Short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome

Summary

Short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome (MONDO:0011227) is a disease caused by GSC (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GSC (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome
Mondo ID	MONDO:0011227
MeSH	C566544
OMIM	602471
Orphanet	397623
SNOMED CT	417081007
UMLS	C1865361
MedGen	355971
GARD	0017633
Is cancer (heuristic)	no

Also known as: SAMS · SAMS syndrome · short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities · short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities

Data availability: 5 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome

Related subtypes (47): symphalangism, cartilage cancer, vertebral column disorder, patellar tendinitis, necrosis of ear ossicle, laryngeal cartilage cancer, ochronosis disorder, chondroma, periodontal disorder, posterior cranial fossa meningioma, anterior cranial fossa meningioma, middle cranial fossa meningioma, bone marrow disorder, cranial nodular fasciitis, flatfoot, bone disorder, skeletal tuberculosis, arthropathy, tooth disorder, primary basilar invagination, Brachymorphism-onychodysplasia-dysphalangism syndrome, cherubism, fibrodysplasia ossificans progressiva, Marfan syndrome, Buschke-Ollendorff syndrome, scalp defects-postaxial polydactyly syndrome, cartilage-hair hypoplasia, Teebi-Shaltout syndrome, ossification of the posterior longitudinal ligament of the spine, temtamy preaxial brachydactyly syndrome, metaphyseal undermodeling, spondylar dysplasia, and overgrowth, Al-Gazali syndrome, brachydactyly-syndactyly syndrome, endocrine-cerebro-osteodysplasia syndrome, metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, multiple congenital anomalies-hypotonia-seizures syndrome 3, Rienhoff syndrome, Coffin-Siris syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, cartilage development disorder, syndactyly, polydactyly, brachydactyly, sternal neoplasm, short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis, skeletal ligament disorder, brachydactyly-syndactyly-oligodactyly syndrome

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

5 retrieved; paginated sample, class counts are floors:

3 pathogenic, 1 benign, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
126522	NM_173849.3(GSC):c.196_212del (p.Gly66fs)	GSC	Pathogenic	no assertion criteria provided
126523	NM_173849.3(GSC):c.400C>T (p.Gln134Ter)	GSC	Pathogenic	no assertion criteria provided
126524	NM_173849.3(GSC):c.355+1G>C	GSC	Pathogenic	no assertion criteria provided
1699356	NM_173849.3(GSC):c.256G>C (p.Gly86Arg)	GSC	Uncertain significance	criteria provided, single submitter
1285309	NM_173849.3(GSC):c.108G>A (p.Pro36=)	GSC	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
GSC	Strong	Autosomal recessive	short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GSC	Orphanet:397623	Short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome

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
GSC	HGNC:4612	ENSG00000133937	P56915	Homeobox protein goosecoid	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GSC	Homeobox protein goosecoid	Regulates chordin (CHRD).

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GSC	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

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
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GSC	98	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon, tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GSC	542

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GSC	P56915	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation	1	1142.0×	0.001	GSC
Formation of definitive endoderm	1	713.8×	0.001	GSC
Germ layer formation at gastrulation	1	671.8×	0.001	GSC

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
neural crest cell fate specification	1	5617.3×	0.002	GSC
muscle organ morphogenesis	1	1872.4×	0.003	GSC
dorsal/ventral neural tube patterning	1	802.5×	0.003	GSC
gastrulation	1	702.2×	0.003	GSC
signal transduction involved in regulation of gene expression	1	702.2×	0.003	GSC
middle ear morphogenesis	1	702.2×	0.003	GSC
embryonic skeletal system morphogenesis	1	391.9×	0.004	GSC
forebrain development	1	351.1×	0.004	GSC
negative regulation of Wnt signaling pathway	1	343.9×	0.004	GSC
Wnt signaling pathway	1	99.7×	0.011	GSC
regulation of transcription by RNA polymerase II	1	11.7×	0.086	GSC

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
GSC	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	GSC

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)
GSC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.