Neurodegeneration with brain iron accumulation

Summary

Neurodegeneration with brain iron accumulation (MONDO:0018307) is a disease (an umbrella term covering 14 Mondo subtypes) with 10 cohort genes and 5 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Umbrella term: 14 Mondo subtypes
• Cohort genes: 10
• ClinVar variants: 73
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.2	Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration with brain iron accumulation
Mondo ID	MONDO:0018307
MeSH	C538421
OMIM	234200
Orphanet	385
DOID	DOID:0110734
ICD-11	440483530
UMLS	C2931845
MedGen	444156
GARD	0011899
Is cancer (heuristic)	no

Also known as: NBIA · neurodegeneration with brain iron accumulation

Data availability: 73 ClinVar variants.

Disease family

An umbrella term covering 14 Mondo subtypes.

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

Related subtypes (1): hemosiderosis

Subtypes (14): 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 8, 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

73 retrieved; paginated sample, class counts are floors:

27 pathogenic/likely pathogenic, 16 conflicting classifications of pathogenicity, 15 pathogenic, 14 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1221	NM_022089.4(ATP13A2):c.1510G>C (p.Gly504Arg)	ATP13A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2046647	NM_022089.4(ATP13A2):c.774G>A (p.Trp258Ter)	ATP13A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2663862	NM_022089.4(ATP13A2):c.2097del (p.Ser700fs)	ATP13A2	Pathogenic	criteria provided, multiple submitters, no conflicts
3336424	NM_022089.4(ATP13A2):c.352G>T (p.Glu118Ter)	ATP13A2	Pathogenic	criteria provided, single submitter
465253	NM_022089.4(ATP13A2):c.3057del (p.Tyr1020fs)	ATP13A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
546591	NM_022089.4(ATP13A2):c.477+2T>G	ATP13A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2577335	NM_031448.6(C19orf12):c.267del (p.Phe89fs)	C19orf12	Pathogenic	criteria provided, single submitter
31155	NM_031448.6(C19orf12):c.171_181del (p.Gly58fs)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31156	NM_031448.6(C19orf12):c.-2C>T	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31157	NM_031448.6(C19orf12):c.172G>A (p.Gly58Arg)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617481	NM_031448.6(C19orf12):c.161G>A (p.Gly54Glu)	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88866	NM_001031726.4(C19orf12):c.164_166delGGG	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100662	NM_025233.7(COASY):c.1495C>T (p.Arg499Cys)	COASY	Pathogenic	criteria provided, multiple submitters, no conflicts
1722462	NM_025233.7(COASY):c.1068_1069del (p.Cys357fs)	COASY	Pathogenic	criteria provided, single submitter
599342	NM_025233.7(COASY):c.1549_1550del (p.Ser517fs)	COASY	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3629557	NM_000096.4(CP):c.2122G>A (p.Gly708Ser)	CP	Pathogenic	criteria provided, multiple submitters, no conflicts
381716	NM_000096.4(CP):c.1948G>A (p.Gly650Arg)	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
42143	NM_000096.4(CP):c.2066del (p.Pro689fs)	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431113	NM_000096.4(CP):c.2756T>C (p.Leu919Pro)	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679361	NM_025000.4(DCAF17):c.1488_1489del (p.Arg496fs)	DCAF17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
406877	NM_024306.5(FA2H):c.443C>T (p.Pro148Leu)	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
458305	NM_024306.5(FA2H):c.131C>A (p.Pro44Gln)	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1197568	NM_003560.4(PLA2G6):c.1798C>T (p.Arg600Trp)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159741	NM_003560.4(PLA2G6):c.1634A>G (p.Lys545Arg)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159748	NM_003560.4(PLA2G6):c.1799G>A (p.Arg600Gln)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159749	NM_003560.4(PLA2G6):c.1903C>T (p.Arg635Ter)	PLA2G6	Pathogenic	criteria provided, multiple submitters, no conflicts
1722386	NM_003560.4(PLA2G6):c.1511C>T (p.Ser504Leu)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2501145	NM_003560.4(PLA2G6):c.1743-2A>G	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265448	NM_003560.4(PLA2G6):c.2221C>T (p.Arg741Trp)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265449	NM_003560.4(PLA2G6):c.208C>T (p.Arg70Ter)	PLA2G6	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FA2H	Orphanet:171629	Autosomal recessive spastic paraplegia type 35
FA2H	Orphanet:329308	Fatty acid hydroxylase-associated neurodegeneration
CP	Orphanet:48818	Aceruloplasminemia
C19orf12	Orphanet:289560	Mitochondrial membrane protein-associated neurodegeneration
C19orf12	Orphanet:320370	Autosomal recessive spastic paraplegia type 43
WDR45	Orphanet:329284	Beta-propeller protein-associated neurodegeneration
WDR45	Orphanet:697160	Infantile epileptic spasms syndrome
COASY	Orphanet:397725	COASY protein-associated neurodegeneration
ATP13A2	Orphanet:306674	Kufor-Rakeb syndrome
ATP13A2	Orphanet:314632	CLN12 disease
ATP13A2	Orphanet:513436	Autosomal recessive spastic paraplegia type 78
PLA2G6	Orphanet:199351	Adult-onset dystonia-parkinsonism
PLA2G6	Orphanet:35069	Infantile neuroaxonal dystrophy

