Schaaf-Yang syndrome

Summary

Schaaf-Yang syndrome (MONDO:0014243) is a disease caused by MAGEL2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MAGEL2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 162
• Phenotypes (HPO): 81

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		250	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

81 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000789	Infertility	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0001319	Neonatal hypotonia	Very frequent (80-99%)
HP:0001371	Flexion contracture	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002033	Poor suck	Very frequent (80-99%)
HP:0008947	Floppy infant	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0012758	Neurodevelopmental delay	Very frequent (80-99%)
HP:0000046	Small scrotum	Frequent (30-79%)
HP:0000060	Clitoral hypoplasia	Frequent (30-79%)
HP:0000064	Hypoplastic labia minora	Frequent (30-79%)
HP:0000135	Hypogonadism	Frequent (30-79%)
HP:0000478	Abnormality of the eye	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000786	Primary amenorrhea	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001558	Decreased fetal movement	Frequent (30-79%)
HP:0001612	Weak cry	Frequent (30-79%)
HP:0001773	Short foot	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002591	Polyphagia	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0003241	External genital hypoplasia	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004324	Increased body weight	Frequent (30-79%)
HP:0005968	Temperature instability	Frequent (30-79%)
HP:0006889	Intellectual disability, borderline	Frequent (30-79%)
HP:0008197	Absence of pubertal development	Frequent (30-79%)
HP:0008734	Decreased testicular size	Frequent (30-79%)
HP:0010535	Sleep apnea	Frequent (30-79%)
HP:0012166	Skin-picking	Frequent (30-79%)
HP:0012287	Hypothalamic luteinizing hormone-releasing hormone deficiency	Frequent (30-79%)
HP:0012450	Chronic constipation	Frequent (30-79%)
HP:0012506	Small pituitary gland	Frequent (30-79%)
HP:0012743	Abdominal obesity	Frequent (30-79%)
HP:0025160	Abnormal temper tantrums	Frequent (30-79%)
HP:0040288	Nasogastric tube feeding	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0200055	Small hand	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Schaaf-Yang syndrome
Mondo ID	MONDO:0014243
MeSH	C535385
OMIM	208080, 615547
Orphanet	398069
DOID	DOID:0111715
UMLS	C5575066
MedGen	1807366
GARD	0013316
Is cancer (heuristic)	no

Also known as: arthrogryposis, distal, with hypopituitarism, intellectual disability, and facial anomalies · arthrogryposis, distal, with hypopituitarism, mental retardation, and facial anomalies · Chitayat-Hall syndrome · distal arthrogryposis with hypopituitarism, intellectual disability and facial anomalies · Prader-Willi syndrome due to point mutation · PWS due to a point mutation · Schaaf-Yang syndrome · SHFYNG

Data availability: 162 ClinVar variants · 4 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Prader-Willi syndrome › Schaaf-Yang syndrome

Related subtypes (4): Prader-Willi syndrome due to translocation, Prader-Willi syndrome due to imprinting mutation, Prader-Willi syndrome due to maternal uniparental disomy of chromosome 15, Prader-Willi syndrome due to paternal 15q11q13 deletion

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

162 retrieved; paginated sample, class counts are floors:

