Case Report: Schaaf-Yang Syndrome Milder Phenotype Due to Potential Pathogenic Novel Missense Variant as an Unusual Cause of Obesity in a Pediatric Patient.

Introduction: Early-onset severe obesity is usually the result of an underlying genetic disorder, and several genes have recently been shown to cause syndromic and nonsyndromic forms of obesity. The “centrosomal protein 19 (CEP19)” gene encodes for a centrosomal and ciliary protein. Homozygous variants in the CEP19 gene are extremely rare causes of early-onset severe monogenic obesity. Herein, we present a Turkish family with early-onset severe obesity with variable features. Methods: Sanger sequencing and whole-exome sequencing were performed to identify the genetic etiology in the family. Results: The index case was a 12-year-old female who presented with severe obesity (BMI of 62.7 kg/m²), metabolic syndrome, and diabetic ketoacidosis. Her nonidentical twin female siblings also had early-onset severe obesity, metabolic syndrome, and diabetes. In addition, one of the affected siblings had situs inversus abdominalis, polysplenia, lumbar vertebral fusion, and abnormal lateralization. A novel homozygous nonsense (c.169C>T, p. Arg57*) pathogenic variant was detected in exon 3 of the CEP19 gene in all affected members of the family. One unaffected sister and unaffected parents were heterozygous for the variant. This variant is predicted to cause a stop codon at amino acid sequence 57, leading to a truncated CEP19 protein. Discussion/Conclusion: Our study expands the phenotypical manifestations and variation database of CEP19 variants. The findings in one of our patients reaffirm its role in the assembly and function of both motile and immotile cilia.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by neonatal hypotonia, developmental delay/intellectual disability, and characteristic feeding behaviors with failure to thrive during infancy; followed by hyperphagia and excessive weight gain later in childhood. Individuals with PWS also manifest complex behavioral phenotypes. Approximately 25% meet criteria for autism spectrum disorder (ASD). PWS is caused by the absence of paternally expressed, maternally silenced genes at chromosome 15q11-q13. MAGEL2 is one of five protein-coding genes in the PWS-critical domain. Truncating point mutations of the paternal allele of MAGEL2 cause Schaaf-Yang syndrome, which has significant phenotypic overlap with PWS, but is also clinically distinct; based on the presence of joint contractures, and a particularly high prevalence of autism spectrum disorder (up to 75% of affected individuals). The clinical and molecular overlap between PWS and Schaaf-Yang syndrome, but also their distinguishing features provide insight into the pathogenetic mechanisms underlying both disorders.

Prader-Willi syndrome is characterized by severe hypotonia in infancy, with decreased lean mass and increased fat mass in childhood followed by severe hyperphagia and consequent obesity. Scoliosis and other orthopaedic manifestations of hypotonia are common in children with Prader-Willi syndrome and cause significant morbidity. The relationships among hypotonia, reduced muscle mass and scoliosis have been difficult to establish. Inactivating mutations in one Prader-Willi syndrome candidate gene, MAGEL2, cause a Prader-Willi-like syndrome called Schaaf-Yang syndrome, highlighting the importance of loss of MAGEL2 in Prader-Willi syndrome phenotypes. Gene-targeted mice lacking Magel2 have excess fat and decreased muscle, recapitulating altered body composition in Prader-Willi syndrome. We now demonstrate that Magel2 is expressed in the developing musculoskeletal system, and that loss of Magel2 causes muscle-related phenotypes in mice consistent with atrophy caused by altered autophagy. Magel2-null mice serve as a preclinical model for therapies targeting muscle structure and function in children lacking MAGEL2 diagnosed with Prader-Willi or Schaaf-Yang syndrome.

Pathogenic MAGEL2 variants result in the phenotypes of Chitayat-Hall syndrome (CHS), Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). We present five patients with mutations in MAGEL2, including the first patient reported with a missense variant, adding to the limited literature. Further, we performed a systematic review of the CHS and SYS literature, assess the overlap between CHS, SYS and PWS, and analyze genotype-phenotype correlations among them. We conclude that there is neither a clinical nor etiological difference between CHS and SYS, and propose that the two syndromes simply be referred to as MAGEL2-related disorders.

