Expanding the clinical and molecular spectrum of Schaaf-Yang syndrome in China: evidence for a severe phenotypic subgroup associated with MAGEL2 c.1996-Region variants

Abstract

Schaaf-Yang syndrome (SYS) is a rare imprinting-related neurodevelopmental disorder caused by pathogenic variants in the MAGEL2 gene. Although the clinical spectrum of SYS has been increasingly recognized, data from Chinese patients remain limited. We conducted a retrospective questionnaire-based case series to delineate the clinical and molecular characteristics of Chinese individuals with MAGEL2-related disorders among evaluable individuals. We present 28 individuals harboring MAGEL2 variants. Developmental delay or intellectual disability was universal. The cohort exhibited the expected multisystem SYS phenotypes, including neonatal hypotonia, feeding difficulties, respiratory involvement, congenital joint contractures, dysmorphic features, endocrine abnormalities, and neurobehavioral manifestations. We identified 23 distinct MAGEL2 variants, including 15 novel variants. Fifteen patients carried de novo variants, while 13 had paternally inherited variants, consistent with the imprinting mechanism of SYS. In addition to truncating variants, eight individuals carried missense variants, and their phenotypes appeared to be at the mild end of the SYS spectrum. The MAGEL2 c.1996 site was a mutational hotspot, with variants affecting this locus identified in seven patients, including five with the recurrent c.1996dupC variant. Four patients harboring variants at the c.1996 site died of respiratory failure during infancy. This study provides the first systematic characterization of Chinese patients with SYS and expands the clinical and molecular spectrum of MAGEL2-related disease. Our findings identify early respiratory dysfunction as a major determinant of disease severity and suggest that truncating variants affecting the MAGEL2 c.1996 site might be associated with more severe phenotypes and potentially an increased risk of early mortality. This exploratory observation requires confirmation in larger longitudinal cohorts. Recognition of this genotype–phenotype pattern may help guide early molecular diagnosis, risk assessment, and clinical management in the early life stage of individuals with SYS.