Clinical characteristics.

Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder that shares multiple clinical features with the genetically related Prader-Willi syndrome. It usually manifests at birth with muscular hypotonia in all and distal joint contractures in a majority of affected individuals. Gastrointestinal/feeding problems are particularly pronounced in infancy and childhood, but can transition to hyperphagia and obesity in adulthood. Respiratory distress is present in many individuals at birth, with approximately half requiring intubation and mechanical ventilation, and approximately 20% requiring tracheostomy. Skeletal manifestations such as joint contractures, scoliosis, and decreased bone mineral density are frequently observed. All affected individuals show developmental delay, resulting in intellectual disability of variable degree, from low-normal intelligence to severe intellectual disability. Other findings may include short stature, seizures, eye anomalies, and hypogonadism.

Diagnosis/testing.

The diagnosis of Schaaf-Yang syndrome is established in a proband by identification of a heterozygous pathogenic variant in the paternally derived MAGEL2 allele by molecular genetic testing. The 15q11.2 locus that includes MAGEL2 is maternally imprinted, meaning that only the paternally derived allele is expressed while the maternally derived allele is inactivated.

Management.

Treatment of manifestations: Feeding therapy or supplemental tube feeding may be required for persistent feeding issues; assisted ventilation to include either noninvasive or invasive intervention; CPAP for sleep apnea; growth hormone therapy in those with short stature and/or linear growth concerns; standard therapy for gastroesophageal reflux disease, metabolic syndrome, constipation, skeletal abnormalities, low bone mineral density, developmental delay/cognitive impairment, seizures, eye anomalies, undescended testes, hypogonadism and pubertal abnormalities, and hypothyroidism.

Surveillance: At each visit: measurement of growth parameters and evaluation of nutritional status & safety of oral intake; assessment of developmental progress, educational needs, and self-help skills; monitor for signs and symptoms of constipation, sleep apnea, respiratory insufficiency, scoliosis, progression of contractures, and puberty (from ages 10-17 years). Behavioral assessment annually; DXA scan every two years starting at the age five years, transitioning to every three to five years in adulthood; ophthalmology evaluation as recommended by an ophthalmologist; polysomnography annually for those on long-term GH therapy or as recommended by a sleep specialist.

Genetic counseling.

Schaaf-Yang syndrome is inherited in an autosomal dominant, maternally imprinted manner (i.e., a heterozygous pathogenic variant on the paternally derived MAGEL2 allele results in disease; a pathogenic variant on the maternally derived MAGEL2 allele does not result in disease because normally the maternally derived MAGEL2 allele is silenced). Approximately 50% of individuals diagnosed with SYS inherited a MAGEL2 pathogenic variant from a clinically unaffected father and the remainder are de novo. If the father of the proband is heterozygous for the MAGEL2 pathogenic variant identified in the proband, the risk to both male and female sibs is 50%. The recurrence risk within the family of the proband's mother is that of the general population. Once the MAGEL2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

SYS should be suspected in individuals with the following clinical and suggestive laboratory findings.

Clinical findings

• Generalized hypotonia of infancy
• Respiratory distress in infancy
• Infant feeding difficulties with failure to thrive
• Hyperphagia with subsequent obesity in childhood or adolescence
• Mild-to-profound developmental delay or intellectual disability
• Autism spectrum disorder or autistic features
• Nonspecific dysmorphic facial features, including a pointed chin, frontal bossing, and low-set ears
• Short stature
• Joint contractures of variable severity, ranging from mild contractures of the distal phalanges of the hands to severe arthrogryposis multiplex congenita
• Endocrinopathy, including:
  • Hypopituitarism
  • Growth hormone deficiency
  • Hypogonadism and/or undervirilization in males

Suggestive laboratory findings

• Normal methylation analysis of the 15q11.2 region (Prader-Willi/Angelman syndrome locus)
• Any of the following hormonal or metabolic findings [McCarthy et al 2018b]:
  • Low IGF-1 levels despite normal weight and adequate nutrition
  • Elevated glucose levels on oral glucose tolerance testing (OGTT)
  • Elevated fasting ghrelin levels

Establishing the Diagnosis

The diagnosis of Schaaf-Yang syndrome is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in the paternally derived MAGEL2 allele by molecular genetic testing (see Table 1).

