Infantile cerebellar-retinal degeneration

Summary

Infantile cerebellar-retinal degeneration (MONDO:0013802) is a disease caused by ACO2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ACO2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 59

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	infantile cerebellar-retinal degeneration
Mondo ID	MONDO:0013802
OMIM	614559
Orphanet	313850
DOID	DOID:0050883
UMLS	C3281192
MedGen	482822
GARD	0013264
Is cancer (heuristic)	no

Also known as: ICRD · infantile cerebellar retinal degeneration · infantile cerebellar-retinal degeneration

Data availability: 59 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of energy metabolism › tricarboxylic acid cycle disorder › infantile cerebellar-retinal degeneration

Related subtypes (3): oxoglutaricaciduria, tricarboxylic acid cycle, defect of, fumaric aciduria

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

59 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 12 pathogenic, 7 likely pathogenic, 7 conflicting classifications of pathogenicity, 6 benign, 2 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1120200	NM_001098.3(ACO2):c.1091T>C (p.Val364Ala)	ACO2	Pathogenic	no assertion criteria provided
1679318	NM_001098.3(ACO2):c.1776T>A (p.Cys592Ter)	ACO2	Pathogenic	criteria provided, single submitter
1711154	NM_001098.3(ACO2):c.940+5G>C	ACO2	Pathogenic	no assertion criteria provided
189312	NM_001098.3(ACO2):c.776G>A (p.Gly259Asp)	ACO2	Pathogenic	no assertion criteria provided
189313	NM_001098.3(ACO2):c.2208G>C (p.Lys736Asn)	ACO2	Pathogenic	no assertion criteria provided
189314	NM_001098.3(ACO2):c.2328_2331del (p.Lys776fs)	ACO2	Pathogenic	criteria provided, single submitter
29584	NM_001098.3(ACO2):c.336C>G (p.Ser112Arg)	ACO2	Pathogenic	no assertion criteria provided
4683088	NM_001098.3(ACO2):c.1776_1783del (p.Cys592_Asp595delinsTer)	ACO2	Pathogenic	criteria provided, single submitter
803705	NM_001098.3(ACO2):c.1390G>T (p.Glu464Ter)	ACO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
803706	NM_001098.3(ACO2):c.1966_1969del (p.Arg656fs)	ACO2	Pathogenic	criteria provided, single submitter
978053	NM_001098.3(ACO2):c.1240T>G (p.Phe414Val)	ACO2	Pathogenic	no assertion criteria provided
978054	NM_001098.3(ACO2):c.1787A>G (p.His596Arg)	ACO2	Pathogenic	no assertion criteria provided
978056	NM_001098.3(ACO2):c.433-2_433-1inv	ACO2	Pathogenic	no assertion criteria provided
1184574	NM_001098.3(ACO2):c.865G>C (p.Glu289Gln)	ACO2	Likely pathogenic	no assertion criteria provided
1184575	NM_001098.3(ACO2):c.927G>C (p.Lys309Asn)	ACO2	Likely pathogenic	no assertion criteria provided
1184576	NM_001098.3(ACO2):c.1687C>G (p.Gln563Glu)	ACO2	Likely pathogenic	no assertion criteria provided
2579234	GRCh38/hg38 22q13.2(chr22:41527570-41532843)x1	ACO2	Likely pathogenic	criteria provided, single submitter
3065644	NM_001098.3(ACO2):c.569G>A (p.Gly190Asp)	ACO2	Likely pathogenic	criteria provided, single submitter
3767184	NM_001098.3(ACO2):c.1492G>A (p.Ala498Thr)	ACO2	Likely pathogenic	criteria provided, single submitter
242873	NM_001098.3(ACO2):c.2338_2339del (p.Gln780fs)	POLR3H	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1354645	NM_001098.3(ACO2):c.934C>T (p.Arg312Trp)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
189310	NM_001098.3(ACO2):c.220C>G (p.Leu74Val)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218316	NM_001098.3(ACO2):c.1819C>T (p.Arg607Cys)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218317	NM_001098.3(ACO2):c.2135C>T (p.Pro712Leu)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522983	NM_001098.3(ACO2):c.1550C>T (p.Thr517Met)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
562211	NM_001098.3(ACO2):c.2153T>C (p.Ile718Thr)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
728759	NM_001098.3(ACO2):c.1387G>T (p.Gly463Trp)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031072	NM_001098.3(ACO2):c.2302G>A (p.Ala768Thr)	ACO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1321276	NM_001098.3(ACO2):c.487G>A (p.Val163Met)	ACO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1321277	NM_001098.3(ACO2):c.1032G>A (p.Glu344=)	ACO2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
ACO2	Definitive	Autosomal recessive	infantile cerebellar-retinal degeneration	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACO2	Orphanet:313850	Infantile cerebellar-retinal degeneration
ACO2	Orphanet:98676	Autosomal recessive isolated optic atrophy
KREMEN1	Orphanet:708036	Ectodermal dysplasia with agenesis of maxillary lateral incisors and mandibular anterior teeth
POLR3H	Orphanet:243	46,XX gonadal dysgenesis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACO2	HGNC:118	ENSG00000100412	Q99798	Aconitate hydratase, mitochondrial	gencc,clinvar
KREMEN1	HGNC:17550	ENSG00000183762	Q96MU8	Kremen protein 1	clinvar
POLR3H	HGNC:30349	ENSG00000100413	Q9Y535	DNA-directed RNA polymerase III subunit RPC8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACO2	Aconitate hydratase, mitochondrial	Catalyzes the isomerization of citrate to isocitrate via cis-aconitate.
KREMEN1	Kremen protein 1	Receptor for Dickkopf proteins.
POLR3H	DNA-directed RNA polymerase III subunit RPC8	DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACO2	Enzyme (other)	yes	4.2.1.3	AconitaseA/IPMdHydase_ssu_swvl, Acoase/IPM_deHydtase_lsu_aba, Aconitase_mito-like
KREMEN1	Other/Unknown	no		Kringle, CUB_dom, WSC_carb-bd
POLR3H	Other/Unknown	no		RNAP_E/RPC8, Rpb7-like_N, NA-bd_OB-fold

