The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families

Purpose: Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2 , which is located in the Prader-Willi critical region 15q11–13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients’ phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype. Methods: Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2 , 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant. Results: All cases harbor truncating mutations of MAGEL2 , and nucleotides c.1990–1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints. Conclusion: This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2 , refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families. Genet Med 19 1, 45–52.