Teebi hypertelorism syndrome 1

Summary

Teebi hypertelorism syndrome 1 (MONDO:0800025) is a disease caused by SPECC1L (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SPECC1L (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 29
• Phenotypes (HPO): 39

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		25	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0000233	Thin vermilion border	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000426	Prominent nasal bridge	Very frequent (80-99%)
HP:0000574	Thick eyebrow	Very frequent (80-99%)
HP:0002553	Highly arched eyebrow	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000049	Shawl scrotum	Frequent (30-79%)
HP:0000232	Everted lower lip vermilion	Frequent (30-79%)
HP:0000311	Round face	Frequent (30-79%)
HP:0000349	Widow’s peak	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001537	Umbilical hernia	Frequent (30-79%)
HP:0001831	Short toe	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0004209	Clinodactyly of the 5th finger	Frequent (30-79%)
HP:0004467	Preauricular pit	Frequent (30-79%)
HP:0006101	Finger syndactyly	Frequent (30-79%)
HP:0011039	Abnormality of the helix	Frequent (30-79%)
HP:0011220	Prominent forehead	Frequent (30-79%)
HP:0000086	Ectopic kidney	Occasional (5-29%)
HP:0000202	Orofacial cleft	Occasional (5-29%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0001539	Omphalocele	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0001636	Tetralogy of Fallot	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0006288	Advanced eruption of teeth	Occasional (5-29%)
HP:0010458	Female pseudohermaphroditism	Occasional (5-29%)
HP:0010751	Chin dimple	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Teebi hypertelorism syndrome 1
Mondo ID	MONDO:0800025
OMIM	145420
Orphanet	1519
DOID	DOID:0080698
SNOMED CT	724284005
GARD	0000957
Is cancer (heuristic)	no

Also known as: Brachycephalofrontonasal dysplasia · craniofrontonasal dysplasia, Teebi type · hypertelorism, Teebi type · Teebi hypertelorism syndrome · Teebi syndrome

Data availability: 29 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › Teebi hypertelorism syndrome › Teebi hypertelorism syndrome 1

