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

Abstract

PurposeTruncating 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, manifesting 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 appear to cause little to no clinical phenotype.MethodsHere we report a total of 18 new individuals with Schaaf-Yang syndrome from 14 families, including one family with three individuals found to be affected with a truncating variant of MAGEL2, 11 individuals clinically affected, but not tested molecularly, and a presymptomatic fetal sibling with carrying the pathogenic MAGEL2 variant.ResultsAll cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and one fetus harboring a c.1996dupC (p.Q666fs) mutation and two fetuses harboring a c.1996delC (p.Q666fs). The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to individuals with neurobehavioral disease and contractures of the small finger joints.ConclusionThis 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 of affected families.

Hormonal, metabolic and skeletal phenotype of Schaaf-Yang syndrome: a comparison to Prader-Willi syndrome

“…Proband information is summarised in table 1. Patients 1, 7 and 8 of this study had been reported previously as patients 2, 3, and 1, respectively, by Fountain et al 4. Patients 3 and 5 of this study had been reported previously as patients CMH383 and CMH382 by Soden et al 7.…”

A De Novo Nonsense Mutation in MAGEL2 in a Patient Initially Diagnosed as Opitz-C: Similarities Between Schaaf-Yang and Opitz-C Syndromes

“…Several de novo truncating mutations, similar to the one described here, have been reported previously in patients with Schaaf-Yang syndrome (SHFYNG, MIM #615547)67, a condition with some resemblances to Prader-Willi syndrome, and in two patients with a distinct severe arthrogryposis phenotype8. Very recently, Fountain et al 9. described 18 additional SHFYNG patients with similar mutations.…”

“…10 for further comparisons), and in patients with a severe form of arthrogryposis with reduced fetal movement and perinatal death8. Recently, Fountain et al 9,. described a large series of SHFYNG patients, all with a truncating MAGEL2 mutation on the paternal chromosome.…”

Chitayat-Hall and Schaaf-Yang syndromes:a common aetiology: expanding the phenotype of MAGEL2-related disorders

“…The variant was not present in parents or unaffected siblings, and was determined to be on the paternal allele (online supplementary figure 4). Patient 4-I has a previously reported frameshift insertion (c.1996dupC(p.Gln666Profs*47))6 in MAGEL2 , inherited from her unaffected father.…”