Autosomal recessive congenital ichthyosis 10

Summary

Autosomal recessive congenital ichthyosis 10 (MONDO:0014011) is a disease caused by PNPLA1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: PNPLA1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 110

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive congenital ichthyosis 10
Mondo ID	MONDO:0014011
OMIM	615024
DOID	DOID:0060719
UMLS	C3554355
MedGen	767269
GARD	0015897
Is cancer (heuristic)	no

Also known as: ARCI10 · autosomal recessive congenital ichthyosis type 10 · ichthyosis, congenital, autosomal recessive 10 · ichthyosis, congenital, autosomal recessive type 10

Data availability: 110 ClinVar variants · 5 GenCC gene-disease records.

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 › congenital non-bullous ichthyosiform erythroderma › autosomal recessive congenital ichthyosis 10

Related subtypes (5): autosomal recessive congenital ichthyosis 2, autosomal recessive congenital ichthyosis 3, autosomal recessive congenital ichthyosis 6, autosomal recessive congenital ichthyosis 7, autosomal recessive congenital ichthyosis 9

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

110 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 21 conflicting classifications of pathogenicity, 18 likely pathogenic, 16 benign, 9 pathogenic/likely pathogenic, 8 pathogenic, 4 benign/likely benign, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
219235	NM_172107.4(KCNQ2):c.917C>T (p.Ala306Val)	KCNQ2	Pathogenic	criteria provided, multiple submitters, no conflicts
1323478	NM_001374623.1(PNPLA1):c.892C>T (p.Arg298Ter)	PNPLA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1691290	NM_001374623.1(PNPLA1):c.100G>C (p.Ala34Pro)	PNPLA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2579650	NM_001374623.1(PNPLA1):c.488C>T (p.Pro163Leu)	PNPLA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3335972	NM_001374623.1(PNPLA1):c.417_418delinsTC (p.Ser140Pro)	PNPLA1	Pathogenic	criteria provided, multiple submitters, no conflicts
375256	NM_001374623.1(PNPLA1):c.418T>C (p.Ser140Pro)	PNPLA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375258	NM_001374623.1(PNPLA1):c.335C>A (p.Ser112Tyr)	PNPLA1	Pathogenic/Likely pathogenic	no assertion criteria provided
3900745	NM_001374623.1(PNPLA1):c.536A>G (p.Gln179Arg)	PNPLA1	Pathogenic	criteria provided, single submitter
39561	NM_001374623.1(PNPLA1):c.391G>T (p.Glu131Ter)	PNPLA1	Pathogenic	no assertion criteria provided
39562	NM_001374623.1(PNPLA1):c.176C>T (p.Ala59Val)	PNPLA1	Pathogenic	no assertion criteria provided
451071	NM_001374623.1(PNPLA1):c.646T>C (p.Cys216Arg)	PNPLA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617846	NM_001374623.1(PNPLA1):c.387C>A (p.Asp129Glu)	PNPLA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
633797	NM_001374623.1(PNPLA1):c.149C>A (p.Ala50Glu)	PNPLA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
633818	NM_001374623.1(PNPLA1):c.727TAC[2] (p.Tyr245del)	PNPLA1	Pathogenic	criteria provided, single submitter
684640	NM_001374623.1(PNPLA1):c.1300del (p.Ala434fs)	PNPLA1	Pathogenic	criteria provided, multiple submitters, no conflicts
684645	NM_001374623.1(PNPLA1):c.421A>G (p.Lys141Glu)	PNPLA1	Pathogenic	no assertion criteria provided
684647	NM_001374623.1(PNPLA1):c.158C>G (p.Ser53Trp)	PNPLA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445879	NM_001374623.1(PNPLA1):c.736C>T (p.Arg246Ter)	PNPLA1	Likely pathogenic	criteria provided, single submitter
3336275	NM_001374623.1(PNPLA1):c.158C>T (p.Ser53Leu)	PNPLA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382149	NM_001374623.1(PNPLA1):c.88G>A (p.Gly30Arg)	PNPLA1	Likely pathogenic	criteria provided, single submitter
3391281	NM_001374623.1(PNPLA1):c.121del (p.Arg41fs)	PNPLA1	Likely pathogenic	criteria provided, single submitter
3392516	NM_001374623.1(PNPLA1):c.715-2A>C	PNPLA1	Likely pathogenic	criteria provided, single submitter
3593567	NM_001374623.1(PNPLA1):c.206-1G>A	PNPLA1	Likely pathogenic	criteria provided, single submitter
3593568	NM_001374623.1(PNPLA1):c.1136_1152del (p.Lys379fs)	PNPLA1	Likely pathogenic	criteria provided, single submitter
3593569	NM_001374623.1(PNPLA1):c.1289C>G (p.Ser430Ter)	PNPLA1	Likely pathogenic	criteria provided, single submitter
3593570	NM_001374623.1(PNPLA1):c.1384+2T>C	PNPLA1	Likely pathogenic	criteria provided, single submitter
375255	NM_001374623.1(PNPLA1):c.820del (p.Arg274fs)	PNPLA1	Likely pathogenic	no assertion criteria provided
375259	NM_001374623.1(PNPLA1):c.266C>T (p.Pro89Leu)	PNPLA1	Likely pathogenic	no assertion criteria provided
3899872	NM_001374623.1(PNPLA1):c.655C>T (p.Gln219Ter)	PNPLA1	Likely pathogenic	criteria provided, single submitter
3900744	NM_001374623.1(PNPLA1):c.485C>G (p.Pro162Arg)	PNPLA1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 7 · 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
PNPLA1	Strong	Autosomal recessive	autosomal recessive congenital ichthyosis 10	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PNPLA1	Orphanet:79394	Congenital ichthyosiform erythroderma
KCNQ2	Orphanet:140927	Self-limited neonatal-infantile epilepsy
KCNQ2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
KCNQ2	Orphanet:1949	Self-limited neonatal epilepsy
KCNQ2	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
KCNQ2	Orphanet:306	Self-limited infantile epilepsy
KCNQ2	Orphanet:439218	KCNQ2-related developmental and epileptic encephalopathy