Note: (1) The 15q11.2 locus that includes MAGEL2 is maternally imprinted, meaning that only the paternally derived allele is expressed while the maternally derived allele is inactivated. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (3) Identification of a heterozygous MAGEL2 variant of uncertain significance in the paternal allele neither establishes nor rules out a diagnosis of SYS.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive combination of findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of SYS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Schaaf-Yang Syndrome (SYS) is a rare, paternally derived neurodevelopmental disorder that shares multiple clinical features with the genetically related Prader-Willi syndrome. It usually manifests at birth with muscular hypotonia in all and distal joint contractures in a majority of affected individuals.

To date, more than 250 individuals have been identified with a paternally derived pathogenic variant in MAGEL2 [Schaaf et al 2013, Fountain et al 2017, McCarthy et al 2018a, McCarthy et al 2018b]. The following description of the phenotypic features associated with this condition is based on these reports.

Muscular hypotonia is, to a variable degree, present in almost all neonates with SYS, and can be severe in some instances. Reduced fetal movements may be reported prenatally. Hypotonia also contributes to different aspects of the neonatal phenotype, such as feeding difficulties and respiratory distress.

Gastrointestinal/feeding problems are particularly pronounced in infancy and childhood, but can transition to hyperphagia and obesity in adulthood.

• Almost all affected individuals have feeding problems in infancy. Most infants are dependent on special feeding techniques (special nipple, nasogastric tube feeding) during the first months of life.
• While feeding problems resolve in about half during the first year of life, insufficient oral food uptake remains a problem in the other half, and these affected individuals eventually require gastrostomy tube placement, which could be continued into childhood.
• Although not a hallmark of SYS in childhood, hyperphagia and obesity can be found in a significant proportion of affected adults, and the incidence of hyperphagia appears to increase with age [Schaaf et al 2013, McCarthy et al 2018a, McCarthy et al 2018b].
• Chronic constipation is present in the majority of affected individuals.
• Gastroesophageal reflux is present in more than half of affected individuals.

Stature. Approximately 50%-60% of individuals with SYS have short stature, defined as height below the third percentile. In a cohort of 78 affected individuals reported by McCarthy et al [2018a], average height was on the 22nd percentile for age.

• Growth hormone (GH) treatment has been effective in some affected individuals [McCarthy et al 2018b].
• A retrospective analysis of GH treatment in children with SYS including 14 treated and 12 untreated individuals found a significant increase in body height in the treated group over a course of six months (improvement of mean height z-scores from -2.6 before to -1.7 after treatment) [Hebach et al 2021].
• Satisfaction with GH therapy was high among parents of treated individuals, who reported a subjective increase or strong increase in muscle strength in 13 of 14 individuals.
• Based on seven individuals for whom sufficient data was available, a non-significant improvement of mean weight for stature Z-scores (decrease by 0.8 after 6 months on GH therapy) was noted. The authors hypothesized that this may indicate a positive effect of GH treatment on body composition, which would be in line with established effects of GH therapy in children with Prader-Willi syndrome [Lindgren et al 1998].
• Worsening of sleep apnea was reported in one individual with SYS who was on GH, and worsening of scoliosis/kyphosis was reported in two individuals in the treatment group, without the need to interrupt or discontinue GH therapy.
• The authors proposed that the same precautions should be taken in individuals with SYS undergoing GH therapy that apply for individuals with Prader-Willi syndrome (see Management).

Head circumference. Most individuals with SYS have a normal head circumference.

Respiratory abnormalities. Respiratory distress is present in many individuals with SYS at time of birth, with approximately half of all individuals requiring intubation and mechanical ventilation, and approximately 20% requiring tracheostomy.

• More than half of the individuals reported by McCarthy et al [2018a] required mechanical ventilation during the first two months of life.
• Central apnea and/or obstructive sleep apnea is seen in approximately 75% of all affected individuals.
• Episodes of apnea or severe respiratory distress can occur, especially during the first year of life [McCarthy et al 2018a], and contribute to a higher mortality compared to the general population during infancy.

