Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis

Summary

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (MONDO:0008726) is a disease caused by POR (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: POR (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 63

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis
Mondo ID	MONDO:0008726
OMIM	201750
Orphanet	63269
NCIT	C178415
UMLS	C3150099
MedGen	461449
GARD	0016665
Is cancer (heuristic)	no

Also known as: ABS1 · Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis · Antley-Bixler syndrome with genital anomaly and disorder of steroidogenesis

Data availability: 63 ClinVar variants · 3 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 › autosomal genetic disease › autosomal recessive disease › craniosynostosis syndrome, autosomal recessive › Antley-Bixler syndrome › Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis

Related subtypes (1): Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

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

63 retrieved; paginated sample, class counts are floors:

15 likely pathogenic, 13 uncertain significance, 10 pathogenic/likely pathogenic, 10 pathogenic, 7 conflicting classifications of pathogenicity, 6 benign, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
16902	NM_001395413.1(POR):c.850G>C (p.Ala284Pro)	LOC126860075	Pathogenic	criteria provided, multiple submitters, no conflicts
1324955	NM_001395413.1(POR):c.1816C>T (p.Gln606Ter)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1405328	NM_001395413.1(POR):c.723-2A>T	POR	Pathogenic	criteria provided, multiple submitters, no conflicts
1454425	NM_001395413.1(POR):c.1837C>T (p.Arg613Ter)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16901	NM_001395413.1(POR):c.1466T>A (p.Val489Glu)	POR	Pathogenic	no assertion criteria provided
16905	NM_001395413.1(POR):c.722+1G>A	POR	Pathogenic	no assertion criteria provided
16907	NM_001395413.1(POR):c.1361G>A (p.Arg454His)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16910	NM_001395413.1(POR):c.1320dup (p.Ile441fs)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16911	NM_001395413.1(POR):c.1724A>G (p.Tyr575Cys)	POR	Pathogenic	no assertion criteria provided
16914	NM_001395413.1(POR):c.559_571dup (p.Arg191fs)	POR	Pathogenic	no assertion criteria provided
16915	NM_001395413.1(POR):c.1606G>A (p.Gly536Arg)	POR	Pathogenic	criteria provided, multiple submitters, no conflicts
1723238	NM_001395413.1(POR):c.821+1G>A	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1941965	NM_001395413.1(POR):c.768del (p.Lys257fs)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2715315	NM_001395413.1(POR):c.40G>T (p.Glu14Ter)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2851692	NM_001395413.1(POR):c.115del (p.Thr39fs)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2919493	NM_001395413.1(POR):c.735C>G (p.Tyr245Ter)	POR	Pathogenic	criteria provided, multiple submitters, no conflicts
3594771	NM_001395413.1(POR):c.1718dup (p.Tyr573Ter)	POR	Pathogenic	criteria provided, multiple submitters, no conflicts
632505	NM_001395413.1(POR):c.1354del (p.Gln452fs)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632506	NM_001395413.1(POR):c.1651C>T (p.Arg551Ter)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
691923	NM_001395413.1(POR):c.1434C>A (p.Tyr478Ter)	POR	Pathogenic	criteria provided, multiple submitters, no conflicts
1254698	NM_001395413.1(POR):c.1811A>G (p.Tyr604Cys)	POR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679929	NM_001395413.1(POR):c.1477T>C (p.Trp493Arg)	POR	Likely pathogenic	no assertion criteria provided
16912	NM_001395413.1(POR):c.1826_1849del (p.Leu609_Trp617delinsArg)	POR	Likely pathogenic	criteria provided, single submitter
2822770	NM_001395413.1(POR):c.1240-2A>G	POR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3339945	NM_001395413.1(POR):c.1685T>C (p.Leu562Pro)	POR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3594762	NM_001395413.1(POR):c.191_192del (p.Val64fs)	POR	Likely pathogenic	criteria provided, single submitter
3594763	NM_001395413.1(POR):c.671G>A (p.Trp224Ter)	POR	Likely pathogenic	criteria provided, single submitter
3594764	NM_001395413.1(POR):c.723-1G>T	POR	Likely pathogenic	criteria provided, single submitter
3594765	NM_001395413.1(POR):c.808dup (p.Glu270fs)	POR	Likely pathogenic	criteria provided, single submitter
3594766	NM_001395413.1(POR):c.880C>T (p.Gln294Ter)	POR	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 4 · 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
POR	Definitive	Autosomal recessive	Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis	7
PORCN	Definitive	Autosomal recessive	Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PORCN	Orphanet:2092	Focal dermal hypoplasia
PORCN	Orphanet:98938	Colobomatous microphthalmia
POR	Orphanet:63269	Antley-Bixler syndrome with genital anomaly and disorder of steroidogenesis
POR	Orphanet:95699	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