Introduction: Severe childhood obesity can be caused by pathogenic variants in several genes involved in monogenic and syndromic obesity. Recently, heterozygous variants in pleckstrin homology domain interacting protein (PHIP) have been identified in patients with obesity as part of Chung-Jansen syndrome. Case Presentation: The index patient is a 5-year-old boy with severe obesity since 1 year of age, developmental delay, facial dysmorphism, and behavior problems. Whole-exome sequencing identified a novel missense variant in PHIP (c.3182C>A, p.Ala1061Glu) in the index patient. Further genetic testing in family members revealed segregation of the same PHIP variant in the brother and mother, who both presented with severe childhood obesity and developmental delay or learning difficulties. The PHIP missense variant was predicted pathogenic by multiple in silico tools and affects a highly conserved residue. Conclusion: Early-onset obesity may be monogenic. Our finding expands the spectrum of disease-causing variants in PHIP and demonstrates variable intrafamilial clinical expressivity and severity. Screening for PHIP variants should be included in genetic testing in patients with severe early-onset obesity.

Context: Rare copy number variants (CNVs) have been associated with the development of severe obesity. However, the potential disease-causing contribution of individual genes within the region of CNVs is often not known. Objective: Screening of rare variants in genes involved in CNVs in Finnish patients with severe early-onset obesity to find candidate genes linked to severe obesity. Methods: Custom-made targeted exome sequencing panel to search for rare (minor allele frequency <0.1%) variants in genes affected by previously identified CNVs in 92 subjects (median age 14 years) with early-onset severe obesity (median body mass index (BMI) Z-score + 4.0). Results: We identified thirteen rare heterozygous variants of unknown significance in eleven subjects in twelve of the CNV genes. Two rare missense variants (p.Pro405Arg and p.Tyr232Cys) were found in SORCS1, a gene highly expressed in the brain and previously linked to diabetes risk. Four rare variants were in genes in the proximal 16p11.2 region (a frameshift variant in TAOK2 and missense variants in SEZ6L2, ALDOA and KIF22) and three rare missense variants were in genes in the 22q11.21 region (AIFM3, ARVCF and KLHL22). Conclusion: We report several rare variants in CNV genes in subjects with childhood obesity. However, the role of the individual genes in the previously identified rare CNVs to development of obesity remains uncertain. More studies are needed to understand the potential role of the specific genes within obesity associated CNVs.

Introduction: Schaaf-Yang syndrome (SYS) is a rare autosomal dominant disorder, first identified in 2013, resulting from mutations in the paternal allele of the MAGEL2 gene. Schaaf-Yang syndrome exhibits clinical features similar to those of Prader-Willi syndrome (PWS), including hypotonia, joint contractures, developmental delay, and intellectual disability. However, SYS is also characterized by unique manifestations, such as recurrent hyperthermia, feeding difficulties, respiratory distress, and seizures. This case report describes the first SYS case identified in Iran. Case Presentation: A one-year-old female, born to consanguineous parents, presented with recurrent episodes of hyperthermia, respiratory distress, and seizures since the neonatal period. Despite initial empirical treatment with broad-spectrum antibiotics for suspected infections, her symptoms persisted. Physical examination revealed hypotonia, camptodactyly, and hand contractures. Genetic testing confirmed SYS with a MAGEL2 gene mutation (c.1923dupC, p.V643Gfs*70) and probable pathogenic variants in ASPM and KIF7. The hyperthermia was attributed to hypothalamic dysfunction, a hallmark of SYS, rather than an infectious cause. The patient remains under follow-up without specific pharmacological intervention. Conclusions: This case emphasizes the importance of considering SYS in patients presenting with unexplained fever, seizures, and neurodevelopmental delays. Early genetic testing is crucial for diagnosing SYS and differentiating it from conditions such as PWS or infection-related disorders. Timely diagnosis can improve management strategies and help reduce the risk of lasting neurological impairments associated with this genetic disorder.

SUMMARYThe human cortex acquires its advanced cognitive capacity through tightly regulated developmental programs, disruption of which underlies neurodevelopmental disorders such as Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). While SYS results from pathogenic variants in the imprinted gene MAGEL2, PWS arises from chromosomal deletions, imprinting defects or uniparental disomy encompassing the MAGEL2 locus. However, the contribution of MAGEL2 to disease pathogenesis and human corticogenesis is not fully understood. Here, we performed integrated transcriptomic, proteomic, and ubiquitinomic profiling of cortical neurons derived from CRISPR/Cas9-engineered isogenic human pluripotent stem cells (hiPSC) modeling SYS and PWS. Beyond PWS-specific signatures including dysregulated ribosomal processes, we identified MAGEL2-dependent defects shared across both disorders. These include reduced progenitor proliferation, accelerated neuronal maturation, impaired migration and adhesion, as well as abnormal synaptic development, collectively linking PWS and SYS at the level of cortical development. Notably, these phenotypes partially overlap with those observed in other neurodevelopmental disorders, suggesting that MAGEL2 governs core pathways broadly vulnerable in disease. Together, our findings establish MAGEL2 as a key regulator of human cortical development, provide a unifying mechanistic framework for SYS and PWS, accessible via a web-based platform.