Musculoskeletal features. Skeletal manifestations such as joint contractures, scoliosis, and decreased bone mineral density are frequently observed. Joint contractures may be detected prenatally.

• Distal joint contractures of the upper limbs are present in the majority of affected individuals. The severity of this symptom varies from isolated contractures of the interphalangeal joints to severe arthrogryposis multiplex congenita [Mejlachowicz et al 2015].
• Scoliosis is present in more than half of affected individuals. Exaggerated kyphosis can be observed in some.
• Low bone mineral density (>2 SD below the mean) was reported in the majority of affected individuals studied by McCarthy et al [2018b].

Developmental delay (DD) / intellectual disability (ID). All individuals with SYS show DD, resulting in ID of variable degree, from low-normal intelligence to severe ID. The severity of ID is likely influenced by an individual's MAGEL2 genotype (see Genotype-Phenotype Correlations).

• Motor milestones are usually delayed – on average, children with SYS sit independently at age 18 months, crawl at 31 months, and walk at 50 months.
• First words are spoken at an average age of 36 months, and the first two-word sentence at an average of 40 months.
• However, affected individuals vary greatly with regard to motor and language development, and some adults with SYS do not acquire speech or independent walking [McCarthy et al 2018a].
• A few affected individuals have borderline intellectual function [Marbach et al 2020].
• Neurologic deterioration following febrile illness has been reported in four individuals with SYS [Negishi et al 2019].

Behavioral problems. Autistic behavior is present in about three quarters of affected individuals.

• Common findings include social withdrawal, restricted interests/fascinations, or stereotypic behavior such as hand flapping when stressed.
• 75%-80% of affected individuals meet the formal clinical diagnostic criteria of autism spectrum disorder (ASD) [McCarthy et al 2018a].
• Additionally, skin picking and self-injurious behavior, which are frequent among individuals with ASD, are present in 70%-80% of those with SYS. Whether this behavior coincides with other features of ASD or whether it occurs as an isolated symptom is as yet unknown.

Seizures of focal or generalized onset have been reported in a minority of affected individuals [Fountain et al 2017, McCarthy et al 2018a].

Two of the four individuals with neurologic deterioration following febrile illness reported by Negishi et al [2019] developed seizures after two to three days of fever. Cranial MRIs revealed unilateral white matter hyperintensities on diffusion-weighted imaging in one individual, while the other showed bilateral high signal intensity areas in the putamen and globus pallidus on T₂-weighted imaging [Negishi et al 2019].

Eye abnormalities are found in the majority of affected individuals, and may include esotropia, myopia, and/or strabismus, as well as nystagmus and microcornea. The number and severity of eye anomalies varies among individuals.

Genitourinary abnormalities. Hypogonadism may be apparent at the time of birth, with undescended testicles and a small penis in males, or may become apparent later in childhood or adolescence.

• Hypogonadism is reported in 15%-25% of females and 55%-65% of males, although McCarthy et al [2018b] reported that values of follicle-stimulating hormone, luteinizing hormone, and testosterone in nine individuals (2 postpubertal and 7 prepubertal individuals) were within the normal range for sex and pubertal status.
• While true hypogonadotropic hypogonadism is among the cardinal features of PWS, it may be less frequent among individuals with SYS.

Facial features. Facial dysmorphisms are mostly nonspecific. A few features are seen with frequency; these include a pointed, prominent chin and frontal bossing (see Suggestive Findings).

Other associated features

• Temperature instability has been reported, with a majority of affected individuals experiencing excessive cold or excessive sweating [McCarthy et al 2018a].
• Hypothyroidism has been observed in some affected adults (see Prader-Willi Syndrome).

Phenotype in adults. Based on data from a group of seven adults, the phenotype of SYS appears to be variable.