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
REPS1	HGNC:15578	ENSG00000135597	Q96D71	RalBP1-associated Eps domain-containing protein 1	clinvar
FA2H	HGNC:21197	ENSG00000103089	Q7L5A8	Fatty acid 2-hydroxylase	clinvar
CP	HGNC:2295	ENSG00000047457	P00450	Ceruloplasmin	clinvar
CRAT	HGNC:2342	ENSG00000095321	P43155	Carnitine O-acetyltransferase	clinvar
C19orf12	HGNC:25443	ENSG00000131943	Q9NSK7	Protein C19orf12	clinvar
DCAF17	HGNC:25784	ENSG00000115827	Q5H9S7	DDB1- and CUL4-associated factor 17	clinvar
WDR45	HGNC:28912	ENSG00000196998	Q9Y484	WD repeat domain phosphoinositide-interacting protein 4	clinvar
COASY	HGNC:29932	ENSG00000068120	Q13057	Bifunctional coenzyme A synthase	clinvar
ATP13A2	HGNC:30213	ENSG00000159363	Q9NQ11	Polyamine-transporting ATPase 13A2	clinvar
PLA2G6	HGNC:9039	ENSG00000184381	O60733	85/88 kDa calcium-independent phospholipase A2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
REPS1	RalBP1-associated Eps domain-containing protein 1	May coordinate the cellular actions of activated EGF receptors and Ral-GTPases.
FA2H	Fatty acid 2-hydroxylase	Catalyzes the hydroxylation of free fatty acids at the C-2 position to produce 2-hydroxy fatty acids, which are building blocks of sphingolipids and glycosphingolipids common in neural tissue and epidermis.
CP	Ceruloplasmin	Multifunctional blue, copper-binding (6-7 atoms per molecule) glycoprotein.
CRAT	Carnitine O-acetyltransferase	Catalyzes the reversible transfer of acyl groups from carnitine to coenzyme A (CoA) and regulates the acyl-CoA/CoA ratio.
DCAF17	DDB1- and CUL4-associated factor 17	May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex.
WDR45	WD repeat domain phosphoinositide-interacting protein 4	Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation.
COASY	Bifunctional coenzyme A synthase	Bifunctional enzyme that catalyzes the fourth step of the coenzyme A biosynthetic pathway, the adenylation of 4’-phosphopantetheine, and the fifth step, the phosphorylation of dephospho-CoA to CoA.
ATP13A2	Polyamine-transporting ATPase 13A2	ATPase which acts as a lysosomal polyamine exporter with high affinity for spermine.
PLA2G6	85/88 kDa calcium-independent phospholipase A2	Calcium-independent phospholipase involved in phospholipid remodeling with implications in cellular membrane homeostasis, mitochondrial integrity and signal transduction.

