MAGEL2

Chr 15AD

MAGE family member L2

Also known as: NDNL1, PWLS, SHFYNG, nM15

NCBI Gene: 54551 ENSG00000254585 UniProt: Q9UJ55 OMIM: 605283

MAGEL2 encodes a protein that functions in early endosomes and is paternally imprinted within the Prader-Willi syndrome chromosomal region at 15q11-q13. Mutations cause Schaaf-Yang syndrome, which follows an autosomal dominant inheritance pattern. The protein is highly intolerant to loss-of-function mutations, suggesting haploinsufficiency as the likely pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Prader-Willi syndrome (PWS) is caused by the loss of expression of imprinted genes in chromosome 15q11-q13 region. Affected individuals exhibit neonatal hypotonia, developmental delay, and childhood-onset obesity. Necdin (NDN), a gene involved in the terminal differentiation of neurons, localizes to this region of the genome and has been implicated as one of the genes responsible for the etiology of PWS. This gene is structurally similar to NDN, is also localized to the PWS chromosomal region, and is paternally imprinted, suggesting a possible role for it in PWS. [provided by RefSeq, Oct 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.311 OMIM phenotype

Clinical Summary— MAGEL2

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Gene-Disease Validity (ClinGen)

Schaaf-Yang syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.975

Z-score 3.75

OE 0.10 (0.04–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

-0.56Z-score

OE missense 1.08 (1.00–1.18)

399 obs / 368.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.10 (0.04–0.31)

0≤0.351.4

Missense OE?1.08 (1.00–1.18)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 2 / 20.2Missense obs/exp: 399 / 368.6Syn Z: -1.72

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMAGEL2-related Schaaf-Yang syndromeLOFAD

This gene — mechanism propensity

0.4190th %ile

GOF

0.3193th %ile

LOF

0.58top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.31

DN1 literature citation

Literature Evidence

DNThe concept that a deletion of the entire gene could have milder effects than a truncating mutation is intriguing. Because MAGEL2 is a one-exon gene, one could speculate that truncating mutations may result in a truncated protein, which then could have a dominant-negative effect.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References