• Cognitive abilities vary from complete dependence on external care to mild ID or borderline cognitive function.
• Most affected adults reported to date are verbal and have basic reading skills, and some are able to work in a structured environment.
• Frequent behavioral issues include a lack of activity and motivation, stubbornness, and social withdrawal. Features of ASD are present in most, and heightened anxiety is reported in almost all cases.
• Obsessive-compulsive disorder and attention-deficit disorder are also reported, and one affected adult has been diagnosed with schizophrenia [Marbach et al 2020].
• Overeating and obesity characterizes the majority of adults with SYS. While variable, the onset of obesity appears to be later than in PWS, where it usually occurs in childhood.
• Obesity in adulthood can lead to features of metabolic syndrome, including hyperlipidemia and insulin resistance.

Prognosis. The overall life expectancy of individuals with SYS is reduced due to a greater risk of fatal complications, mostly during infancy and childhood. These include severe respiratory distress due to central and/or obstructive apnea. Sleep monitoring, pulse oximetry, and increased vigilance for breathing irregularities may mitigate these risks to some extent. Survival into adulthood is possible: one reported individual is alive at age 36 years [Marbach et al 2020]. Similar to Prader-Willi syndrome (see Genetically Related Disorders), adults with SYS may suffer from obesity and asssociated complications such as metabolic syndrome. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are under-recognized and under-reported.

Genotype-Phenotype Correlations

The c.1996dupC variant is the most prevalent pathogenic variant, found in 40%-50% of affected individuals. Compared to affected individuals who have other truncating variants, those with the c.1996dupC variant display a more severe phenotype, including a higher prevalence of joint contractures, more severe respiratory complications, more pronounced DD, and a higher rate of profound ID [McCarthy et al 2018a].

The pathogenic c.1996delC variant has been found to be pre- or perinatally lethal in all nine individuals with the variant reported to date [Mejlachowicz et al 2015, Fountain et al 2017, Guo et al 2019].

Penetrance

Penetrance is considered to be 100% for individuals with a pathogenic MAGEL2 variant on their paternal allele, regardless of the sex of the affected individual (i.e., all should display symptoms associated with SYS). Individuals with a pathogenic MAGEL2 variant on their maternal allele will be unaffected.

Nomenclature

Jobling et al [2018] demonstrated that Chitayat-Hall syndrome, which was first described in 1990 [Chitayat et al 1990], is caused by a heterozygous pathogenic variant on the paternal allele of MAGEL2, demonstrating a common genetic etiology with SYS.

Prior to the description of SYS as a distinct genetic condition, individuals with Schaaf-Yang syndrome may have been diagnosed with Prader-Willi-like syndrome (PWLS). PWLS is considered to be an umbrella term for a genetically heterogeneous group of disorders with phenotypic similarities to PWS [Cheon 2016].

Prevalence

More than 250 individuals with SYS have been reported to date. SYS affects both sexes and all ethnicities equally.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Schaaf-Yang syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Schaaf-Yang syndrome (SYS) is inherited in an autosomal dominant, maternally imprinted manner (i.e., a heterozygous pathogenic variant on the paternally derived MAGEL2 allele results in disease; a pathogenic variant on the maternally derived MAGEL2 allele does not result in disease because normally the maternally derived MAGEL2 allele is silenced).

Risk to Family Members

Parents of a proband

• Approximately 50% of individuals diagnosed with SYS inherited a MAGEL2 pathogenic variant from a clinically unaffected father.
• Approximately 50% of individuals diagnosed with SYS have the disorder as the result of a de novo pathogenic variant on the paternally derived MAGEL2 allele.
• Molecular genetic testing is recommended for the biological father of the proband to confirm his genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is situated on the paternal allele but is not identified in paternal DNA, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a father with germline (or somatic and germline) mosaicism. Paternal somatic/germline mosaicism has been reported [Patak et al 2019].
    Note: Testing of paternal leukocyte DNA may not detect all instances of somatic mosaicism.
• The mother of a proband will not be affected with SYS nor will she be heterozygous for a MAGEL2 pathogenic variant.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's father:

• If the father of the proband is heterozygous for the MAGEL2 pathogenic variant identified in the proband, the risk to both male and female sibs is 50%. The penetrance of SYS is considered to be complete (i.e., a person who is heterozygous for a MAGEL2 pathogenic variant on the paternal allele will show features of the disorder). However, some interfamilial clinical variability is to be expected.
• If the MAGEL2 pathogenic variant is not detected in the leukocyte DNA of the biological father of the proband, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of paternal germline mosaicism [Soden et al 2014, Patak et al 2019].

