Facial cleft

Summary

Facial cleft (MONDO:0015411) is a disease (an umbrella term covering 9 Mondo subtypes) with 2 cohort genes and 1 clinical trial.

At a glance

• Umbrella term: 9 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 2
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	facial cleft
Mondo ID	MONDO:0015411
Orphanet	141229
ICD-11	11389088
NCIT	C124510
SNOMED CT	92821006
UMLS	C0685787
MedGen	146898
GARD	0019964
Is cancer (heuristic)	no

Also known as: cleft face · craniofacial cleft

Data availability: 2 ClinVar variants.

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › facial cleft

Related subtypes (51): disorder of sexual differentiation, hereditary neurocutaneous angioma, nevoid basal cell carcinoma syndrome, angioosteohypertrophic syndrome, Larsen syndrome, schwannomatosis, linear nevus sebaceous syndrome, lethal Larsen-like syndrome, pseudodiastrophic dysplasia, focal dermal hypoplasia, microtia, neurofibromatosis-Noonan syndrome, Becker nevus syndrome, Legius syndrome, bone fragility with contractures, arterial rupture, and deafness, blindness - scoliosis - arachnodactyly syndrome, cutis laxa - Marfanoid syndrome, Maffucci syndrome, hydrops fetalis, ankyloblepharon filiforme-imperforate anus syndrome, developmental anomaly of metabolic origin, progeroid syndrome, Desbuquois dysplasia, cysts and fistulae of the face and oral cavity, macroglossia, middle ear anomaly, cleft palate, cutis laxa, infectious embryofetopathy, toxic or drug-related embryofetopathy, hemihyperplasia-multiple lipomatosis syndrome, phakomatosis pigmentokeratotica, phakomatosis pigmentovascularis, PTEN hamartoma tumor syndrome, marfanoid habitus-inguinal hernia-advanced bone age syndrome, neurofibromatosis type 1, multiple congenital anomalies/dysmorphic syndrome, congenital limb malformation, hereditary hemorrhagic telangiectasia, urogenital tract malformation, congenital anomaly of kidney and urinary tract, anotia, central nervous system malformation, Ehlers-Danlos syndrome, X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome, joint laxity, short stature, and myopia, diaphragmatic malformation, abdominal wall malformation, port-wine nevi-mega cisterna magna-hydrocephalus syndrome, conjoined twins, TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations

Subtypes (9): bifid nose, commissural facial cleft, median cleft of the upper lip and maxilla, Tessier number 5 facial cleft, Tessier number 6 facial cleft, midline cervical cleft, coloboma of superior eyelid, coloboma of inferior eyelid, median cleft lip/mandibule

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

2 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1172668	NM_003079.5(SMARCE1):c.310T>C (p.Trp104Arg)	SMARCE1	Pathogenic	criteria provided, single submitter
1065336	NM_001374353.1(GLI2):c.3784C>T (p.His1262Tyr)	GLI2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMARCE1	Orphanet:1465	Coffin-Siris syndrome
SMARCE1	Orphanet:2495	Meningioma
SMARCE1	Orphanet:263662	Familial multiple meningioma
GLI2	Orphanet:220386	Semilobar holoprosencephaly
GLI2	Orphanet:280195	Septopreoptic holoprosencephaly
GLI2	Orphanet:280200	Microform holoprosencephaly
GLI2	Orphanet:420584	Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome
GLI2	Orphanet:93924	Lobar holoprosencephaly
GLI2	Orphanet:93925	Alobar holoprosencephaly
GLI2	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
GLI2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMARCE1	HGNC:11109	ENSG00000073584	Q969G3	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1	clinvar
GLI2	HGNC:4318	ENSG00000074047	P10070	Zinc finger protein GLI2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMARCE1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
GLI2	Zinc finger protein GLI2	Functions as a transcription regulator in the hedgehog (Hh) pathway.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMARCE1	Other/Unknown	no		HMG_box_dom, HMG_box_dom_sf
GLI2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
embryo	1
ganglionic eminence	1
germinal epithelium of ovary	1
tibia	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMARCE1	197	ubiquitous	marker	calcaneal tendon, embryo, ganglionic eminence
GLI2	211	ubiquitous	marker	tibia, germinal epithelium of ovary, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLI2	3,112
SMARCE1	2,977