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
heart right ventricle	1
left ventricle myocardium	1
decidua	1
parotid gland	1
upper arm skin	1
anterior cingulate cortex	1
prefrontal cortex	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACO2	291	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium
KREMEN1	248	ubiquitous	marker	upper arm skin, decidua, parotid gland
POLR3H	232	ubiquitous	marker	prefrontal cortex, anterior cingulate cortex, right frontal lobe

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACO2	4,776
POLR3H	1,630
KREMEN1	1,061

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR3H	Q9Y535	29
KREMEN1	Q96MU8	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACO2	Q99798	95.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by LRP5 mutants	1	543.8×	0.021	KREMEN1
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	1	237.9×	0.021	KREMEN1
RNA Polymerase III Chain Elongation	1	211.5×	0.021	POLR3H
Signaling by WNT in cancer	1	200.3×	0.021	KREMEN1
Maturation of TCA enzymes and regulation of TCA cycle	1	190.3×	0.021	ACO2
RNA Polymerase III Transcription Termination	1	165.5×	0.021	POLR3H
Citric acid cycle (TCA cycle)	1	141.0×	0.021	ACO2
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	141.0×	0.021	POLR3H
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	135.9×	0.021	POLR3H
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	135.9×	0.021	POLR3H
RNA Polymerase III Transcription Initiation	1	112.0×	0.021	POLR3H
RNA Polymerase III Transcription	1	108.8×	0.021	POLR3H
Cytosolic sensors of pathogen-associated DNA	1	95.2×	0.021	POLR3H
RNA Polymerase III Abortive And Retractive Initiation	1	92.8×	0.021	POLR3H
Protein localization	1	63.4×	0.029	ACO2
Mitochondrial protein import	1	56.0×	0.031	ACO2
TCF dependent signaling in response to WNT	1	39.2×	0.039	KREMEN1
Mitochondrial protein degradation	1	38.1×	0.039	ACO2
Signaling by WNT	1	37.3×	0.039	KREMEN1
Aerobic respiration and respiratory electron transport	1	29.5×	0.047	ACO2
Diseases of signal transduction by growth factor receptors and second messengers	1	18.9×	0.069	KREMEN1
Innate Immune System	1	8.5×	0.144	POLR3H
Gene expression (Transcription)	1	6.0×	0.193	POLR3H
Disease	1	4.4×	0.240	KREMEN1
Immune System	1	4.3×	0.240	POLR3H
Metabolism of proteins	1	4.1×	0.241	ACO2
Metabolism	1	3.9×	0.245	ACO2
Signal Transduction	1	3.4×	0.267	KREMEN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
citrate metabolic process	1	1404.3×	0.011	ACO2
transcription initiation at RNA polymerase III promoter	1	802.5×	0.011	POLR3H
negative regulation of axon regeneration	1	510.7×	0.011	KREMEN1
cell communication	1	280.9×	0.011	KREMEN1
transcription by RNA polymerase III	1	255.3×	0.011	POLR3H
negative regulation of ossification	1	208.1×	0.011	KREMEN1
regulation of canonical Wnt signaling pathway	1	181.2×	0.011	KREMEN1
nucleobase-containing compound metabolic process	1	175.5×	0.011	POLR3H
tricarboxylic acid cycle	1	170.2×	0.011	ACO2
limb development	1	137.0×	0.012	KREMEN1
generation of precursor metabolites and energy	1	114.6×	0.013	ACO2
negative regulation of canonical Wnt signaling pathway	1	39.3×	0.036	KREMEN1
Wnt signaling pathway	1	33.2×	0.039	KREMEN1
defense response to virus	1	23.1×	0.052	POLR3H
innate immune response	1	11.2×	0.098	POLR3H
apoptotic process	1	9.6×	0.107	KREMEN1
signal transduction	1	5.3×	0.176	KREMEN1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
ACO2	0	0
KREMEN1	0	0
POLR3H	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACO2	4.2.1.3	aconitate hydratase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	ACO2
E	Difficult family or no structure, no drug	2	KREMEN1, POLR3H

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACO2	0	—
KREMEN1	0	—
POLR3H	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.