Offspring of a proband. Each child of a proband with SYS has a 50% chance of inheriting the MAGEL2 pathogenic variant: if the proband is male, heterozygous offspring will be affected; if the proband is female, heterozygous offspring will remain asymptomatic (see Penetrance).

Other family members. Because SYS is inherited in an autosomal dominant, maternally imprinted manner:

• The recurrence risk within the family of the proband's mother is that of the general population.
• If the father of the proband is heterozygous for a MAGEL2 pathogenic variant, or if the genetic status of the father is unknown, the recurrence risk to members of the father's family is increased. Targeted genetic testing of the father's mother (the paternal grandmother of the proband) may indicate increased recurrence risks for offspring of the father's sibs.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• Genetic counseling (including discussion of potential risks to offspring and reproductive options) should be offered to the parents of affected individuals and to males who are heterozygous for a maternally inherited MAGEL2 pathogenic variant.
• Genetic counseling is also recommended for members of the paternal family of the proband (such as the father's mother and sibs) if the proband's father is heterozygous for a MAGEL2 pathogenic variant.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the MAGEL2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

MAGEL2 is a maternally imprinted (silenced), paternally expressed, single-exon gene located within the Prader-Willi critical region (PWCR) on chromosome 15q11.2. It encodes the MAGEL2 protein, which belongs to the MAGE protein family. MAGEL2 binds to and regulates the activity of the E3 RING ubiquitin ligase TRIM27 (tripartite motif containing 27). MAGEL2, USP7 (ubiquitin-specific peptidase 7), and TRIM27 are known to colocalize at endosomes where they form the MUST (MAGEL2-USP7-TRIM27) protein complex, which facilitates retromer-mediated endosomal protein recycling by ubiquitination of the WASH actin nuclear promoting factor [Tacer & Potts 2017]. Disruption of MAGEL2 protein function is predicted to impair autophagy and potentially other ubiquitination-dependent cellular processes. Indeed, truncating variants in MAGEL2 have been shown to result in decreased autophagy and increased expression of mammalian target of rapamycin (mTOR) in fibroblasts derived from affected individuals. iPSC-derived neurons (iNeurons) derived from patient cells exhibited elevated mTOR activity and defective dendrite formation [Crutcher et al 2019], suggesting that SYS manifests on the cellular level as a disorder of neuronal development.

Given its position within the PWCR, it is remarkable that individuals with MAGEL2 pathogenic variants on the paternally derived allele show, on average, more pronounced cognitive deficits than those who have PWS as a result of a contiguous gene deletion within the PWCR on the paternally derived chromosome 15. Additionally, individuals who have smaller, atypical deletions within the PWCR on the paternally derived chromosome that include MAGEL2 but not the SNORD116 cluster may show even milder phenotypes than individuals with typical PWS [Kanber et al 2009]. This suggests either a neomorphic or dominant-negative effect of truncated MAGEL2 proteins, when compared to simple loss of protein expression from the paternal allele. Alternatively, "leaky" expression of the maternal allele of MAGEL2 in the absence of a paternal allele has been discussed as a possible explanation [Buiting et al 2014].

Mechanism of disease causation. Loss of function (paternal allele)

MAGEL2-specific laboratory technical considerations. MAGEL2 is an imprinted gene. Only paternally inherited pathogenic variants cause disease; therefore, parental testing is important for variant interpretation.