Protein-family classification

Druggable: 4 · Difficult: 3 · Unknown: 3 · Druggable fraction: 0.4

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)	3	3.6×	0.223
Scaffold/PPI	2	3.5×	0.276
Kinase	1	2.8×	0.513
Transcription factor	1	0.8×	0.906
Other/Unknown	3	0.5×	0.976

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
REPS1	Other/Unknown	no		EH_dom, EF_hand_dom, EF-hand-dom_pair
FA2H	Enzyme (other)	yes	1.14.18.6	Cyt_B5-like_heme/steroid-bd, Fatty_acid_hydroxylase, Scs7
CP	Enzyme (other)	yes	1.16.3.1	Cu-oxidase_2nd, Cu_oxidase_Cu_BS, Cupredoxin
CRAT	Enzyme (other)	yes	2.3.1.7	Carn_acyl_trans, CAT-like_dom_sf, Cho/carn_acyl_trans_1_2
C19orf12	Other/Unknown	no		C19orf12
DCAF17	Other/Unknown	no		DCAF17
WDR45	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
COASY	Kinase	yes	2.7.1.24	Depp_CoAkinase, Cyt_trans-like, Rossmann-like_a/b/a_fold
ATP13A2	Transcription factor	no		P_typ_ATPase, P-type_TPase_V, ATPase_P-typ_transduc_dom_A_sf
PLA2G6	Scaffold/PPI	no	3.1.1.4	Ankyrin_rpt, PNPLA_dom, Acyl_Trfase/lysoPLipase

Expression context

Cohort genes with no expression data: 0.

9 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
parotid gland	2
right uterine tube	2
ventricular zone	1
C1 segment of cervical spinal cord	1
corpus callosum	1
spinal cord	1
liver	1
palpebral conjunctiva	1
right lobe of liver	1
left testis	1
male germ cell	1
sperm	1
endothelial cell	1
epithelial cell of pancreas	1
kidney epithelium	1
adrenal tissue	1
cortical plate	1
male germ line stem cell (sensu Vertebrata) in testis	1
apex of heart	1
granulocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
REPS1	258	ubiquitous	marker	ventricular zone, right uterine tube, parotid gland
FA2H	213	broad	marker	C1 segment of cervical spinal cord, spinal cord, corpus callosum
CP	234	broad	marker	right lobe of liver, liver, palpebral conjunctiva
CRAT	289	ubiquitous	marker	sperm, male germ cell, left testis
C19orf12	253	ubiquitous	marker	endothelial cell, kidney epithelium, epithelial cell of pancreas
DCAF17	220	ubiquitous	yes	cortical plate, male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue
WDR45	293	ubiquitous	marker	apex of heart, mucosa of stomach, granulocyte
COASY	280	ubiquitous	marker	parotid gland, mucosa of transverse colon, lower esophagus mucosa
ATP13A2	249	ubiquitous	marker	right frontal lobe, right hemisphere of cerebellum, prefrontal cortex
PLA2G6	232	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 19.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COASY	3,273
CP	2,661
ATP13A2	2,267
FA2H	2,099
PLA2G6	1,769
DCAF17	1,488
REPS1	1,377
WDR45	1,233
CRAT	1,056
C19orf12	584

