Acromelic frontonasal dysostosis

Summary

Acromelic frontonasal dysostosis (MONDO:0011359) is a disease caused by ZSWIM6 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ZSWIM6 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 27
• Phenotypes (HPO): 37

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		22	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0000239	Large fontanelles	Very frequent (80-99%)
HP:0000248	Brachycephaly	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000455	Broad nasal tip	Very frequent (80-99%)
HP:0000456	Bifid nasal tip	Very frequent (80-99%)
HP:0000506	Telecanthus	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001274	Agenesis of corpus callosum	Very frequent (80-99%)
HP:0001762	Talipes equinovarus	Very frequent (80-99%)
HP:0001841	Preaxial foot polydactyly	Very frequent (80-99%)
HP:0002056	Abnormality of the glabella	Very frequent (80-99%)
HP:0002084	Encephalocele	Very frequent (80-99%)
HP:0002435	Meningocele	Very frequent (80-99%)
HP:0006866	Midline central nervous system lipomas	Very frequent (80-99%)
HP:0008388	Abnormal toenail morphology	Very frequent (80-99%)
HP:0009099	Median cleft palate	Very frequent (80-99%)
HP:0009928	Thick nasal alae	Very frequent (80-99%)
HP:0011803	Bifid nose	Very frequent (80-99%)
HP:0000161	Median cleft lip	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002190	Choroid plexus cyst	Frequent (30-79%)
HP:0040326	Hypoplasia of the olfactory bulb	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000154	Wide mouth	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0002690	Large sella turcica	Occasional (5-29%)
HP:0002781	Upper airway obstruction	Occasional (5-29%)
HP:0003065	Patellar hypoplasia	Occasional (5-29%)
HP:0005772	Aplasia/Hypoplasia of the tibia	Occasional (5-29%)
HP:0006951	Retrocerebellar cyst	Occasional (5-29%)
HP:0010627	Anterior pituitary hypoplasia	Occasional (5-29%)
HP:0040075	Hypopituitarism	Occasional (5-29%)
HP:0000501	Glaucoma	Very rare (<1-4%)
HP:0025247	Dermoid cyst	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acromelic frontonasal dysostosis
Mondo ID	MONDO:0011359
MeSH	C566345
OMIM	603671
Orphanet	1827
DOID	DOID:0060342
SNOMED CT	715427008
UMLS	C1863616
MedGen	350933
GARD	0005539
Is cancer (heuristic)	no

Also known as: acromelic frontonasal dysostosis · AFND · frontonasal dysplasia acromelic · Toriello syndrome

Data availability: 27 ClinVar variants · 4 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 › acromelic frontonasal dysostosis

Related subtypes (8): frontorhiny, Pai syndrome, frontofacionasal dysplasia, oculoauriculofrontonasal syndrome, 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

27 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 6 conflicting classifications of pathogenicity, 3 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
155772	NM_020928.2(ZSWIM6):c.3487C>T (p.Arg1163Trp)	ZSWIM6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1176044	NM_020928.2(ZSWIM6):c.29C>A (p.Pro10His)	ZSWIM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1389671	NM_020928.2(ZSWIM6):c.1867A>G (p.Thr623Ala)	ZSWIM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1441542	NM_020928.2(ZSWIM6):c.2372G>A (p.Arg791Lys)	ZSWIM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1469970	NM_020928.2(ZSWIM6):c.1781A>G (p.Asn594Ser)	ZSWIM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1641320	NM_020928.2(ZSWIM6):c.121G>A (p.Ala41Thr)	ZSWIM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
931663	NM_020928.2(ZSWIM6):c.151GCG[7] (p.Ala56dup)	ZSWIM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3892947	NC_000001.11:g.60162591ACA[1]		Uncertain significance	criteria provided, single submitter
3892948	NC_000001.11:g.60162926_60162927del		Uncertain significance	criteria provided, single submitter
3892949	NC_000001.11:g.60162929_60162932del		Uncertain significance	criteria provided, single submitter
1029795	NM_020928.2(ZSWIM6):c.2281C>T (p.Arg761Trp)	ZSWIM6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033558	NM_020928.2(ZSWIM6):c.1991T>C (p.Met664Thr)	ZSWIM6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033559	NM_020928.2(ZSWIM6):c.683A>G (p.His228Arg)	ZSWIM6	Uncertain significance	criteria provided, single submitter
1472897	NM_020928.2(ZSWIM6):c.79_96dup (p.Ser27_Gly32dup)	ZSWIM6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1489110	NM_020928.2(ZSWIM6):c.31G>A (p.Ala11Thr)	ZSWIM6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1490982	NM_020928.2(ZSWIM6):c.13G>A (p.Gly5Arg)	ZSWIM6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1806114	NM_020928.2(ZSWIM6):c.2248G>A (p.Gly750Arg)	ZSWIM6	Uncertain significance	criteria provided, multiple submitters, no conflicts
2444153	NM_020928.2(ZSWIM6):c.1760G>C (p.Arg587Thr)	ZSWIM6	Uncertain significance	criteria provided, multiple submitters, no conflicts
3068050	NM_020928.2(ZSWIM6):c.3407C>A (p.Ala1136Asp)	ZSWIM6	Uncertain significance	criteria provided, single submitter
3393274	NM_020928.2(ZSWIM6):c.2824A>G (p.Thr942Ala)	ZSWIM6	Uncertain significance	criteria provided, single submitter
3592738	NM_020928.2(ZSWIM6):c.323G>A (p.Arg108His)	ZSWIM6	Uncertain significance	criteria provided, single submitter
3768971	NM_020928.2(ZSWIM6):c.3466C>T (p.Arg1156Trp)	ZSWIM6	Uncertain significance	criteria provided, multiple submitters, no conflicts
548607	NM_020928.2(ZSWIM6):c.440_454del (p.Ala147_Gly151del)	ZSWIM6	Uncertain significance	criteria provided, single submitter
1049368	NM_020928.2(ZSWIM6):c.1472A>G (p.Asn491Ser)	ZSWIM6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1636238	NM_020928.2(ZSWIM6):c.498A>G (p.Ala166=)	ZSWIM6	Likely benign	criteria provided, multiple submitters, no conflicts
585031	NM_020928.2(ZSWIM6):c.1906G>A (p.Val636Met)	ZSWIM6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
789474	NM_020928.2(ZSWIM6):c.1722C>T (p.Asp574=)	ZSWIM6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
ZSWIM6	Strong	Autosomal dominant	acromelic frontonasal dysostosis	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZSWIM6	Orphanet:1827	Acromelic frontonasal dysplasia

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
ZSWIM6	HGNC:29316	ENSG00000130449	Q9HCJ5	Zinc finger SWIM domain-containing protein 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZSWIM6	Zinc finger SWIM domain-containing protein 6	involved in nervous system development, important for striatal morphology and motor regulation.

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)
ZSWIM6	Transcription factor	no		Znf_SWIM, ZSWIM4-8_C

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
cauda epididymis	1
oviduct epithelium	1
subthalamic nucleus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZSWIM6	251	ubiquitous	marker	oviduct epithelium, cauda epididymis, subthalamic nucleus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZSWIM6	565

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZSWIM6	Q9HCJ5	79.99

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
striatal medium spiny neuron differentiation	1	4213.0×	2e-04	ZSWIM6

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
ZSWIM6	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	ZSWIM6

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)
ZSWIM6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.