autosomal recessive congenital ichthyosis 4B

Summary

autosomal recessive congenital ichthyosis 4B (MONDO:0009443) is a disease caused by ABCA12 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: ABCA12 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 101
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		200	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000364	Hearing abnormality	Very frequent (80-99%)
HP:0000457	Depressed nasal ridge	Very frequent (80-99%)
HP:0000656	Ectropion	Very frequent (80-99%)
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0007431	Congenital ichthyosiform erythroderma	Very frequent (80-99%)
HP:0008064	Ichthyosis	Very frequent (80-99%)
HP:0001019	Erythroderma	Frequent (30-79%)
HP:0001376	Limitation of joint mobility	Frequent (30-79%)
HP:0012472	Eclabion	Frequent (30-79%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0001161	Hand polydactyly	Occasional (5-29%)
HP:0001645	Sudden cardiac death	Occasional (5-29%)
HP:0001829	Foot polydactyly	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0002047	Malignant hyperthermia	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0100716	Self-injurious behavior	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive congenital ichthyosis 4B
Mondo ID	MONDO:0009443
OMIM	242500
Orphanet	457
DOID	DOID:0060713
NCIT	C98934
SNOMED CT	205548006
UMLS	C0598226
MedGen	108615
GARD	0006568
MedDRA	10019163
NORD	1287
Is cancer (heuristic)	no

Also known as: ARCI4B · autosomal recessive congenital ichthyosis type 4B · Harlequin fetus · Harlequin foetus · Harlequin Ichthyosis · harlequin ichthyosis · HI · hi · ichthyosis , congenital, autosomal recessive 4b (harlequin) · ichthyosis congenita, Harlequin foetus type · ichthyosis congenita, Harlequin type · ichthyosis fetalis, Harlequin type · ichthyosis, congenital, autosomal recessive 4B · ichthyosis, congenital, autosomal recessive type 4B

Data availability: 101 ClinVar variants · 3 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › epidermal disease › ichthyosis › inherited ichthyosis › autosomal recessive congenital ichthyosis › autosomal recessive congenital ichthyosis 4A › autosomal recessive congenital ichthyosis 4B

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

101 retrieved; paginated sample, class counts are floors:

25 likely pathogenic, 24 pathogenic, 17 benign, 17 uncertain significance, 9 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 4 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1322149	NM_173076.3(ABCA12):c.3882G>A (p.Trp1294Ter)	ABCA12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686889	NM_173076.3(ABCA12):c.3656C>T (p.Ala1219Val)	ABCA12	Pathogenic	no assertion criteria provided
1693261	NM_173076.3(ABCA12):c.7344-1G>C	ABCA12	Pathogenic	no assertion criteria provided
2203257	NM_173076.3(ABCA12):c.5848C>T (p.Arg1950Ter)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
2203258	NM_173076.3(ABCA12):c.3666C>A (p.Tyr1222Ter)	ABCA12	Pathogenic	criteria provided, single submitter
2506520	NM_173076.3(ABCA12):c.5046_5050del (p.Lys1682fs)	ABCA12	Pathogenic	criteria provided, single submitter
264999	NM_173076.3(ABCA12):c.859C>T (p.Arg287Ter)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
265000	NM_173076.3(ABCA12):c.1300C>T (p.Arg434Ter)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
265001	NM_173076.3(ABCA12):c.2140C>T (p.Arg714Ter)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
265005	NM_173076.3(ABCA12):c.3889C>T (p.Arg1297Ter)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
2734375	NM_173076.3(ABCA12):c.6858del (p.Phe2286fs)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
2734376	NM_173076.3(ABCA12):c.4543C>T (p.Arg1515Ter)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
2855	NM_173076.3(ABCA12):c.4139A>G (p.Asn1380Ser)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
2856	NM_173076.3(ABCA12):c.4951G>A (p.Gly1651Ser)	ABCA12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2859	NM_173076.3(ABCA12):c.7323del (p.Val2442fs)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
2860	NM_173076.3(ABCA12):c.5012del (p.Asn1671fs)	ABCA12	Pathogenic	no assertion criteria provided
2862	NM_173076.3(ABCA12):c.6610C>T (p.Arg2204Ter)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
2863	NM_173076.3(ABCA12):c.3535G>A (p.Gly1179Arg)	ABCA12	Pathogenic	no assertion criteria provided
2864	NM_173076.3(ABCA12):c.(872+1_873-1)_(985+1_986-1)del (p.Ser291Argfs)	ABCA12	Pathogenic	no assertion criteria provided
2910157	NM_173076.3(ABCA12):c.5121_5124del (p.Asp1707fs)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
2970184	NM_173076.3(ABCA12):c.4798C>T (p.Gln1600Ter)	ABCA12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3585394	NM_173076.3(ABCA12):c.1583del (p.Asn528fs)	ABCA12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775914	NM_173076.3(ABCA12):c.873-2A>G	ABCA12	Pathogenic	criteria provided, single submitter
419453	NM_173076.3(ABCA12):c.7444C>T (p.Arg2482Ter)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
4279824	NM_173076.3(ABCA12):c.7342del (p.Ser2448fs)	ABCA12	Pathogenic	criteria provided, single submitter
4819646	NM_173076.3(ABCA12):c.3810del (p.Trp1269_Tyr1270insTer)	ABCA12	Pathogenic	criteria provided, single submitter
617618	NM_173076.3(ABCA12):c.5743dup (p.Ile1915fs)	ABCA12	Pathogenic	no assertion criteria provided
488389	NM_173076.3(ABCA12):c.6234-1G>C	SNHG31	Pathogenic	criteria provided, multiple submitters, no conflicts
1526223	NM_173076.3(ABCA12):c.4676G>T (p.Gly1559Val)	ABCA12	Likely pathogenic	criteria provided, single submitter
2507035	NM_173076.3(ABCA12):c.5878C>T (p.Arg1960Ter)	ABCA12	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
ABCA12	Definitive	Autosomal recessive	autosomal recessive congenital ichthyosis 4B	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCA12	Orphanet:313	Lamellar ichthyosis
ABCA12	Orphanet:457	Harlequin ichthyosis
ABCA12	Orphanet:79394	Congenital ichthyosiform erythroderma