Revision History

• 4 November 2021 (cps) Revision: information on growth hormone (GH) therapy updated by authors
• 11 February 2021 (ma) Review posted live
• 31 August 2020 (cps) Original submission

Literature Cited

• Berini J, Spica Russotto V, Castelnuovo P, Di Candia S, Gargantini L, Grugni G, Iughetti L, Nespoli L, Nosetti L, Padoan G, Pilotta A, Trifirò G, Chiumello G, Salvatoni A, et al. Growth hormone therapy and respiratory disorders: long-term follow-up in PWS children. J Clin Endocrinol Metab. 2013;98:E1516–23. [PubMed: 23894156]
• Buiting K, Di Donato N, Beygo J, Bens S, von der Hagen M, Hackmann K, Horsthemke B. Clinical phenotypes of MAGEL2 mutations and deletions. Orphanet J Rare Dis. 2014;9:40. [PMC free article: PMC3987887] [PubMed: 24661356]
• Cheon CK. Genetics of Prader-Willi syndrome and Prader-Will-Like syndrome. Ann Pediatr Endocrinol Metab. 2016;21:126–35. [PMC free article: PMC5073158] [PubMed: 27777904]
• Chitayat D, Hall JG, Couch RM, Phang MS, Baldwin VJ. Syndrome of mental retardation, facial anomalies, hypopituitarism, and distal arthrogryposis in sibs. Am J Med Genet. 1990;37:65–70. [PubMed: 2240046]
• Crutcher E, Pal R, Naini F, Zhang P, Laugsch M, Kim J, Bajic A, Schaaf CP. mTOR and autophagy pathways are dysregulated in murine and human models of Schaaf-Yang syndrome. Sci Rep. 2019;9:15935. [PMC free article: PMC6828689] [PubMed: 31685878]
• Deal CL, Tony M, Höybye C, Allen DB, Tauber M, Christiansen JS, et al. GrowthHormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. J Clin Endocrinol Metab. 2013;98:E1072–87. [PMC free article: PMC3789886] [PubMed: 23543664]
• Fountain MD, Aten E, Cho MT, Juusola J, Walkiewicz MA, Ray JW, Xia F, Yang Y, Graham BH, Bacino CA, Potocki L, van Haeringen A, Ruivenkamp CA, Mancias P, Northrup H, Kukolich MK, Weiss MM, van Ravenswaaij-Arts CM, Mathijssen IB, Levesque S, Meeks N, Rosenfeld JA, Lemke D, Hamosh A, Lewis SK, Race S, Stewart LL, Hay B, Lewis AM, Guerreiro RL, Bras JT, Martins MP, Derksen-Lubsen G, Peeters E, Stumpel C, Stegmann S, Bok LA, Santen GW, Schaaf CP. The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families. Genet Med. 2017;19:45–52. [PMC free article: PMC5116288] [PubMed: 27195816]
• Guo W, Nie Y, Yan Z, Zhu X, Wang Y, Guan S, Kuo Y, Zhang W, Zhi X, Wei Y, Yan L, Qiao J. Genetic testing and PGD for unexplained recurrent fetal malformations with MAGEL2 gene mutation. Sci China Life Sci. 2019;62:886–94. [PubMed: 31152388]
• Hebach NR, Caro P, Martin-Giacalone BA, Lupo PJ, Marbach F, Choukair D, Schaaf CP. A retrospective analysis of growth hormone therapy in children with Schaaf-Yang syndrome. Clin Genet. 2021;100:298–307. [PubMed: 34013972]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Jobling R, Stavropoulos DJ, Marshall CR, Cytrynbaum C, Axford MM, Londero V, Moalem S, Orr J, Rossignol F, Lopes FD, Gauthier J, Alos N, Rupps R, McKinnon M, Adam S, Nowaczyk MJM, Walker S, Scherer SW, Nassif C, Hamdan FF, Deal CL, Soucy JF, Weksberg R, Macleod P, Michaud JL, Chitayat D. Chitayat-Hall and Schaaf-Yang syndromes: a common aetiology: expanding the phenotype of MAGEL2-related disorders. J Med Genet. 2018;55:316–21. [PubMed: 29599419]
• Kanber D, Giltay J, Wieczorek D, Zogel C, Hochstenbach R, Caliebe A, Kuechler A, Horsthemke B, Buiting K. A paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader-Willi syndrome. Eur J Hum Genet. 2009;17:582–90. [PMC free article: PMC2986273] [PubMed: 19066619]
