Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome

Summary

Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome (MONDO:0013760) is a disease caused by ELOVL4 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ELOVL4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome
Mondo ID	MONDO:0013760
OMIM	614457
Orphanet	352333
UMLS	C3280856
MedGen	482486
GARD	0017515
Is cancer (heuristic)	no

Also known as: congenital ichthyosis-intellectual disability-spastic tetraplegia syndrome · ichthyosis, spastic quadriplegia, and intellectual disability · ichthyosis, spastic quadriplegia, and mental retardation · ISQMR

Data availability: 13 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic dyslipidemia › congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome

Related subtypes (28): familial apolipoprotein C-II deficiency, sitosterolemia, cerebrotendinous xanthomatosis, rhizomelic chondrodysplasia punctata type 1, apparent mineralocorticoid excess, GM1 gangliosidosis type 1, familial lipoprotein lipase deficiency, sea-blue histiocyte syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, CHIME syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, Barth syndrome, CHILD syndrome, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, Krabbe disease due to saposin A deficiency, lipoprotein glomerulopathy, hereditary spastic paraplegia 39, PHARC syndrome, hyperlipoproteinemia, type 1D, intellectual disability, autosomal recessive 53, hyperphosphatasia-intellectual disability syndrome, mevalonate kinase deficiency, fatty acid hydroxylase-associated neurodegeneration, nephrotic syndrome 14, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction, peroxisome biogenesis disorder due to PEX5 defect in the PEX7-binding domain, lysosomal acid lipase deficiency

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

13 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 3 pathogenic, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
143056	NM_022726.4(ELOVL4):c.504G>C (p.Leu168Phe)	ELOVL4	Pathogenic	criteria provided, multiple submitters, no conflicts
30494	NM_022726.4(ELOVL4):c.646C>T (p.Arg216Ter)	ELOVL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30495	NM_022726.4(ELOVL4):c.690del (p.Ile230fs)	ELOVL4	Pathogenic	no assertion criteria provided
435057	NM_022726.4(ELOVL4):c.512T>C (p.Ile171Thr)	ELOVL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
561002	NM_022726.4(ELOVL4):c.215del (p.Pro72fs)	ELOVL4	Pathogenic	criteria provided, single submitter
433192	NM_022726.4(ELOVL4):c.289-2A>G	ELOVL4	Likely pathogenic	criteria provided, single submitter
358148	NM_022726.4(ELOVL4):c.351T>A (p.Asn117Lys)	ELOVL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
561003	NM_022726.4(ELOVL4):c.670-1G>A	ELOVL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002929	NM_022726.4(ELOVL4):c.164T>A (p.Leu55His)	ELOVL4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1212717	NM_022726.4(ELOVL4):c.134C>G (p.Ser45Cys)	ELOVL4	Uncertain significance	criteria provided, multiple submitters, no conflicts
936456	NM_022726.4(ELOVL4):c.226C>T (p.Arg76Cys)	ELOVL4	Uncertain significance	criteria provided, multiple submitters, no conflicts
137205	NM_022726.4(ELOVL4):c.814G>C (p.Glu272Gln)	ELOVL4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
137206	NM_022726.4(ELOVL4):c.895A>G (p.Met299Val)	ELOVL4	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · 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
ELOVL4	Definitive	Autosomal recessive	congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ELOVL4	Orphanet:1955	Spinocerebellar ataxia type 34
ELOVL4	Orphanet:352333	Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome
ELOVL4	Orphanet:827	Stargardt disease

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
ELOVL4	HGNC:14415	ENSG00000118402	Q9GZR5	Very long chain fatty acid elongase 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ELOVL4	Very long chain fatty acid elongase 4	Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle.

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)
ELOVL4	Other/Unknown	no		ELO_fam, ELO_CS, ELOVL4

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
mammalian vulva	1
upper arm skin	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ELOVL4	228	ubiquitous	marker	upper leg skin, upper arm skin, mammalian vulva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ELOVL4	2,115

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ELOVL4	Q9GZR5	84.53

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
Synthesis of very long-chain fatty acyl-CoAs	1	456.8×	0.002	ELOVL4

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
fatty acid elongation, monounsaturated fatty acid	1	2407.4×	0.001	ELOVL4
fatty acid elongation, polyunsaturated fatty acid	1	2407.4×	0.001	ELOVL4
fatty acid elongation, saturated fatty acid	1	2106.5×	0.001	ELOVL4
very long-chain fatty acid biosynthetic process	1	1296.3×	0.002	ELOVL4
long-chain fatty-acyl-CoA biosynthetic process	1	842.6×	0.002	ELOVL4
unsaturated fatty acid biosynthetic process	1	648.1×	0.002	ELOVL4
sphingolipid biosynthetic process	1	358.6×	0.003	ELOVL4
fatty acid biosynthetic process	1	351.1×	0.003	ELOVL4

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
ELOVL4	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
ELOVL4	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	ELOVL4

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)
ELOVL4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.