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

Abstract

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.

Figure 1. Newly identified truncating mutations of MAGEL2 in Schaaf-Yang syndrome

A, Truncating MAGEL2 mutations reported in this manuscript are indicated by their positions in the coding sequence of the gene. *, 11 individuals with a c.1996dupC mutation; **, two individuals with a c.1996delC mutation. B, Pedigrees of familial cases. Pedigree 1, family of patients 1 and 2; pedigree 2, family of patients 5 and 6; pedigree 3, family of patients 16-18. Blackened squares and circles indicate individuals that are/were clinically affected. Black dots indicate carrier individuals, harboring the familial MAGEL2 mutation on their maternal allele. Maternal alleles are indicated in red, paternal alleles in blue. +, reference sequence for MAGEL2; M, familial MAGEL2 mutation; NT, not tested; P, patient; * obligate carrier.

Figure 2. Hand phenotypes in patients with Schaaf-Yang syndrome

Affected patients manifest a spectrum of phenotypes, including contractures of the interphalangeal joints, camptodactyly, tapering of the fingers, brachydactyly, clinodactyly, and adducted thumbs. A, patient 2; B, patient 3; C, patient 4; D, patient 7; E, patient 9; F, patient 10, G, patient 11; H, patient 13; I, patient 14; J, patient 15; K, patient 17.

Figure 3. Facial phenotype of individuals with Schaaf-Yang syndrome

While several individuals manifest dysmorphic facial features, such as short noses, bushy eyebrows, and prognathism, the consistency of facial characteristics across individuals is limited. A, patient 1; B, patient 2; C, patient 3; D, patient 4; E, patient 7; F, patient 9; G, patient 10; H, patient 11; I, patient 13; J, patient 14; K, patient 15; L, patient 18.