BackgroundNonsense and frameshift mutations in the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13, have been reported to cause Schaaf-Yang syndrome (SYS), a genetic disorder...

Context: The hypothalamic circuit has an essential role in the regulation of appetite and energy expenditure. Pathogenic variants in genes involved in the hypothalamic leptin–melanocortin pathway, including melanocortin-4-receptor (MC4R), have been associated with monogenic obesity.Objective: To determine the rate and spectrum of rare variants in genes involved in melanocortin pathway or hypothalamic development in patients with severe early-onset obesity (height-adjusted weight >60% before age 10 years).Methods: We used a custom-made targeted exome sequencing panel to assess peripheral blood DNA samples for rare (minor allele frequency <0.5%), pathogenic/likely pathogenic variants in 24 genes related to the hypothalamic circuit in 92 subjects (51% males, median age 13.7 years) with early-onset severe obesity (median body mass index (BMI) Z-score + 4.0).Results: We identified a novel frameshift deletion in MC4R (p.V103Afs5*) in two unrelated patients and a previously reported MC4R variant (p.T112M) in one patient. In addition, we identified rare heterozygous missense variants in ADCY3 (p.G1110R), MYT1L (p.R807Q), ISL1 (p.I347F), LRP2 (p.R2479I, and p.N3315S) and a hemizygous missense variant in GRPR (p.L87M) (each in one patient), possibly contributing to the obesity phenotype in these patients. Altogether 8 % (7/92) of the subjects had rare pathogenic/likely pathogenic variants in the studied genes.Conclusions: Rare genetic variants within the hypothalamic circuit are prevalent and contribute to the development of severe early-onset obesity. Targeted exome sequencing is useful in identifying affected subjects. Further studies are needed to evaluate the variants' clinical significance and to define optimal treatment.

Background: Severe early-onset childhood obesity is diagnosed by having a BMI >120% of the 95th percentile before age 5 years. Treatment for early-onset obesity is frequently unsuccessful. Prior studies have shown parents of children with obesity often face stigmatization and those who experience weight bias also experience poorer medical care. Home environment influences many risk factors, and parents are crucial for intervention. Research on the parental perspective of care is lacking and greater understanding could increase the effectiveness of treatment. We sought to understand the common stressors and obstacles parents encounter caring for a child with early-onset severe obesity. Methods: Parents of children with early-onset severe obesity participated in semistructured interviews. Interviews were digitally recorded, transcribed verbatim, coded, and analyzed using hybrid thematic analysis. Results: We identified a global theme of "Isolation in a sea of 'experts'," supported by three organizing themes: (i) Facing barriers at every turn; (ii) Carrying all the burdens; and (iii) Struggling to get their child seen as an individual. Within each organizing theme, subthemes emerged that highlighted the struggles that parents encountered. These included significant conflict with others when attempting to implement dietary changes (e.g., spouses, other children, and extended family), protecting their child's self-esteem, perceived weight bias from medical staff, lack of experienced obesity clinicians, lack of access to weight management services, and judgment from others (e.g., family, friends, and strangers). Conclusions: This study highlighted that many parents of children with early-onset severe obesity felt significant struggles, both internal and external. Understanding the barriers parents face when caring for their children is critical to improving relationships and medical care.

Introduction: Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder caused by truncating mutations of the MAGEL2 gene, located in the Prader-Willi syndrome (PWS) region. PWS and SYS have phenotypic overlap. Patients with SYS are often treated with growth hormone (GH), but evidence for the effectiveness of the treatment in patients with SYS is limited. Methods: This study describes 7 children with SYS. We studied their phenotype, genotype, and the effect of GH treatment on height and body mass index (BMI) during 4 years and on body composition during 1 year. Results: All patients had a normal birth weight. Most patients had hypotonia and feeding difficulties after birth (86%). Full-scale IQ ranged from <50 to 92. All patients above the age of 2 years had psycho-behavioral problems. There were no apparent correlations between the phenotype and the location of the defect in the MAGEL2 gene. Mean (95% CI) height SDS increased significantly from −1.74 (−3.55; 0.07) at start to −0.05 (−1.87; 1.77) after 4 years of GH treatment. Mean (95% CI) BMI SDS decreased significantly from 2.01 (1.02; 3.00) to 1.22 (0.18; 2.26) after 6 months and remained the same during the rest of the follow-up. Fat mass percentage SDS decreased and lean body mass did not change during 1 year of treatment in 3 patients. Conclusion: Patients presented with a phenotype of hypotonia, respiratory insufficiency, and feeding difficulties after birth, endocrine disorders, intellectual disability, and behavioral problems. Treatment with GH significantly improved height SDS and BMI over the course of 4 years.

