Solitary median maxillary central incisor syndrome

Summary

Solitary median maxillary central incisor syndrome (MONDO:0007819) is a disease caused by SHH (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: SHH (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 37

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	solitary median maxillary central incisor syndrome
Mondo ID	MONDO:0007819
MeSH	C537342
OMIM	147250
Orphanet	2286
ICD-11	1834868112
SNOMED CT	707609006
UMLS	C1840235
MedGen	326686
GARD	0004877
Is cancer (heuristic)	no

Also known as: incisors fused · single median maxillary central incisor · single upper central incisor · SMMCI · solitary MEDIAN maxillary central incisor · solitary median maxillary central incisor syndrome

Data availability: 37 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › holoprosencephaly › holoprosencephaly 3 › solitary median maxillary central incisor 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

37 retrieved; paginated sample, class counts are floors:

16 likely pathogenic, 8 uncertain significance, 5 pathogenic, 3 benign/likely benign, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3358962	NM_000193.4(SHH):c.37del (p.Val13fs)	SHH	Pathogenic	criteria provided, single submitter
3775131	NM_000193.4(SHH):c.211del (p.Glu71fs)	SHH	Pathogenic	criteria provided, single submitter
3775132	NM_000193.4(SHH):c.87del (p.Phe30fs)	SHH	Pathogenic	criteria provided, single submitter
430482	NM_000193.4(SHH):c.592T>C (p.Cys198Arg)	SHH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545575	NM_000193.4(SHH):c.1040C>T (p.Pro347Leu)	SHH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8890	NM_000193.4(SHH):c.331A>T (p.Ile111Phe)	SHH	Pathogenic	no assertion criteria provided
8895	NM_000193.4(SHH):c.383G>A (p.Trp128Ter)	SHH	Pathogenic	criteria provided, single submitter
2636187	NM_000193.4(SHH):c.592T>A (p.Cys198Ser)	SHH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3062081	NM_000193.4(SHH):c.812T>C (p.Leu271Pro)	SHH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775121	NM_000193.4(SHH):c.527_535del (p.Glu176_Lys178del)	SHH	Likely pathogenic	criteria provided, single submitter
3775122	NM_000193.4(SHH):c.329C>A (p.Ala110Asp)	SHH	Likely pathogenic	criteria provided, single submitter
3775123	NM_000193.4(SHH):c.428G>A (p.Gly143Asp)	SHH	Likely pathogenic	criteria provided, single submitter
3775124	NM_000193.4(SHH):c.554T>C (p.Val185Ala)	SHH	Likely pathogenic	criteria provided, single submitter
3775125	NM_000193.4(SHH):c.154G>A (p.Ala52Thr)	SHH	Likely pathogenic	criteria provided, single submitter
3775126	NM_000193.4(SHH):c.157G>A (p.Glu53Lys)	SHH	Likely pathogenic	criteria provided, single submitter
3775127	NM_000193.4(SHH):c.431G>T (p.Arg144Leu)	SHH	Likely pathogenic	criteria provided, single submitter
3775128	NM_000193.4(SHH):c.551C>T (p.Ser184Leu)	SHH	Likely pathogenic	criteria provided, single submitter
3775133	NM_000193.4(SHH):c.18A>T (p.Arg6Ser)	SHH	Likely pathogenic	criteria provided, single submitter
3775141	NM_000193.4(SHH):c.1142G>C (p.Arg381Pro)	SHH	Likely pathogenic	criteria provided, single submitter
