or hotspot effect. Phenotypic expressivity varies with mutation location, with distal truncations linked to more severe arthrogryposis and respiratory failure, whereas proximal truncations often present with neurobehavioral features and endocrine dysfunction.
Functional studies reveal that truncated MAGEL2 proteins mis-localize to the nucleus rather than the cytoplasm, suggesting a neomorphic effect ([PMID:36243518], [PMID:38548315]). Proximity labeling (BioID) and proteomic assays implicate MAGEL2 in mRNA N6-methyladenosine binding and RNA interference pathways ([PMID:34265304]). A rat model with a paternal Magel2 truncation recapitulates anxiety-like behavior, social deficits, breathing irregularities, cardiac and body composition alterations, mirroring human SYS phenotypes ([PMID:36637363]).
No studies have robustly refuted the MAGEL2–SYS association, though whole-gene deletions appear to yield milder or absent phenotypes, indicating that truncating point mutations exert dominant-negative or neomorphic effects distinct from haploinsufficiency. Genotype-phenotype correlations suggest mutation position influences severity and specific organ involvement.
In summary, paternal truncating mutations in MAGEL2 cause Schaaf-Yang syndrome through dominant-negative/neomorphic mechanisms, with strong genetic segregation, a recurrent hotspot variant, and concordant functional data. Clinical utility includes targeted genetic testing of MAGEL2 for early diagnosis, respiratory and endocrine monitoring, and exploration of RNA-metabolism biomarkers. Key Take-home: MAGEL2 truncating variants define a clinically and mechanistically coherent imprinting disorder with high diagnostic yield and therapeutic implications.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrong
Functional EvidenceModerateCellular assays show nuclear mislocalization, BioID implicates RNA metabolism, rat model recapitulates key SYS phenotypes |