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
PORCN	HGNC:17652	ENSG00000102312	Q9H237	Protein-serine O-palmitoleoyltransferase porcupine	gencc,clinvar
POR	HGNC:9208	ENSG00000127948	P16435	NADPH–cytochrome P450 reductase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PORCN	Protein-serine O-palmitoleoyltransferase porcupine	Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1(9Z)), to Wnt proteins.
POR	NADPH–cytochrome P450 reductase	This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PORCN	Enzyme (other)	yes	2.3.1.250	MBOAT_fam, LPLAT_7/PORCN-like
POR	Enzyme (other)	yes	1.6.2.4	Flavdoxin-like, OxRdtase_FAD/NAD-bd, Flavoprot_Pyr_Nucl_cyt_Rdtase

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
right adrenal gland	2
lower esophagus mucosa	1
right adrenal gland cortex	1
adrenal tissue	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PORCN	184	ubiquitous	marker	lower esophagus mucosa, right adrenal gland cortex, right adrenal gland
POR	266	ubiquitous	marker	adrenal tissue, right lobe of liver, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POR	2,263
PORCN	802

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POR	P16435	9
PORCN	Q9H237	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
LGK974 inhibits PORCN	1	2855.0×	0.002	PORCN
Cytochrome P450 - arranged by substrate type	1	356.9×	0.008	POR
WNT ligand biogenesis and trafficking	1	211.5×	0.009	PORCN
Phase I - Functionalization of compounds	1	109.8×	0.014	POR
Biological oxidations	1	64.9×	0.018	POR
Metabolism	1	5.8×	0.165	POR

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
nitrate catabolic process	1	8426.0×	0.001	POR
positive regulation of growth plate cartilage chondrocyte proliferation	1	8426.0×	0.001	POR
positive regulation of steroid hormone biosynthetic process	1	8426.0×	0.001	POR
protein palmitoleylation	1	4213.0×	0.001	PORCN
nitric oxide catabolic process	1	4213.0×	0.001	POR
organofluorine metabolic process	1	4213.0×	0.001	POR
Wnt protein secretion	1	2808.7×	0.001	PORCN
P450-containing electron transport chain	1	2808.7×	0.001	POR
demethylation	1	2106.5×	0.001	POR
protein lipidation	1	1685.2×	0.002	PORCN
carnitine metabolic process	1	1203.7×	0.002	POR
flavonoid metabolic process	1	1053.2×	0.002	POR
lipid modification	1	936.2×	0.002	PORCN
electron transport chain	1	766.0×	0.003	POR
cellular response to follicle-stimulating hormone stimulus	1	702.2×	0.003	POR
response to dexamethasone	1	601.9×	0.003	POR
glycoprotein metabolic process	1	561.7×	0.003	PORCN
fatty acid oxidation	1	526.6×	0.003	POR
cellular response to peptide hormone stimulus	1	421.3×	0.003	POR
positive regulation of chondrocyte differentiation	1	401.2×	0.003	POR
nitric oxide biosynthetic process	1	351.1×	0.004	POR
regulation of postsynaptic membrane neurotransmitter receptor levels	1	247.8×	0.005	PORCN
response to hormone	1	216.1×	0.006	POR
positive regulation of smoothened signaling pathway	1	210.7×	0.006	POR
response to nutrient	1	147.8×	0.008	POR
Wnt signaling pathway	1	49.9×	0.021	PORCN
response to xenobiotic stimulus	1	34.5×	0.030	POR
negative regulation of apoptotic process	1	17.4×	0.057	POR

Therapeutics

Drug target analysis

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

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
PORCN	2	2
POR	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
WNT-974	2	PORCN
LAPACHONE	2	POR
ETC-159	1	PORCN

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PORCN	31	Binding:31
POR	21	ADMET:14, Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PORCN	2.3.1.250	[Wnt protein] O-palmitoleoyl transferase
POR	1.6.2.4	NADPH-hemoprotein reductase

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

3 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)
WNT-974	2	PORCN
LAPACHONE	2	POR
ETC-159	1	PORCN

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	2	PORCN, POR
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.