Schaaf-Yang syndrome (SYS) is a genetic disorder caused by truncating variants in the MAGEL2 gene located in the maternally imprinted Prader-Willi syndrome (PWS) region at 15q11-13. The SYS phenotype shares features with PWS, a syndrome with known high incidence of sleep disorders. However, the spectrum of sleep-disorders in SYS has not been described. We performed a retrospective analysis of polysomnograms from 22 patients in an international SYS cohort. Sleep characteristics for individuals with the common c.1996dupC variant (n = 10) were compared to other truncating variants (n = 11). We collected 33 sleep study reports from 22 patients, ages 2 months - 18.5 years (mean 6.5 years). Mean sleep efficiency was 70.5% (range 45%-93%) with arousal index 14.1/h(1.2-45/h). The mean apnea-hypopnea index (AHI) was 19.1/h (0.9-49/h) with mean obstructive AHI (oAHI) of 16.3/h(0.6-49/h). Mean central apnea index was 2.8/h(0-14/h). Mean oxygen desaturation index was 20.8/h(range 0-85/hr). Obstructive sleep apnea (OSA) was diagnosed in 81%, and 62% had moderate or severe OSA. Elevated central apnea index occurred in 9.5%. Comparison by genotype groups and age did not reveal any difference in OSA findings. Periodic limb movement index (PLMI) was elevated in 4/15 (26%). OSA is frequently identified on polysomnography in patients with SYS. The mean PLMI is elevated compared to normative data. Patients with SYS should have routine polysomnography screening due to high risk of sleep disorders.

Short stature is a common phenotype in children with Schaaf-Yang syndrome (SYS). Prader-Willi syndrome (PWS) and SYS share several phenotypic features including short stature, muscular hypotonia and developmental delay/intellectual disability. Evidence exists that similar to PWS, growth hormone (GH) deficiency may also be a feature of SYS. Recombinant human GH (rhGH) therapy has been approved for PWS, but the effects of rhGH therapy in individuals with SYS have not yet been documented. This retrospective, questionnaire-based study analyzes the prevalence of rhGH therapy in children with SYS, the effects of rhGH therapy on anthropometric measures, and parental perception of the treatment. Twenty-six individuals with SYS were sent a clinical questionnaire and a request for growth charts. We found a significant increase in height z-score (p*=0.04) as well as a significant decrease in body mass index 6 months after rhGH therapy initiation (p*=0.04). Furthermore, height z-scores of the treated group (mean z-score=-1.00) were significantly higher than those of the untreated group (mean z-score=-3.36, p=0.01) at time of enrollment. All parents reported an increase in muscle strength and endurance, and several families noted beneficial effects such as improved cognition and motor development.

Schaaf-Yang syndrome (SYS) is a neurodevelopmental disorder caused by truncating variants in the paternal allele of MAGEL2, located in the Prader-Willi critical region, 15q11-q13. Although the phenotypes of SYS overlap those of Prader-Willi syndrome (PWS), including neonatal hypotonia, feeding problems, and developmental delay/intellectual disability, SYS patients show autism spectrum disorder and joint contractures, which are atypical phenotypes for PWS. Therefore, we hypothesized that the truncated Magel2 protein could potentially produce gain-of-function toxic effects. To test the hypothesis, we generated two engineered mouse models; one, an overexpression model that expressed the N-terminal region of Magel2 that was FLAG tagged with a strong ubiquitous promoter, and another, a genome-edited model that carried a truncating variant in Magel2 generated using the CRISPR/Cas9 system. In the overexpression model, all transgenic mice died in the fetal or neonatal period indicating embryonic or neonatal lethality of the transgene. Therefore, overexpression of the truncated Magel2 could show toxic effects. In the genome-edited model, we generated a mouse model carrying a frameshift variant (c.1690_1924del; p(Glu564Serfs*130)) in Magel2. Model mice carrying the frameshift variant in the paternal or maternal allele of Magel2 were termed Magel2P:fs and Magel2M:fs, respectively. The imprinted expression and spatial distribution of truncating Magel2 transcripts in the brain were maintained. Although neonatal Magel2P:fs mice were lighter than wildtype littermates, Magel2P:fs males and females weighed the same as their wildtype littermates by eight and four weeks of age, respectively. Collectively, the overexpression mouse model may recapitulate fetal or neonatal death, which are the severest phenotypes for SYS. In contrast, the genome-edited mouse model maintains genomic imprinting and distribution of truncated Magel2 transcripts in the brain, but only partially recapitulates SYS phenotypes. Therefore, our results imply that simple gain-of-function toxic effects may not explain the patho-mechanism of SYS, but rather suggest a range of effects due to Magel2 variants as in human SYS patients.