83 uncertain significance, 24 likely pathogenic, 22 conflicting classifications of pathogenicity, 21 pathogenic, 6 pathogenic/likely pathogenic, 4 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065480	NM_019066.5(MAGEL2):c.277C>T (p.Pro93Ser)	MAGEL2	Pathogenic	criteria provided, single submitter
1320254	NM_019066.5(MAGEL2):c.2216del (p.Ser738_Ser739insTer)	MAGEL2	Pathogenic	criteria provided, single submitter
1687344	NM_019066.5(MAGEL2):c.2057G>A (p.Trp686Ter)	MAGEL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190122	NM_019066.5(MAGEL2):c.1996dup (p.Gln666fs)	MAGEL2	Pathogenic	criteria provided, multiple submitters, no conflicts
208684	NM_019066.5(MAGEL2):c.1912C>T (p.Gln638Ter)	MAGEL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224132	NM_019066.5(MAGEL2):c.3208G>T (p.Glu1070Ter)	MAGEL2	Pathogenic	criteria provided, single submitter
2499594	NM_019066.5(MAGEL2):c.2895G>A (p.Trp965Ter)	MAGEL2	Pathogenic	criteria provided, single submitter
265643	NM_019066.5(MAGEL2):c.1996C>T (p.Gln666Ter)	MAGEL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3777152	NM_019066.5(MAGEL2):c.3050T>A (p.Leu1017Ter)	MAGEL2	Pathogenic	criteria provided, single submitter
403667	NM_019066.5(MAGEL2):c.2958del (p.Ser987fs)	MAGEL2	Pathogenic	criteria provided, single submitter
440463	NM_019066.5(MAGEL2):c.1996del (p.Gln666fs)	MAGEL2	Pathogenic	criteria provided, multiple submitters, no conflicts
440464	NM_019066.5(MAGEL2):c.2118del (p.Leu708fs)	MAGEL2	Pathogenic	no assertion criteria provided
440466	NM_019066.5(MAGEL2):c.1621C>T (p.Gln541Ter)	MAGEL2	Pathogenic	criteria provided, single submitter
4819080	NM_019066.5(MAGEL2):c.1861_1862del (p.Lys621fs)	MAGEL2	Pathogenic	criteria provided, single submitter
548682	NM_019066.5(MAGEL2):c.1761G>A (p.Trp587Ter)	MAGEL2	Pathogenic	criteria provided, single submitter
548683	NM_019066.5(MAGEL2):c.1762C>T (p.Gln588Ter)	MAGEL2	Pathogenic	no assertion criteria provided
692038	NM_019066.5(MAGEL2):c.188dup (p.Ala64fs)	MAGEL2	Pathogenic	criteria provided, single submitter
803054	NM_019066.5(MAGEL2):c.2199del (p.Glu734fs)	MAGEL2	Pathogenic	criteria provided, single submitter
870506	NM_019066.5(MAGEL2):c.1613C>A (p.Ala538Glu)	MAGEL2	Pathogenic	no assertion criteria provided
89000	NM_019066.5(MAGEL2):c.1652del (p.Val551fs)	MAGEL2	Pathogenic	no assertion criteria provided
89001	NM_019066.5(MAGEL2):c.1802del (p.Pro601fs)	MAGEL2	Pathogenic	criteria provided, single submitter
89002	NM_019066.5(MAGEL2):c.3181_3182del (p.Ile1061fs)	MAGEL2	Pathogenic	criteria provided, single submitter
89003	NM_019066.5(MAGEL2):c.3124C>T (p.Gln1042Ter)	MAGEL2	Pathogenic	criteria provided, multiple submitters, no conflicts
973031	NM_019066.5(MAGEL2):c.1601del (p.Pro534fs)	MAGEL2	Pathogenic	criteria provided, single submitter
974880	NM_019066.5(MAGEL2):c.1808C>G (p.Ser603Ter)	MAGEL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
981450	NM_019066.5(MAGEL2):c.1930C>T (p.Gln644Ter)	MAGEL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
986880	NM_019066.5(MAGEL2):c.2847_2883del (p.Ser950fs)	MAGEL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1098308	NM_019066.5(MAGEL2):c.3583del (p.Met1195fs)	MAGEL2	Likely pathogenic	criteria provided, single submitter
1098309	NM_019066.5(MAGEL2):c.1015C>T (p.Gln339Ter)	MAGEL2	Likely pathogenic	criteria provided, single submitter
1098310	NM_019066.5(MAGEL2):c.648del (p.Thr217fs)	MAGEL2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MAGEL2	Definitive	Autosomal dominant	Schaaf-Yang syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAGEL2	Orphanet:177901	Prader-Willi syndrome due to paternal deletion of 15q11q13 type 1
MAGEL2	Orphanet:177904	Prader-Willi syndrome due to paternal deletion of 15q11q13 type 2
MAGEL2	Orphanet:177910	Prader-Willi syndrome due to imprinting mutation
MAGEL2	Orphanet:398069	Schaaf-Yang syndrome
MAGEL2	Orphanet:98754	Prader-Willi syndrome due to maternal uniparental disomy of chromosome 15
MAGEL2	Orphanet:994	Fetal akinesia deformation sequence

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MAGEL2	HGNC:6814	ENSG00000254585	Q9UJ55	MAGE-like protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAGEL2	MAGE-like protein 2	Probably enhances ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases, possibly through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MAGEL2	Other/Unknown	no		MHD_dom, MAGE, MAGE_WH1

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAGEL2	132	broad	marker	adrenal tissue, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAGEL2	908

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAGEL2	Q9UJ55	44.28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of actin nucleation	1	3370.4×	0.002	MAGEL2
Arp2/3 complex-mediated actin nucleation	1	1053.2×	0.004	MAGEL2
protein K63-linked ubiquitination	1	267.5×	0.006	MAGEL2
regulation of circadian rhythm	1	259.3×	0.006	MAGEL2
rhythmic process	1	251.5×	0.006	MAGEL2
retrograde transport, endosome to Golgi	1	205.5×	0.006	MAGEL2
negative regulation of DNA-templated transcription	1	31.6×	0.036	MAGEL2
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	MAGEL2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAGEL2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MAGEL2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MAGEL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.