Early onset critically ill infants with Schaaf-Yang syndrome: a retrospective study from the China neonatal genomes project and literature review

Abstract

Background: Schaaf-Yang syndrome (SYS) is a recently identified rare neurodevelopmental disorder characterized by neonatal hypotonia, feeding difficulty, joint contractures, autism spectrum disorder and development delay/intellectual disability. It is mainly caused by truncating variants in maternally imprinted gene MAGEL2 within the Prader-Willi syndrome critical region 15q11-q13. Clinical diagnosis of SYS is difficult for clinicians due to its rarity and highly variable phenotypes, while unique inheritance patterns also complicate genetic diagnosis. To date, no published papers have analyzed the clinical consequences and molecular changes in Chinese patients.

Methods: In this study, we retrospectively investigated the mutation spectrums and phenotypic features of 12 SYS infants. The data were from a cohort of critically ill infants from the China neonatal genomes project (CNGP), sponsored by Children's Hospital of Fudan University. We also reviewed relevant literature.

Results: Six previously reported mutations and six novel pathogenic variations of MAGEL2 were identified in 12 unrelated infants. Neonatal respiratory problems were the major complaint for hospitalization, which occurred in 91.7% (11/12) cases. All babies displayed feeding difficulties and a poor suck postnatally, and neonatal dystonia was present in 11 of the cases; joint contractures and multiple congenital defects were also observed. Interestingly, we found that 42.5% (57/134) of the reported SYS patients, including ours carried variants in the c.1996 site, particularly the c.1996dupC variant. The mortality rate was 17.2% (23/134), with the median age of death between 24 gestational weeks in fetuses and 1-month-old in infants. Respiratory failure was the leading cause of death in live-born patients (58.8%, 10/17), especially during the neonatal period.

Conclusions: Our findings expanded the genotype and phenotype spectrum of neonatal SYS patients. The results demonstrated that respiratory dysfunction was a typical characteristic among Chinese SYS neonates that should attract physicians' attention. The early identification of such disorders allows early intervention and can further provide genetic counseling as well as reproductive options for the affected families.

Keywords: MAGEL2; Schaaf-Yang syndrome (SYS); critically ill infant; imprinting disorder; truncated variant.

Figure 1

The structure of MAGEL2 protein and the distribution of the pathogenic variants. MAGEL2 protein contains a proline-rich region (from aa 1 to 819), USP7 binding site (U7BS, from aa 820 to 1034), and MAGE homolog domain (MHD, from residues 1027 to 1195). Region aa 1027 to 1034 represents overlap of domain U7BS and MHD. The pathogenic mutations in MAGEL2 are depicted by their positions. Above the box are frameshift mutations, while below the box are termination mutations. The red dots indicate that more than one person has the mutation at the site. The larger, the more cases, and the digit in the dots means case number. The red squares represent the variants in our patients.

Figure 2

Pedigree and genotypes of MAGEL2 variations analyzed by Sanger sequencing of patients. Sanger results of the variant are shown in the right of each pedigree. Circles are females, squares are males, triangles are fetuses. Empty symbols for nonaffected individuals, filled in black for affected individuals. Crossed symbols for deceased individuals, arrow points to the proband. Ref, reference; F, female; M, male; P, patient.