Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy

Negishi, Yutaka; Ieda, Daisuke; Hori, Ikumi; Nozaki, Yasuyuki; Yamagata, Takanori; Komaki, Hirofumi; Tohyama, Jun; Nagasaki, Keisuke; Tada, Hayato; Saitoh, Shinji

doi:10.1186/s13023-019-1249-4

Cited by 20 publications

(22 citation statements)

References 30 publications

(67 reference statements)

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“…All patients had a heterozygous truncating variant in the MAGEL2 gene, which was c.1996dupC (p.Gln666ProfsTer47) in patients #1 and #2, c.2217delC (p.Ser739Ter) in patient #3, and c.3449_3450delTT (p.Phe1150TrpfsTer4) in patient #4. The variant c.1996dupC has been previously described, [ 2 , 5 – 8 , 11 , 14 , 15 ] whereas c.2217delC and c.3449_3450delTT have never been reported. The allele frequency of p.Gln666ProfsTer47 was 0.002% in gnomAD ( https://gnomad.broadinstitute.org/ ); however, those of p.Phe1150TrpfsTer4 and p.Ser739Ter have not been reported previously.…”

Section: Resultsmentioning

confidence: 99%

“…[ 5 ] In the largest number of cases, as reviewed by McCarthy et al, approximately half the patients with a MAGEL2 mutation showed the variant c.1996dupC, [ 5 ] which occurred in 4 out of 9 East Asian families as used in our study. [ 10 , 14 , 15 , 18 ] Individuals with a c.1996dupC variant of MAGEL2 show higher prevalence of joint contractures, feeding difficulties, respiratory dysfunction, and more profound DD/ID. [ 5 ] Furthermore, deletion of the same nucleotide causes intrauterine fetal or perinatal demise.…”

Section: Discussionmentioning

confidence: 99%

“…No difference in terms of phenotypic severity has been observed between paternally inherited and de novo mutation carriers. [ 2 , 3 , 6 – 15 ]…”

Section: Discussionmentioning

confidence: 99%

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

Ahn

Seo

et al. 2020

Medicine

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Ahn

Seo

et al. 2020

Medicine

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“…However, most SYS patients with a truncating variant in MAGEL2 show more severe clinical features than PWS patients. Indeed, our previous study identified six patients with SYS with a truncating variant, including the common c.1996dupC, and all six patients showed severe intellectual disability and complication of joint contracture, which are atypical for PWS [ 17 ]. Thus, we hypothesized that the truncated Magel2 protein could potentially produce gain-of-function toxic effects, and we generated two types of mouse models expressing truncating mutations of Magel2 .…”

Section: Discussionmentioning

confidence: 99%

Two mouse models carrying truncating mutations in Magel2 show distinct phenotypes

et al. 2020

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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 Magel2 P:fs and Magel2 M:fs , respectively. The imprinted expression and spatial distribution of truncating Magel2 transcripts in the brain were maintained. Although neonatal Magel2 P:fs mice were lighter than wildtype littermates, Magel2 P: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

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“…Schaaf‐Yang Syndrome (SYS) is a genetic disorder caused by truncating variants in the MAGEL2 gene located in the maternally imprinted, paternally expressed Prader‐Willi syndrome (PWS) region at chromosome 15q11‐13 1–3 . While the SYS phenotype shares features with PWS thought to be due to loss of functional MAGEL2 protein in both conditions, recent work has shown that the spectrum of phenotypes in SYS differs from that in PWS 1–4 . Similar to PWS, children with SYS have neonatal hypotonia, developmental delay, autism spectrum disorder, short stature, elevated fat mass, hypogonadism, and obstructive sleep apnea (OSA).…”

Section: Introductionmentioning

confidence: 99%

Polysomnographic characteristics and sleep‐disordered breathing in Schaaf‐Yang syndrome

Powell

Schaaf

Rech

et al. 2020

Pediatric Pulmonology

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Introduction: 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. Methods: 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). Results: 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%). Conclusion: 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.

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Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy

Cited by 20 publications

References 30 publications

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

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

Two mouse models carrying truncating mutations in Magel2 show distinct phenotypes

Polysomnographic characteristics and sleep‐disordered breathing in Schaaf‐Yang syndrome

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