Frontorhiny

Summary

Frontorhiny (MONDO:0007636) is a disease caused by ALX3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: ALX3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 13
• Phenotypes (HPO): 29

Clinical features

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:0000486	Strabismus	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000568	Microphthalmia	Frequent (30-79%)
HP:0000612	Iris coloboma	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0002084	Encephalocele	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002738	Hypoplastic frontal sinuses	Frequent (30-79%)
HP:0002938	Lumbar hyperlordosis	Frequent (30-79%)
HP:0004112	Midline nasal groove	Frequent (30-79%)
HP:0004423	Cranium bifidum occultum	Frequent (30-79%)
HP:0006931	Lipoma of corpus callosum	Frequent (30-79%)
HP:0007370	Aplasia/Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0008591	Congenital conductive hearing impairment	Frequent (30-79%)
HP:0010297	Bifid tongue	Frequent (30-79%)
HP:0011817	Basal encephalocele	Frequent (30-79%)
HP:0025247	Dermoid cyst	Frequent (30-79%)
HP:0040019	Finger clinodactyly	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0000873	Diabetes insipidus	Occasional (5-29%)
HP:0040075	Hypopituitarism	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	frontorhiny
Mondo ID	MONDO:0007636
OMIM	136760
Orphanet	391474
DOID	DOID:0081045
NCIT	C129028
UMLS	C5574965
MedGen	1803615
GARD	0012642
Is cancer (heuristic)	no

Also known as: ALX3-related frontonasal dysplasia · FND1 · frontonasal dysplasia 1 · frontonasal dysplasia type 1 · frontorhiny · isolated median cleft face syndrome · isolated median cleft syndrome

Data availability: 13 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › frontonasal dysplasia › frontorhiny

Related subtypes (8): Pai syndrome, frontofacionasal dysplasia, oculoauriculofrontonasal syndrome, acromelic frontonasal dysostosis, frontonasal dysplasia with alopecia and genital anomaly, frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome, 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

13 retrieved; paginated sample, class counts are floors:

9 pathogenic, 1 benign, 1 conflicting classifications of pathogenicity, 1 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3069203	NM_006492.3(ALX3):c.364C>T (p.Gln122Ter)	ALX3	Pathogenic	criteria provided, single submitter
3775899	NM_006492.3(ALX3):c.553C>T (p.Gln185Ter)	ALX3	Pathogenic	criteria provided, single submitter
3777753	ALX3, GLN202TER	ALX3	Pathogenic	no assertion criteria provided
4642	NM_006492.3(ALX3):c.595-2A>T	ALX3	Pathogenic	no assertion criteria provided
4643	NM_006492.3(ALX3):c.608A>G (p.Asn203Ser)	ALX3	Pathogenic	no assertion criteria provided
4644	NM_006492.3(ALX3):c.502C>G (p.Leu168Val)	ALX3	Pathogenic	no assertion criteria provided
4646	NM_006492.3(ALX3):c.543T>A (p.Tyr181Ter)	ALX3	Pathogenic	no assertion criteria provided
4647	NM_006492.3(ALX3):c.578_581del (p.Thr193fs)	ALX3	Pathogenic	no assertion criteria provided
4648	NM_006492.3(ALX3):c.586C>T (p.Arg196Trp)	ALX3	Pathogenic	no assertion criteria provided
559851	NM_006492.3(ALX3):c.736_737del (p.Leu246fs)	ALX3	Likely pathogenic	criteria provided, single submitter
2569172	NM_006492.3(ALX3):c.662G>A (p.Arg221Gln)	ALX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4645	NM_006492.3(ALX3):c.547C>T (p.Arg183Trp)	ALX3	Uncertain significance	criteria provided, single submitter
1188875	NM_006492.3(ALX3):c.277+33C>T	ALX3	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
ALX3	Definitive	Autosomal recessive	frontorhiny	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALX3	Orphanet:391474	Frontorhiny

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
ALX3	HGNC:449	ENSG00000156150	O95076	Homeobox protein aristaless-like 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALX3	Homeobox protein aristaless-like 3	Transcriptional regulator with a possible role in patterning of mesoderm during development.

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)
ALX3	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

Expression context

Cohort genes with no expression data: 0.

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
male germ line stem cell (sensu Vertebrata) in testis	1
olfactory bulb	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALX3	68	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, olfactory bulb, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALX3	1,262

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALX3	O95076	62.90

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
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.013	ALX3
MITF-M-regulated melanocyte development	1	114.2×	0.013	ALX3
Developmental Biology	1	14.5×	0.069	ALX3

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
embryonic hindlimb morphogenesis	1	581.1×	0.004	ALX3
embryonic forelimb morphogenesis	1	495.6×	0.004	ALX3
pattern specification process	1	468.1×	0.004	ALX3
embryonic skeletal system morphogenesis	1	391.9×	0.004	ALX3
neuron development	1	255.3×	0.005	ALX3
regulation of apoptotic process	1	83.4×	0.014	ALX3
regulation of transcription by RNA polymerase II	1	11.7×	0.086	ALX3

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
ALX3	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	ALX3

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)
ALX3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.