The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families
Department of Pediatrics, Division of Genetics
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetics | Medical Genetics | Nervous System Diseases | Pediatrics
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.
MAGEL2, neurodevelopment, Prader-Willi syndrome, Schaaf-Yang syndrome
DOI of Published Version
Genet Med. 2016 May 19. doi: 10.1038/gim.2016.53. Link to article on publisher's site
Genetics in medicine : official journal of the American College of Medical Genetics
Fountain MD, Hay BN, Santen GW, Schaaf CP. (2016). The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families. Pediatric Publications. https://doi.org/10.1038/gim.2016.53. Retrieved from https://escholarship.umassmed.edu/peds_pp/86