3775145	NM_000193.4(SHH):c.602G>A (p.Gly201Asp)	SHH	Likely pathogenic	criteria provided, single submitter
3775153	NM_000193.4(SHH):c.701T>C (p.Leu234Pro)	SHH	Likely pathogenic	criteria provided, single submitter
3775155	NM_000193.4(SHH):c.980T>C (p.Leu327Pro)	SHH	Likely pathogenic	criteria provided, single submitter
8894	NM_000193.4(SHH):c.995T>C (p.Val332Ala)	SHH	Likely pathogenic	criteria provided, single submitter
2631808	NM_000193.4(SHH):c.698T>G (p.Leu233Arg)	SHH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3161689	NM_000193.4(SHH):c.587G>A (p.Gly196Glu)	SHH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4280089	NM_003041.4(SLC5A2):c.1804C>A (p.Pro602Thr)	RUSF1	Uncertain significance	criteria provided, single submitter
1362086	NM_000193.4(SHH):c.1178C>G (p.Ala393Gly)	SHH	Uncertain significance	criteria provided, multiple submitters, no conflicts
3374719	NM_000193.4(SHH):c.241A>T (p.Asn81Tyr)	SHH	Uncertain significance	criteria provided, single submitter
3594442	NM_000193.4(SHH):c.887G>C (p.Gly296Ala)	SHH	Uncertain significance	criteria provided, single submitter
3892432	NM_000193.4(SHH):c.19T>G (p.Cys7Gly)	SHH	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 20 · 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
SHH	Definitive	Autosomal dominant	solitary median maxillary central incisor syndrome	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SHH	Orphanet:220386	Semilobar holoprosencephaly
SHH	Orphanet:280195	Septopreoptic holoprosencephaly
SHH	Orphanet:280200	Microform holoprosencephaly
SHH	Orphanet:476119	Autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome
SHH	Orphanet:485275	Acquired schizencephaly
SHH	Orphanet:93321	Isolated radial hemimelia
SHH	Orphanet:93336	Polydactyly of a triphalangeal thumb
SHH	Orphanet:93405	Syndactyly type 4
SHH	Orphanet:93924	Lobar holoprosencephaly
SHH	Orphanet:93925	Alobar holoprosencephaly
SHH	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
SHH	Orphanet:988	Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome
SHH	Orphanet:98938	Colobomatous microphthalmia
SIX3	Orphanet:220386	Semilobar holoprosencephaly
SIX3	Orphanet:280195	Septopreoptic holoprosencephaly
SIX3	Orphanet:280200	Microform holoprosencephaly
SIX3	Orphanet:485275	Acquired schizencephaly
SIX3	Orphanet:93924	Lobar holoprosencephaly
SIX3	Orphanet:93925	Alobar holoprosencephaly
SIX3	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SHH	HGNC:10848	ENSG00000164690	Q15465	Sonic hedgehog protein	gencc,clinvar
SIX3	HGNC:10889	ENSG00000138083	O95343	Homeobox protein SIX3	clinvar
RUSF1	HGNC:25848	ENSG00000140688	Q96GQ5	RUS family member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SHH	Sonic hedgehog protein	The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity.
SIX3	Homeobox protein SIX3	Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SHH	Other/Unknown	no		Hedgehog_signalling_dom, Hedgehog, Hedgehog_Hint
SIX3	Transcription factor	no		HD, Homeodomain-like_sf, SIX1_SD
RUSF1	Other/Unknown	no		RUS_fam, UVB_sens_RUS_dom, UVB_sens_C

