Identification of a De Novo MAGEL2 Pathogenic Variant in Schaaf-Yang Syndrome and the Importance of Paternal Allele Confirmation.

backgroundSchaaf-Yang syndrome (SYS) is a rare genetic disorder caused by pathogenic variants in MAGEL2, a paternally expressed and maternally imprinted gene on 15q11.2. Genetic diagnosis of SYS is challenging due to clinical features that overlap with those of other rare syndromic disorders and limited clinician awareness regarding the diagnosis of imprinting disorders.

methodsWe present a neonate presenting with respiratory distress and joint contractures, diagnosed with SYS through comprehensive genetic testing. Whole-exome sequencing identified a heterozygous de novo nonsense variant in MAGEL2 c.2092G>T [p.(Gly698Ter)]. To confirm the paternal origin of this variant, methylation-sensitive restriction enzyme digestion followed by long-range PCR, nested PCR, and Sanger sequencing was performed.

resultsThe MAGEL2 c.2092G>T was absent in both parents, indicating a de novo mutation. Methylation analysis confirmed that the variant resided on the paternal allele, establishing its pathogenicity. A proband diagnostic approach integrating sequence analysis, parental testing, and methylation assays effectively delineates MAGEL2 variants and their inheritance patterns.

conclusionOur study underscores the importance of combining genomic sequencing with methylation assay to accurately diagnose SYS, especially for de novo variants. The proposed diagnostic workflow facilitates reliable identification of pathogenic MAGEL2 mutations and their parental origin, improving diagnostic precision in clinical settings. Further research is needed to elucidate the molecular mechanisms underlying MAGEL2-related disorders and develop targeted therapies.