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMARCE1	Q969G3	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GLI2	P10070	42.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX2 regulates chondrocyte maturation	1	1142.0×	0.015	GLI2
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	815.7×	0.015	GLI2
Formation of the canonical BAF (cBAF) complex	1	317.2×	0.016	SMARCE1
Formation of the polybromo-BAF (pBAF) complex	1	317.2×	0.016	SMARCE1
Formation of the embryonic stem cell BAF (esBAF) complex	1	300.5×	0.016	SMARCE1
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	228.4×	0.017	SMARCE1
Regulation of endogenous retroelements	1	184.2×	0.019	SMARCE1
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	150.3×	0.020	SMARCE1
Regulation of MITF-M-dependent genes involved in pigmentation	1	132.8×	0.020	SMARCE1
Degradation of GLI2 by the proteasome	1	112.0×	0.021	GLI2
MITF-M-dependent gene expression	1	90.6×	0.022	SMARCE1
Hedgehog ‘off’ state	1	89.2×	0.022	GLI2
Hedgehog ‘on’ state	1	79.3×	0.022	GLI2
RMTs methylate histone arginines	1	73.2×	0.022	SMARCE1
Transcriptional regulation by RUNX1	1	73.2×	0.022	SMARCE1
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	58.9×	0.025	SMARCE1
MITF-M-regulated melanocyte development	1	57.1×	0.025	SMARCE1
Chromatin organization	1	40.8×	0.032	SMARCE1
Chromatin modifying enzymes	1	36.1×	0.033	SMARCE1
Epigenetic regulation of gene expression	1	35.7×	0.033	SMARCE1
RNA Polymerase II Transcription	1	11.3×	0.099	SMARCE1
Gene expression (Transcription)	1	8.9×	0.119	SMARCE1
Generic Transcription Pathway	1	7.5×	0.134	SMARCE1
Developmental Biology	1	7.2×	0.134	SMARCE1

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
ventral midline development	1	2808.7×	0.005	GLI2
floor plate formation	1	2808.7×	0.005	GLI2
spinal cord ventral commissure morphogenesis	1	2808.7×	0.005	GLI2
hindgut morphogenesis	1	2106.5×	0.005	GLI2
tube development	1	2106.5×	0.005	GLI2
cerebellar cortex morphogenesis	1	1404.3×	0.006	GLI2
spinal cord dorsal/ventral patterning	1	1053.2×	0.006	GLI2
ventral spinal cord development	1	936.2×	0.006	GLI2
epidermal cell differentiation	1	842.6×	0.006	GLI2
positive regulation of T cell differentiation in thymus	1	766.0×	0.006	GLI2
hindbrain development	1	561.7×	0.008	GLI2
osteoblast development	1	495.6×	0.008	GLI2
embryonic digestive tract development	1	495.6×	0.008	GLI2
nucleosome disassembly	1	401.2×	0.008	SMARCE1
developmental growth	1	366.4×	0.008	GLI2
branching morphogenesis of an epithelial tube	1	366.4×	0.008	GLI2
regulation of G0 to G1 transition	1	337.0×	0.008	SMARCE1
proximal/distal pattern formation	1	324.1×	0.008	GLI2
pituitary gland development	1	324.1×	0.008	GLI2
mammary gland development	1	324.1×	0.008	GLI2
regulation of nucleotide-excision repair	1	300.9×	0.008	SMARCE1
positive regulation of DNA replication	1	290.6×	0.008	GLI2
regulation of mitotic metaphase/anaphase transition	1	247.8×	0.008	SMARCE1
hair follicle morphogenesis	1	247.8×	0.008	GLI2
pattern specification process	1	234.1×	0.008	GLI2
positive regulation of T cell differentiation	1	227.7×	0.008	SMARCE1
positive regulation of myoblast differentiation	1	183.2×	0.010	SMARCE1
positive regulation of stem cell population maintenance	1	172.0×	0.010	SMARCE1
positive regulation of double-strand break repair	1	172.0×	0.010	SMARCE1
regulation of G1/S transition of mitotic cell cycle	1	153.2×	0.010	SMARCE1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMARCE1	0	0
GLI2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SMARCE1	7	Binding:7
GLI2	6	Binding:6

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	SMARCE1, GLI2

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)
SMARCE1	7	—
GLI2	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04931056	Not specified	COMPLETED	A Post Market Clinical Follow-up Study on Biomet Microfixation HTR PEKK (Midface), Facial & Mandibular Plates.