Frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome

Summary

Frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome (MONDO:0013271) is a disease caused by ALX1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ALX1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 7
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000327	Hypoplasia of the maxilla	Frequent (30-79%)
HP:0000349	Widow’s peak	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0000384	Preauricular skin tag	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Frequent (30-79%)
HP:0000430	Underdeveloped nasal alae	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000568	Microphthalmia	Frequent (30-79%)
HP:0000625	Eyelid coloboma	Frequent (30-79%)
HP:0000653	Sparse eyelashes	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001274	Agenesis of corpus callosum	Frequent (30-79%)
HP:0002006	Facial cleft	Frequent (30-79%)
HP:0005258	Pectoral muscle hypoplasia/aplasia	Frequent (30-79%)
HP:0005466	Hypoplasia of the frontal bone	Frequent (30-79%)
HP:0009119	Aplasia/Hypoplasia of the frontal sinuses	Frequent (30-79%)
HP:0011803	Bifid nose	Frequent (30-79%)
HP:0040019	Finger clinodactyly	Frequent (30-79%)
HP:0045075	Sparse eyebrow	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001636	Tetralogy of Fallot	Occasional (5-29%)
HP:0004423	Cranium bifidum occultum	Occasional (5-29%)
HP:0006931	Lipoma of corpus callosum	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome
Mondo ID	MONDO:0013271
OMIM	613456
Orphanet	306542
DOID	DOID:0081047
UMLS	C3150706
MedGen	462056
GARD	0012640
Is cancer (heuristic)	no

Also known as: ALX1-related frontonasal dysplasia · FND3 · frontonasal dysplasia 3 · frontonasal dysplasia type 3

Data availability: 7 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › frontonasal dysplasia › frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome

Related subtypes (8): frontorhiny, Pai syndrome, frontofacionasal dysplasia, oculoauriculofrontonasal syndrome, acromelic frontonasal dysostosis, frontonasal dysplasia with alopecia and genital anomaly, craniofrontonasal dysplasia-Poland anomaly syndrome, six2-related frontonasal dysplasia

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

7 retrieved; paginated sample, class counts are floors:

3 pathogenic, 1 likely pathogenic, 1 benign/likely benign, 1 uncertain significance, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3069063	NC_000012.11:g.(?85673997)(85695563_?)del	ALX1	Pathogenic	criteria provided, single submitter
8111	NM_006982.3(ALX1):c.531+1G>A	ALX1	Pathogenic	no assertion criteria provided
827658	NM_006982.3(ALX1):c.661-1G>C	ALX1	Pathogenic	no assertion criteria provided
2572390	NM_006982.3(ALX1):c.151C>T (p.Gln51Ter)	ALX1	Likely pathogenic	criteria provided, single submitter
3779432	NM_006982.3(ALX1):c.869C>T (p.Thr290Ile)	ALX1	Uncertain significance	criteria provided, single submitter
287469	NM_006982.3(ALX1):c.191G>T (p.Arg64Leu)	ALX1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
4795894	NM_006982.3(ALX1):c.689C>G (p.Ala230Gly)	ALX1	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
ALX1	Definitive	Autosomal recessive	frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALX1	Orphanet:306542	Frontonasal dysplasia-severe microphthalmia-severe facial clefting 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
ALX1	HGNC:1494	ENSG00000180318	Q15699	ALX homeobox protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALX1	ALX homeobox protein 1	Sequence-specific DNA-binding transcription factor that binds palindromic sequences within promoters and may activate or repress the transcription of a subset of genes.

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)
ALX1	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf

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
metanephros cortex	1
primordial germ cell in gonad	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALX1	86	broad	marker	primordial germ cell in gonad, metanephros cortex, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALX1	1,088

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALX1	Q15699	61.32

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
mesenchymal cell development	1	2407.4×	0.003	ALX1
stem cell development	1	2407.4×	0.003	ALX1
embryonic limb morphogenesis	1	401.2×	0.007	ALX1
embryonic skeletal system morphogenesis	1	391.9×	0.007	ALX1
positive regulation of epithelial to mesenchymal transition	1	318.0×	0.007	ALX1
neuron development	1	255.3×	0.007	ALX1
roof of mouth development	1	247.8×	0.007	ALX1
neural tube closure	1	187.2×	0.008	ALX1
anterior/posterior pattern specification	1	181.2×	0.008	ALX1
negative regulation of DNA-templated transcription	1	31.6×	0.041	ALX1
positive regulation of DNA-templated transcription	1	27.9×	0.042	ALX1
negative regulation of transcription by RNA polymerase II	1	17.7×	0.061	ALX1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	ALX1

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
ALX1	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	ALX1

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)
ALX1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.