Diagnosis of Schaaf-Yang syndrome in Korean children with developmental delay and hypotonia

Abstract

Schaaf-Yang syndrome (SYS) is a recently identified disorder caused by a loss-of-function mutation in a maternally imprinted gene, MAGEL2 , at 15q11.2q13. Due to its extreme rarity and wide range of clinical severity, clinical suspicion is difficult for a physician. In the current study, its frequency among the Korean pediatric patients with developmental delay (DD) or intellectual disability (ID) was assessed. As the first report of Korean patients with SYS, our study aims to increase the awareness of this condition among the physicians taking care of the pediatric patients with DD/ID and hypotonia. The patients diagnosed with SYS by whole-exome sequencing (WES) among the 460 Korean pediatric patients with DD/ID were included, and their clinical and molecular features were reviewed. Four patients (0.9%) were diagnosed with SYS. Profound DD (4 patients), multiple anomalies including joint contractures and facial dysmorphism (4 patients), generalized hypotonia (3 patients), and severe respiratory difficulty requiring mechanical ventilation (3 patients) were noted in most cases, similar to those in previous reports. Sleep apnea (2 patients), autistic features (2 patients), a high grade of gastroesophageal reflux (1 patient), and seizures (1 patient) were found as well. A total of 3 different truncating MAGEL2 mutations were identified. A previously-reported mutation, to be the most common one, c.1996dupC, was found in 2 patients. The other 2 mutations, c.2217delC and c.3449_3450delTT were novel mutations. As MAGEL2 is maternally imprinted, 2 patients had inherited the MAGEL2 mutation from their respective healthy fathers. SYS is an extremely rare cause of DD/ID. However, hypotonia, joint contractures, profound DD/ID and facial dysmorphism are the suggestive clinical features for SYS. As a maternally imprinted disorder, it should be reminded that SYS may be inherited in form of a mutation from a healthy father.

Preimplantation Genetic Testing (PGT) and Prenatal Diagnosis of Schaaf-Yang Syndrome: A Report of Three Families and a Research on Genotype–Phenotype Correlations

“…Together with the 11 patients in our study, data from a total of 127 patients with SYS were pooled and were available for analysis. We numbered patients according to the literature sources: 1–91 [ 8 ], 92–95 [ 23 ], 96 [ 24 ], 97–102 [ 6 ], 103–104 [ 9 ], 105–108 [ 11 ], 109 [ 25 ], 110 [ 26 ], 111 [ 27 ], 112–115 [ 28 ], 116 [ 29 ] and 117–127 (New).…”

“…Neurodevelopmental delay with unexplained dyspnea is clinically extremely hazardous, leading to death in the neonatal period of SYS patients [ 9 , 10 ]. As SYS does not comply with Mendelian inheritance laws and the underlying pathological mechanisms and genotype–phenotype correlations remain to be elucidated, clinical suspicion of SYS in the differential diagnosis in pediatric patients with hypotonia and developmental delay/intellectual disability is not high because of the physicians’ unfamiliarity [ 11 ].…”

A Korean Child with Schaaf-Yang Syndrome Presented with Hearing Impairment: A Case Report

“…The c.1996dup (p.Q666fs) variant of MAGEL2 is the most common causative variant found in approximately half of known individuals with SYS 2) . In Korea, four cases of SYS have been reported, with two patients harboring the variant c.1996dup 5) . In the present report, a heterozygous truncating variant of c.2895G>A (p.Trp965*) in MAGEL2 was detected by WES, which was found to be a de novo variant by Sanger sequencing of samples from both parents.…”

Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2

“…In contrast, non-sense or frameshift mutations in the paternal allele of MAGEL2 are predicted to encode a truncated protein lacking the MAGE Homology Domain (MHD) and have been associated with SYS 1. Since then, over a hundred patients with SYS have been reported and phenotypically described 1–28. Patients with SYS and PWS show overlapping clinical phenotypes, including neonatal hypotonia, intellectual disability (ID), developmental delay (DD), early feeding difficulties, endocrinological disturbances (hypogonadism and other hormonal imbalances) and sleep disorders.…”