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCA12	HGNC:14637	ENSG00000144452	Q86UK0	Glucosylceramide transporter ABCA12	gencc,clinvar
SNHG31	HGNC:54196	ENSG00000229267		small nucleolar RNA host gene 31	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABCA12	Glucosylceramide transporter ABCA12	Transports lipids such as glucosylceramides from the outer to the inner leaflet of lamellar granules (LGs) membrane, whereby the lipids are finally transported to the keratinocyte periphery via the trans-Golgi network and LGs and released…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Transporter	1	38.9×	0.051
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCA12	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
SNHG31	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
penis	1
upper arm skin	1
upper leg skin	1
hindlimb stylopod muscle	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCA12	95	broad	marker	penis, upper leg skin, upper arm skin
SNHG31	118		yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCA12	1,137
SNHG31	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABCA12	Q86UK0	68.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 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
Defective ABCA12 causes ARCI4B	1	11420.0×	6e-04	ABCA12
ABC transporters in lipid homeostasis	1	601.0×	0.005	ABCA12
ABC transporter disorders	1	439.2×	0.005	ABCA12
Disorders of transmembrane transporters	1	139.3×	0.012	ABCA12
ABC-family protein mediated transport	1	121.5×	0.012	ABCA12
Transport of small molecules	1	25.1×	0.046	ABCA12
Disease	1	13.1×	0.076	ABCA12

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
positive regulation of intracellular lipid transport	1	16852.0×	0.001	ABCA12
corneocyte desquamation	1	8426.0×	0.001	ABCA12
secretion by cell	1	1685.2×	0.002	ABCA12
ceramide transport	1	1532.0×	0.002	ABCA12
regulation of keratinocyte differentiation	1	1203.7×	0.002	ABCA12
phospholipid efflux	1	1123.5×	0.002	ABCA12
regulation of insulin secretion involved in cellular response to glucose stimulus	1	936.2×	0.002	ABCA12
regulated exocytosis	1	887.0×	0.002	ABCA12
ceramide metabolic process	1	802.5×	0.002	ABCA12
cellular homeostasis	1	802.5×	0.002	ABCA12
surfactant homeostasis	1	802.5×	0.002	ABCA12
positive regulation of protein localization to cell surface	1	766.0×	0.002	ABCA12
positive regulation of cholesterol efflux	1	624.1×	0.003	ABCA12
cholesterol efflux	1	526.6×	0.003	ABCA12
establishment of skin barrier	1	455.5×	0.003	ABCA12
lung alveolus development	1	351.1×	0.004	ABCA12
lipid homeostasis	1	337.0×	0.004	ABCA12
lipid transport	1	263.3×	0.004	ABCA12
keratinization	1	234.1×	0.005	ABCA12
protein localization to plasma membrane	1	108.7×	0.010	ABCA12
intracellular protein transport	1	64.8×	0.015	ABCA12

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
ABCA12	0	0
SNHG31	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	1	ABCA12
E	Difficult family or no structure, no drug	1	SNHG31

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ABCA12	0	—
SNHG31	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.