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
PNPLA1	HGNC:21246	ENSG00000180316	Q8N8W4	Omega-hydroxyceramide transacylase	gencc,clinvar
KCNQ2	HGNC:6296	ENSG00000075043	O43526	Potassium voltage-gated channel subfamily KQT member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PNPLA1	Omega-hydroxyceramide transacylase	Omega-hydroxyceramide transacylase involved in the synthesis of omega-O-acylceramides (esterified omega-hydroxyacyl-sphingosine; EOS), which are extremely hydrophobic lipids involved in skin barrier formation.
KCNQ2	Potassium voltage-gated channel subfamily KQT member 2	Pore-forming subunit of the voltage-gated potassium (Kv) M-channel which is responsible for the M-current, a key controller of neuronal excitability.

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
Ion channel	1	55.8×	0.036
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PNPLA1	Enzyme (other)	yes	2.3.1.296	PNPLA_dom, Acyl_Trfase/lysoPLipase, PLPL
KCNQ2	Ion channel	yes		K_chnl_volt-dep_KCNQ, K_chnl_volt-dep_KCNQ2, Ion_trans_dom

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
skin of abdomen	1
skin of leg	1
zone of skin	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PNPLA1	104	tissue_specific	marker	skin of abdomen, skin of leg, zone of skin
KCNQ2	183	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNQ2	3,388
PNPLA1	584

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNQ2	O43526	39

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PNPLA1	Q8N8W4	64.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Interaction between L1 and Ankyrins	1	368.4×	0.016	KCNQ2
Voltage gated Potassium channels	1	243.0×	0.016	KCNQ2
Potassium Channels	1	134.3×	0.017	KCNQ2
L1CAM interactions	1	120.2×	0.017	KCNQ2
Axon guidance	1	45.1×	0.027	KCNQ2
Neuronal System	1	44.3×	0.027	KCNQ2
Nervous system development	1	42.9×	0.027	KCNQ2
Developmental Biology	1	14.5×	0.069	KCNQ2

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
omega-hydroxyceramide biosynthetic process	1	8426.0×	9e-04	PNPLA1
triglyceride catabolic process	1	401.2×	0.009	PNPLA1
ceramide biosynthetic process	1	210.7×	0.009	PNPLA1
action potential	1	179.3×	0.009	KCNQ2
lipid homeostasis	1	168.5×	0.009	PNPLA1
potassium ion transmembrane transport	1	68.0×	0.020	KCNQ2
chemical synaptic transmission	1	38.6×	0.029	KCNQ2
nervous system development	1	23.0×	0.043	KCNQ2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
KCNQ2	FLUPIRTINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNQ2	4	4
PNPLA1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FLUPIRTINE	4	KCNQ2
EZOGABINE	4	KCNQ2
FLINDOKALNER	3	KCNQ2
AZETUKALNER	3	KCNQ2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KCNQ2	145	Binding:136, Functional:7, ADMET:1, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PNPLA1	2.3.1.296	omega-hydroxyceramide transacylase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
KCNQ2	145

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

4 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)
FLUPIRTINE	4	KCNQ2
EZOGABINE	4	KCNQ2
FLINDOKALNER	3	KCNQ2
AZETUKALNER	3	KCNQ2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNQ2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PNPLA1
E	Difficult family or no structure, no drug	0

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)
PNPLA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.