Schaaf-Yang Syndrome via the MAGEL2 Gene

Schaaf-Yang Syndrome is a neurodevelopmental disorder with significant phenotypic overlap to Prader-Willi syndrome (PWS), which is characterized by severe hypotonia, feeding difficulties, failure to thrive, developmental delay, hypogonadotropic hypogonadism, intellectual disability, behavioral anomalies, strabismus, scoliosis, sleep disturbances, and characteristic facial anomalies (Fountain and Schaaf. 2016. PubMed ID: 28933382).

Schaaf-Yang syndrome is differentiated from PWS based on the presence of joint contractures and lack of hyperphagia, which usually results in morbid obesity (Fountain and Schaaf. 2016. PubMed ID: 28933382; Cassidy et al. 2012. PubMed ID: 22237428). An autism spectrum disorder (ASD) diagnosis is also more frequently reported in individuals with Schaff-Yang Syndrome (75% of affected individuals) compared to those diagnosed with PWS (approximately 25% of individuals) (Fountain and Schaaf. 2016. PubMed ID: 28933382).

ASD encompasses several neurodevelopmental disorders characterized by varying degrees of social impairment, communication ability, and propensity for restricted interests and repetitive behavior(s) (Levy et al. 2009. PubMed ID: 19819542). ASD usually presents by age 3. Diagnosis is based on the degree and severity of symptoms and behaviors (Diagnostic and Statistical Manual of Mental Disorders (DSM-5); McPartland et al. 2016). Comorbidities occur in more than 70% of cases and include intellectual disability (ID), epilepsy, language deficits, and gastrointestinal problems (Sztainberg and Zoghbi. 2016. PubMed ID: 27786181). Recent studies using whole exome trios have identified novel gene candidates, with familial and de novo variants from several hundred genes now implicated in the development of ASD (Bourgeron. 2016. PubMed ID: 27289453).

MAGEL2 (Melanoma antigen-like 2) encodes an ubiquitin ligase enhancer that is necessary for endosomal protein recycling and is highly expressed in the hypothalamus and central nervous system (Schaaf et al. 2013. PubMed ID: 24076603; Doyle et al. 2010. PubMed ID: 20864041; Tacer and Potts. 2017. PubMed ID: 28626083). Paternally-inherited protein truncating variants in MAGEL2 (nonsense and frameshift) have exclusively been reported in individuals with autosomal dominant Schaaf-Yang syndrome as the maternal allele is imprinted (Fountain et al. 2017. PubMed ID: 27195816; Mejlachowicz et al. 2015. PubMed ID: 26365340; Schaaf et al. 2013. PubMed ID: 24076603). Prader-Willi syndrome is generally associated with genomic alterations at the 15q11-13 locus on the paternal allele which encompasses the PWS critical region (MKRN3, MAGEL2, NDN, NAPAP1, SNURF-SNRPN, and small nucleolar RNA genes) (Cassidy et al. 2012. PubMed ID: 22237428; Fountain and Schaaf. 2016. PubMed ID: 28933382; Buiting. 2010. PubMed ID: 20803659).

Individuals with paternally-inherited MAGEL2 full gene deletions have milder phenotypes than those who inherit MAGEL2 protein truncating variants. Individuals with deletions encompassing MAGEL2 but not the SNORD116 locus are generally asymptomatic (with the exception of delayed motor development) and have not been reported to present with joint contractures, ASD, or hyperphagia (Buiting et al. 2014. PubMed ID: 24661356; Kanber et al. 2009. PubMed ID: 19066619). Mouse studies suggest that deletion of the MAGEL2 promoter and coding region may result in partial reactivation of the maternal allele (Matarazzo and Muscatelli. 2013. PubMed ID: 25003016) and thus a milder phenotype. It has also been hypothesized that truncated MAGEL2 has neomorphic activity (Fountain and Schaaf. 2016. PubMed ID: 28933382).

Prevalence of Prader Willi syndrome is estimated to range between 1/10,000 to 1/30,000 births and is the most common cause of syndromic obesity in the context of intellectual disability (Angulo et al. 2015. PubMed ID: 26062517). However, approximately 30 individuals with paternally-inherited protein truncating variants in MAGEL2 have been reported in the literature with Schaaf-Yang syndrome (Fountain et al. 2017. PubMed ID: 27195816). Due to paralogy issues from c.1 to c.1845, this tests analytical sensitivity to detect protein truncating variants is less than 100%.

With respect to ASD phenotypes, genetic evaluation of autism spectrum disorder (ASD) patients is estimated to identify a cause in up to 40% of cases. The combined diagnostic yield of chromosomal microarray testing and FMR1 CGG-repeat expansion testing is approximately 11%-15% (Schaefer and Mendelsohn. 2013. PubMed ID: 23519317). The role of nucleotide substitutions and small insertions/deletions in autism-related genes is less clear, but may be as high at 15%, depending on the penetrance of the candidates (Schaefer and Mendelsohn. 2013. PubMed ID: 23519317; Casanova et al. 2016. PubMed ID: 26985359). To date, almost 1,000 genes have documented associations with ASD. It has been reported that nearly 60% of the total variation occurs in approximately 200 genes each of which have several ASD-associated variants (Stenson et al. 2014. PubMed ID: 24077912).

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides partial coverage of the single coding exon of the MAGEL2 gene. We define full coverage as >20X NGS reads or Sanger sequencing.

Due to sequence paralogy issues, we are unable to Sanger confirm variants called by NGS within MAGEL2 (NM_019066.4) from c.1 to c.1845 (g.23891045).