• Lindgren AC, Hagenäs L, Müller J, Blichfeldt S, Rosenborg M, Brismar T, Ritzén EM. Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favourably. Acta Paediatr. 1998;87:28–31. [PubMed: 9510443]
• Marbach F, Elgizouli M, Rech M, Beygo J, Erger F, Velmans C, Stumpel CTRM, Stegmann APA, Beck-Wödl S, Gillessen-Kaesbach G, Horsthemke B, Schaaf CP, Kuechler A. The adult phenotype of Schaaf-Yang syndrome. Orphanet J Rare Dis. 2020;15:294. [PMC free article: PMC7574436] [PubMed: 33076953]
• McCarthy J, Lupo PJ, Kovar E, Rech M, Bostwick B, Scott D, Kraft K, Roscioli T, Charrow J, Schrier Vergano SA, Lose E, Smiegel R, Lacassie Y, Schaaf CP. Schaaf-Yang syndrome overview: report of 78 individuals. Am J Med Genet A. 2018a;176:2564–74. [PMC free article: PMC6585857] [PubMed: 30302899]
• McCarthy JM, McCann-Crosby BM, Rech ME, Yin J, Chen CA, Ali MA, Nguyen HN, Miller JL, Schaaf CP. Hormonal, metabolic and skeletal phenotype of Schaaf-Yang syndrome: a comparison to Prader-Willi syndrome. J Med Genet. 2018b;55:307–15. [PubMed: 29496979]
• Mejlachowicz D, Nolent F, Maluenda J, Ranjatoelina-Randrianaivo H, Giuliano F, Gut I, Sternberg D, Laquerrière A, Melki J. Truncating mutations of MAGEL2, a gene within the Prader-Willi locus, are responsible for severe arthrogryposis. Am J Hum Genet. 2015;97:616–20. [PMC free article: PMC4596890] [PubMed: 26365340]
• Negishi Y, Ieda D, Hori I, Nozaki Y, Yamagata T, Komaki H, Tohyama J, Nagasaki K, Tada H, Saitoh S. Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy. Orphanet J Rare Dis. 2019;14:277. [PMC free article: PMC6888944] [PubMed: 31791363]
• Patak J, Gilfert J, Byler M, Neerukonda V, Thiffault I, Cross L, Amudhavalli S, Pacio-Miguez M, Palomares-Bralo M, Garcia-Minaur S, Santos-Simarro F, Powis Z, Alcaraz W, Tang S, Jurgens J, Barry B, England E, Engle E, Hess J, Lebel RR. MAGEL2-related disorders: a study and case series. Clin Genet. 2019;96:493–505. [PMC free article: PMC6864226] [PubMed: 31397880]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Schaaf CP, Gonzalez-Garay ML, Xia F, Potocki L, Gripp KW, Zhang B, Peters BA, McElwain MA, Drmanac R, Beaudet AL, Caskey CT, Yang Y. Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism. Nat Genet. 2013;45:1405–8. [PMC free article: PMC3819162] [PubMed: 24076603]
• Soden SE, Saunders CJ, Willig LK, Farrow EG, Smith LD, Petrikin JE, LePichon JB, Miller NA, Thiffault I, Dinwiddie DL, Twist G, Noll A, Heese BA, Zellmer L, Atherton AM, Abdelmoity AT, Safina N, Nyp SS, Zuccarelli B, Larson IA, Modrcin A, Herd S, Creed M, Ye Z, Yuan X, Brodsky RA, Kingsmore SF. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med. 2014;6:265ra168.
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Tacer KF, Potts PR. Cellular and disease functions of the Prader-Willi Syndrome gene MAGEL2. Biochem J. 2017;474:2177–90. [PMC free article: PMC5594744] [PubMed: 28626083]
• Urreizti R, Cueto-Gonzalez AM, Franco-Valls H, Mort-Farre S, Roca-Ayats N, Ponomarenko J, Cozzuto L, Company C, Bosio M, Ossowski S, Montfort M, Hecht J, Tizzano EF, Cormand B, Vilageliu L, Opitz JM, Neri G, Grinberg D, Balcells S. A de novo nonsense mutation in MAGEL2 in a patient initially diagnosed as Opitz-C: similarities between Schaaf-Yang and Opitz-C syndromes. Sci Rep. 2017;7:44138. [PMC free article: PMC5345063] [PubMed: 28281571]