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
epithelial cell of pancreas	1
right lobe of liver	1
nasal cavity epithelium	1
pigmented layer of retina	1
retina	1
adenohypophysis	1
left ovary	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SHH	131	broad	marker	buccal mucosa cell, right lobe of liver, epithelial cell of pancreas
SIX3	92	broad	marker	pigmented layer of retina, retina, nasal cavity epithelium
RUSF1	260	ubiquitous	marker	adenohypophysis, left ovary, right ovary

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SHH	4,953
SIX3	1,536
RUSF1	765

Intra-cohort edges

A	B	Sources
SHH	SIX3	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SHH	Q15465	20

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RUSF1	Q96GQ5	85.65
SIX3	O95343	70.38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 3 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
HHAT G278V doesn’t palmitoylate Hh-Np	1	2284.0×	0.003	SHH
Formation of lateral plate mesoderm	1	2284.0×	0.003	SHH
Release of Hh-Np from the secreting cell	1	1427.5×	0.003	SHH
Hh mutants abrogate ligand secretion	1	1427.5×	0.003	SHH
Ligand-receptor interactions	1	1427.5×	0.003	SHH
Formation of axial mesoderm	1	815.7×	0.004	SHH
Activation of SMO	1	634.4×	0.005	SHH
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	601.0×	0.005	SHH
Developmental Lineage of Pancreatic Acinar Cells	1	300.5×	0.008	SHH
Gastrulation	1	259.6×	0.008	SHH
Hh mutants are degraded by ERAD	1	243.0×	0.008	SHH
Developmental Cell Lineages	1	223.9×	0.008	SHH
Hedgehog ligand biogenesis	1	211.5×	0.008	SHH
Class B/2 (Secretin family receptors)	1	190.3×	0.008	SHH
Signaling by Hedgehog	1	184.2×	0.008	SHH
Hedgehog ‘on’ state	1	158.6×	0.009	SHH
GPCR ligand binding	1	64.2×	0.020	SHH
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.022	SHH
Signaling by GPCR	1	40.1×	0.029	SHH
Developmental Biology	1	14.5×	0.076	SHH
Disease	1	13.1×	0.080	SHH
Signal Transduction	1	10.2×	0.098	SHH

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
telencephalon regionalization	2	2808.7×	2e-05	SHH, SIX3
thyroid gland development	2	543.6×	3e-04	SHH, SIX3
proximal/distal axis specification	1	8426.0×	0.001	SIX3
polarity specification of anterior/posterior axis	1	8426.0×	0.001	SHH
trachea morphogenesis	1	8426.0×	0.001	SHH
right lung development	1	8426.0×	0.001	SHH
left lung development	1	8426.0×	0.001	SHH
primary prostatic bud elongation	1	8426.0×	0.001	SHH
regulation of prostatic bud formation	1	8426.0×	0.001	SHH
obsolete regulation of mesenchymal cell proliferation involved in prostate gland development	1	8426.0×	0.001	SHH
mesenchymal smoothened signaling pathway involved in prostate gland development	1	8426.0×	0.001	SHH
positive regulation of sclerotome development	1	8426.0×	0.001	SHH
tracheoesophageal septum formation	1	8426.0×	0.001	SHH
negative regulation of ureter smooth muscle cell differentiation	1	8426.0×	0.001	SHH
positive regulation of ureter smooth muscle cell differentiation	1	8426.0×	0.001	SHH
negative regulation of kidney smooth muscle cell differentiation	1	8426.0×	0.001	SHH
positive regulation of kidney smooth muscle cell differentiation	1	8426.0×	0.001	SHH
protein import into nucleus	2	144.0×	0.001	SHH, SIX3
regulation of cell population proliferation	2	115.4×	0.001	SHH, SIX3
optic vesicle morphogenesis	1	4213.0×	0.002	SIX3
positive regulation of skeletal muscle cell proliferation	1	4213.0×	0.002	SHH
intein-mediated protein splicing	1	4213.0×	0.002	SHH
trunk neural crest cell migration	1	4213.0×	0.002	SHH
regulation of nodal signaling pathway	1	4213.0×	0.002	SHH
positive regulation of mesenchymal cell proliferation involved in ureter development	1	4213.0×	0.002	SHH
ventral midline development	1	2808.7×	0.002	SHH
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	2808.7×	0.002	SHH
negative regulation of alpha-beta T cell differentiation	1	2808.7×	0.002	SHH
regulation of glial cell proliferation	1	2808.7×	0.002	SHH
bud outgrowth involved in lung branching	1	2808.7×	0.002	SHH

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SHH	VISMODEGIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SHH	1	4
SIX3	0	0
RUSF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VISMODEGIB	4	SHH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SHH	27	Binding:23, Functional:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
VISMODEGIB	4	SHH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SHH
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	2	SIX3, RUSF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SIX3	0	SHH
RUSF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.