Neurodegeneration with brain iron accumulation 8

Summary

Neurodegeneration with brain iron accumulation 8 (MONDO:0054764) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration with brain iron accumulation 8
Mondo ID	MONDO:0054764
OMIM	617917
UMLS	C4693587
MedGen	1645224
GARD	0025970
Is cancer (heuristic)	no

Also known as: NBIA8 · neurodegeneration with brain iron accumulation 8

Data availability: 15 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › iron metabolism disease › neurodegeneration with brain iron accumulation › neurodegeneration with brain iron accumulation 8

Related subtypes (13): pantothenate kinase-associated neurodegeneration, Woodhouse-Sakati syndrome, neurodegeneration with brain iron accumulation 5, aceruloplasminemia, neuroferritinopathy, Kufor-Rakeb syndrome, neurodegeneration with brain iron accumulation 4, neurodegeneration with brain iron accumulation 6, PLA2G6-associated neurodegeneration, fatty acid hydroxylase-associated neurodegeneration, early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome, neurodegeneration with brain iron accumulation 7, neurodegeneration with brain iron accumulation 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

15 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
4845764	NM_000755.5(CRAT):c.495del (p.Lys166fs)	CRAT	Likely pathogenic	criteria provided, single submitter
503495	NM_000755.5(CRAT):c.962G>A (p.Arg321His)	CRAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1061101	NM_000755.5(CRAT):c.817C>T (p.Arg273Trp)	CRAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1494128	NM_000755.5(CRAT):c.784G>A (p.Ala262Thr)	CRAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1503952	NM_000755.5(CRAT):c.350A>T (p.Tyr117Phe)	CRAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
2688866	NM_000755.5(CRAT):c.1738C>T (p.Pro580Ser)	CRAT	Uncertain significance	criteria provided, single submitter
2688867	NM_000755.5(CRAT):c.654_655del (p.His218fs)	CRAT	Uncertain significance	criteria provided, single submitter
3382098	NM_000755.5(CRAT):c.1373G>A (p.Arg458His)	CRAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
3382099	NM_000755.5(CRAT):c.982C>T (p.Gln328Ter)	CRAT	Uncertain significance	criteria provided, single submitter
3775922	NM_000755.5(CRAT):c.245G>A (p.Arg82His)	CRAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
684522	NM_000755.5(CRAT):c.830G>A (p.Arg277His)	CRAT	Uncertain significance	criteria provided, single submitter
1167063	NM_000755.5(CRAT):c.1114C>A (p.Leu372Met)	CRAT	Benign	criteria provided, multiple submitters, no conflicts
1167064	NM_000755.5(CRAT):c.984+9C>T	CRAT	Benign	criteria provided, multiple submitters, no conflicts
1598967	NM_000755.5(CRAT):c.1797C>T (p.Asn599=)	CRAT	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1640077	NM_000755.5(CRAT):c.1452C>T (p.Asp484=)	CRAT	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 0 · 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
CRAT	Limited	Autosomal recessive	neurodegeneration with brain iron accumulation 8	2

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
CRAT	HGNC:2342	ENSG00000095321	P43155	Carnitine O-acetyltransferase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRAT	Carnitine O-acetyltransferase	Catalyzes the reversible transfer of acyl groups from carnitine to coenzyme A (CoA) and regulates the acyl-CoA/CoA ratio.

Protein-family classification

Druggable: 1 · 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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CRAT	Enzyme (other)	yes	2.3.1.7	Carn_acyl_trans, CAT-like_dom_sf, Cho/carn_acyl_trans_1_2

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
left testis	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRAT	289	ubiquitous	marker	sperm, male germ cell, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRAT	1,056

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CRAT	P43155	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Beta-oxidation of pristanoyl-CoA	1	1142.0×	0.006	CRAT
Peroxisomal lipid metabolism	1	671.8×	0.006	CRAT
Branched-chain amino acid catabolism	1	475.8×	0.006	CRAT
Protein localization	1	190.3×	0.009	CRAT
Peroxisomal protein import	1	173.0×	0.009	CRAT
Fatty acid metabolism	1	131.3×	0.010	CRAT
Metabolism of lipids	1	31.6×	0.036	CRAT
Metabolism	1	11.6×	0.086	CRAT

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
carnitine metabolic process, CoA-linked	1	5617.3×	4e-04	CRAT
short-chain fatty acid metabolic process	1	5617.3×	4e-04	CRAT
medium-chain fatty acid metabolic process	1	2808.7×	5e-04	CRAT
fatty acid beta-oxidation using acyl-CoA oxidase	1	1123.5×	9e-04	CRAT

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
CRAT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CRAT	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CRAT	2.3.1.7	carnitine O-acetyltransferase

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	1	CRAT
D	Druggable family + AlphaFold only, no drug	0
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)
CRAT	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.