ANE syndrome

Summary

ANE syndrome (MONDO:0012794) is a disease caused by RBM28 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RBM28 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 8
• Phenotypes (HPO): 28

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000044	Hypogonadotropic hypogonadism	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000668	Hypodontia	Frequent (30-79%)
HP:0000670	Carious teeth	Frequent (30-79%)
HP:0000771	Gynecomastia	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0000824	Decreased response to growth hormone stimulation test	Frequent (30-79%)
HP:0000953	Hyperpigmentation of the skin	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001596	Alopecia	Frequent (30-79%)
HP:0002333	Motor deterioration	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0002751	Kyphoscoliosis	Frequent (30-79%)
HP:0002828	Multiple joint contractures	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0006480	Premature loss of teeth	Frequent (30-79%)
HP:0007373	Motor neuron atrophy	Frequent (30-79%)
HP:0007481	Hyperpigmented nevi	Frequent (30-79%)
HP:0009487	Ulnar deviation of the hand	Frequent (30-79%)
HP:0010627	Anterior pituitary hypoplasia	Frequent (30-79%)
HP:0011735	Adrenocorticotropin deficient adrenal insufficiency	Frequent (30-79%)
HP:0030353	Decreased serum insulin-like growth factor 1	Frequent (30-79%)
HP:0031074	Abnormal response to ACTH stimulation test	Frequent (30-79%)
HP:0040171	Decreased serum testosterone concentration	Frequent (30-79%)
HP:0100578	Lipoatrophy	Frequent (30-79%)
HP:0003700	Generalized amyotrophy	Occasional (5-29%)
HP:0008202	Reduced circulating prolactin concentration	Occasional (5-29%)
HP:0008245	Pituitary hypothyroidism	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ANE syndrome
Mondo ID	MONDO:0012794
MeSH	C567425
OMIM	612079
Orphanet	157954
DOID	DOID:0112244
UMLS	C2677535
MedGen	394313
GARD	0016987
Is cancer (heuristic)	no

Also known as: alopecia, neurologic defects, and endocrinopathy syndrome · alopecia-progressive neurological defect-endocrinopathy syndrome · ANE syndrome · anes

Data availability: 8 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › ANE syndrome

Related subtypes (35): Neu-Laxova syndrome, cutaneous mycosis, integumentary system benign neoplasm, integumentary system cancer, nipple neoplasm, nail disorder, disorder of pilosebaceous unit, Bartholin duct cyst, benign mammary dysplasia, skin disorder, breast fibrosis, breast mucosa-associated lymphoid tissue lymphoma, panniculitis, alopecia-epilepsy-pyorrhea-intellectual disability syndrome, autosomal dominant deafness - onychodystrophy syndrome, keratoderma hereditarium mutilans, Rombo syndrome, Sjogren-Larsson syndrome, mucosulfatidosis, ichthyosis prematurity syndrome, frontonasal dysplasia with alopecia and genital anomaly, peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome, mandibulofacial dysostosis with alopecia, cutis laxa, X-linked ichthyosis syndrome, demodicidosis, Proteus-like syndrome, familial atypical multiple mole melanoma syndrome, familial tumoral calcinosis, subcutaneous tissue disorder, Bartholin gland neoplasm, pseudoxanthoma elasticum (inherited or acquired), skin appendage disorder, keratinization disease, paraneoplastic cutaneous syndrome

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

8 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
732	NM_018077.3(RBM28):c.1052T>C (p.Leu351Pro)	RBM28	Pathogenic	no assertion criteria provided
802364	NM_018077.3(RBM28):c.541+1del	RBM28	Pathogenic	criteria provided, single submitter
2691762	NM_018077.3(RBM28):c.1489_1492dup (p.Val498fs)	RBM28	Likely pathogenic	no assertion criteria provided
802363	NM_018077.3(RBM28):c.946G>T (p.Ala316Ser)	RBM28	Likely pathogenic	criteria provided, single submitter
1028085	NM_018077.3(RBM28):c.1745G>A (p.Arg582Gln)	RBM28	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435384	NM_018077.3(RBM28):c.2182A>T (p.Thr728Ser)	RBM28	Uncertain significance	criteria provided, single submitter
3780541	NM_018077.3(RBM28):c.459dup (p.Arg154fs)	RBM28	Uncertain significance	criteria provided, single submitter
4819285	NM_018077.3(RBM28):c.626del (p.Ser209fs)	RBM28	Uncertain significance	criteria provided, single submitter

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
RBM28	Strong	Autosomal recessive	ANE syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RBM28	Orphanet:157954	ANE 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
RBM28	HGNC:21863	ENSG00000106344	Q9NW13	RNA-binding protein 28	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RBM28	RNA-binding protein 28	Nucleolar component of the spliceosomal ribonucleoprotein complexes.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RBM28	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBD_domain_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
apex of heart	1
calcaneal tendon	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RBM28	285	ubiquitous	marker	sural nerve, calcaneal tendon, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RBM28	3,328

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RBM28	Q9NW13	70.39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Major pathway of rRNA processing in the nucleolus and cytosol	1	61.7×	0.016	RBM28

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
RNA splicing	1	88.2×	0.013	RBM28
mRNA processing	1	78.8×	0.013	RBM28

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
RBM28	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
RBM28	1	Binding:1

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	RBM28

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)
RBM28	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.