Related subtypes (1): Teebi hypertelorism syndrome 2

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

29 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 4 pathogenic, 3 conflicting classifications of pathogenicity, 3 benign/likely benign, 2 pathogenic/likely pathogenic, 1 likely pathogenic, 1 likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1676270	NM_015330.6(SPECC1L):c.1195C>G (p.Arg399Gly)	SPECC1L	Pathogenic	no assertion criteria provided
183671	NM_015330.6(SPECC1L):c.1189A>C (p.Thr397Pro)	SPECC1L	Pathogenic	criteria provided, single submitter
445948	NM_015330.6(SPECC1L):c.3293G>A (p.Arg1098Gln)	SPECC1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
561337	NM_015330.6(SPECC1L):c.1246G>A (p.Ala416Thr)	SPECC1L	Pathogenic	criteria provided, single submitter
561338	NM_015330.6(SPECC1L):c.1258G>A (p.Glu420Lys)	SPECC1L	Pathogenic	no assertion criteria provided
599382	NM_015330.6(SPECC1L):c.1249A>C (p.Thr417Pro)	SPECC1L	Pathogenic/Likely pathogenic	no assertion criteria provided
3256759	NM_015330.6(SPECC1L):c.200C>T (p.Thr67Met)	SPECC1L	Likely pathogenic	no assertion criteria provided
1316183	NM_015330.6(SPECC1L):c.1399C>T (p.Arg467Cys)	SPECC1L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
183672	NM_015330.6(SPECC1L):c.3247G>A (p.Gly1083Ser)	SPECC1L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2436280	NM_015330.6(SPECC1L):c.2801C>T (p.Ala934Val)	SPECC1L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1679678	NM_015330.6(SPECC1L):c.539C>G (p.Ala180Gly)	SPECC1L	Uncertain significance	criteria provided, multiple submitters, no conflicts
1684289	NM_015330.6(SPECC1L):c.3137_3139del (p.Phe1046del)	SPECC1L	Uncertain significance	criteria provided, single submitter
2664281	NM_015330.6(SPECC1L):c.578A>G (p.Lys193Arg)	SPECC1L	Uncertain significance	no assertion criteria provided
3066111	NM_015330.6(SPECC1L):c.3314T>G (p.Met1105Arg)	SPECC1L	Uncertain significance	criteria provided, single submitter
3168822	NM_015330.6(SPECC1L):c.2231C>T (p.Ala744Val)	SPECC1L	Uncertain significance	criteria provided, multiple submitters, no conflicts
3376317	NM_015330.6(SPECC1L):c.1187T>C (p.Leu396Pro)	SPECC1L	Uncertain significance	criteria provided, single submitter
3377302	NM_015330.6(SPECC1L):c.1030A>G (p.Asn344Asp)	SPECC1L	Uncertain significance	criteria provided, single submitter
3587860	NM_015330.6(SPECC1L):c.2206C>T (p.His736Tyr)	SPECC1L	Uncertain significance	criteria provided, single submitter
3587861	NM_015330.6(SPECC1L):c.2745G>T (p.Glu915Asp)	SPECC1L	Uncertain significance	criteria provided, single submitter
3892535	NM_015330.6(SPECC1L):c.523A>G (p.Ile175Val)	SPECC1L	Uncertain significance	criteria provided, single submitter
4277561	NM_015330.6(SPECC1L):c.2992A>G (p.Arg998Gly)	SPECC1L	Uncertain significance	criteria provided, single submitter
4531821	NM_015330.6(SPECC1L):c.574G>T (p.Ala192Ser)	SPECC1L	Uncertain significance	criteria provided, single submitter
4759502	NM_015330.6(SPECC1L):c.1547T>C (p.Leu516Ser)	SPECC1L	Uncertain significance	no assertion criteria provided
1708090	NM_015330.6(SPECC1L):c.1062del (p.Gln354fs)	SPECC1L-ADORA2A	Uncertain significance	criteria provided, single submitter
445410	NM_015330.6(SPECC1L):c.562C>T (p.Leu188Phe)	SPECC1L	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
712283	NM_015330.6(SPECC1L):c.1359C>T (p.Ser453=)	SPECC1L	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
731574	NM_015330.6(SPECC1L):c.153+5T>G	SPECC1L	Likely benign	criteria provided, multiple submitters, no conflicts
731859	NM_015330.6(SPECC1L):c.463C>T (p.Arg155Cys)	SPECC1L	Benign	criteria provided, multiple submitters, no conflicts
708645	NM_015330.6(SPECC1L):c.2149A>G (p.Thr717Ala)	SPECC1L-ADORA2A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
SPECC1L	Definitive	Autosomal dominant	hypertelorism, Teebi type	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPECC1L	Orphanet:141258	Tessier number 4 facial cleft
SPECC1L	Orphanet:141276	Tessier number 7 facial cleft
SPECC1L	Orphanet:1519	SPECC1L-related hypertelorism syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPECC1L	HGNC:29022	ENSG00000100014	Q69YQ0	Cytospin-A	gencc,clinvar
SPECC1L-ADORA2A	HGNC:49185	ENSG00000258555		SPECC1L-ADORA2A readthrough (NMD candidate)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPECC1L	Cytospin-A	Involved in cytokinesis and spindle organization.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPECC1L	Other/Unknown	no		CH_dom, CH_dom_sf, F-actin_Monoox_Mical
SPECC1L-ADORA2A	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
tendon	1
ganglionic eminence	1
smooth muscle tissue	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPECC1L	274	ubiquitous	marker	calcaneal tendon, tendon, male germ line stem cell (sensu Vertebrata) in testis
SPECC1L-ADORA2A	65	ubiquitous	yes	stromal cell of endometrium, smooth muscle tissue, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPECC1L	1,695
SPECC1L-ADORA2A	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SPECC1L	Q69YQ0	67.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 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
neural crest cell delamination	1	16852.0×	6e-04	SPECC1L
anterior neural tube closure	1	4213.0×	0.001	SPECC1L
negative regulation of actin filament depolymerization	1	2808.7×	0.001	SPECC1L
adherens junction organization	1	510.7×	0.004	SPECC1L
negative regulation of microtubule depolymerization	1	495.6×	0.004	SPECC1L
actin cytoskeleton organization	1	79.1×	0.018	SPECC1L
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	78.4×	0.018	SPECC1L
cell migration	1	61.5×	0.020	SPECC1L
cell division	1	46.2×	0.024	SPECC1L
cell adhesion	1	37.5×	0.027	SPECC1L

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SPECC1L	1	2
SPECC1L-ADORA2A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SPECC1L

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SPECC1L	6	Binding:6

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

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)
MOLIBRESIB	2	SPECC1L

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	1	SPECC1L
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SPECC1L-ADORA2A

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)
SPECC1L-ADORA2A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.