Intra-cohort edges

A	B	Sources
ATP13A2	C19orf12	string_interaction
ATP13A2	DCAF17	string_interaction
ATP13A2	FA2H	string_interaction
ATP13A2	PLA2G6	string_interaction
C19orf12	COASY	string_interaction
C19orf12	DCAF17	string_interaction
C19orf12	FA2H	string_interaction
C19orf12	PLA2G6	string_interaction
C19orf12	WDR45	string_interaction
COASY	DCAF17	string_interaction
COASY	FA2H	string_interaction
COASY	WDR45	string_interaction
DCAF17	FA2H	string_interaction
DCAF17	PLA2G6	string_interaction
DCAF17	REPS1	string_interaction
DCAF17	WDR45	string_interaction
FA2H	PLA2G6	string_interaction
FA2H	WDR45	string_interaction
PLA2G6	WDR45	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 6 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP13A2	Q9NQ11	25
CP	P00450	4
CRAT	P43155	3
WDR45	Q9Y484	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COASY	Q13057	89.51
DCAF17	Q5H9S7	87.38
PLA2G6	O60733	86.16
FA2H	Q7L5A8	85.53
C19orf12	Q9NSK7	59.50
REPS1	Q96D71	57.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 10 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages)	1	634.4×	0.022	CP
Defective CP causes aceruloplasminemia (ACERULOP)	1	634.4×	0.022	CP
Acyl chain remodeling of CL	1	211.5×	0.044	PLA2G6
Coenzyme A biosynthesis	1	158.6×	0.044	COASY
Beta-oxidation of pristanoyl-CoA	1	126.9×	0.044	CRAT
Peroxisomal lipid metabolism	1	74.6×	0.058	CRAT
Metal ion SLC transporters	1	66.8×	0.058	CP
Branched-chain amino acid catabolism	1	52.9×	0.058	CRAT
Role of phospholipids in phagocytosis	1	50.8×	0.058	PLA2G6
Acyl chain remodelling of PC	1	47.0×	0.058	PLA2G6
Acyl chain remodelling of PE	1	43.8×	0.058	PLA2G6
Iron uptake and transport	1	38.5×	0.060	CP
Sphingolipid de novo biosynthesis	1	31.7×	0.067	FA2H
COPI-independent Golgi-to-ER retrograde traffic	1	23.1×	0.079	PLA2G6
Ion transport by P-type ATPases	1	23.1×	0.079	ATP13A2
Protein localization	1	21.1×	0.081	CRAT
Peroxisomal protein import	1	19.2×	0.084	CRAT
Fatty acid metabolism	1	14.6×	0.103	CRAT
Macroautophagy	1	12.8×	0.111	WDR45
Cargo recognition for clathrin-mediated endocytosis	1	11.6×	0.115	REPS1
Post-translational protein phosphorylation	1	11.1×	0.115	CP
Ion channel transport	1	10.7×	0.115	ATP13A2
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	9.6×	0.118	CP
Clathrin-mediated endocytosis	1	9.5×	0.118	REPS1
Neddylation	1	5.3×	0.196	DCAF17
Metabolism of lipids	1	3.5×	0.271	CRAT
Transport of small molecules	1	2.8×	0.317	ATP13A2
Metabolism	1	1.3×	0.555	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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
autophagy	3	33.0×	0.006	C19orf12, WDR45, ATP13A2
spermine transmembrane transport	1	1685.2×	0.010	ATP13A2
extracellular exosome biogenesis	1	842.6×	0.010	ATP13A2
regulation of sebum secreting cell proliferation	1	842.6×	0.010	FA2H
regulation of acinar cell proliferation	1	842.6×	0.010	FA2H
sebaceous gland cell differentiation	1	561.7×	0.010	FA2H
glucosylceramide biosynthetic process	1	561.7×	0.010	FA2H
regulation of autophagosome size	1	561.7×	0.010	ATP13A2
carnitine metabolic process, CoA-linked	1	561.7×	0.010	CRAT
short-chain fatty acid metabolic process	1	561.7×	0.010	CRAT
platelet activating factor metabolic process	1	561.7×	0.010	PLA2G6
regulation of lysosomal protein catabolic process	1	561.7×	0.010	ATP13A2
cardiolipin acyl-chain remodeling	1	421.3×	0.010	PLA2G6
phosphatidylethanolamine catabolic process	1	421.3×	0.010	PLA2G6
polyamine transmembrane transport	1	421.3×	0.010	ATP13A2
galactosylceramide biosynthetic process	1	337.0×	0.010	FA2H
nucleophagy	1	337.0×	0.010	WDR45
regulation of chaperone-mediated autophagy	1	337.0×	0.010	ATP13A2
autophagosome organization	1	337.0×	0.010	ATP13A2
negative regulation of lysosomal protein catabolic process	1	337.0×	0.010	ATP13A2
central nervous system myelin maintenance	1	280.9×	0.010	FA2H
regulation of intracellular protein transport	1	280.9×	0.010	ATP13A2
plasma membrane raft organization	1	280.9×	0.010	FA2H
phosphatidic acid metabolic process	1	280.9×	0.010	PLA2G6
medium-chain fatty acid metabolic process	1	280.9×	0.010	CRAT
regulation of autophagy of mitochondrion	1	280.9×	0.010	ATP13A2
intracellular iron ion homeostasis	2	48.9×	0.010	CP, ATP13A2
regulation of hair cycle	1	240.7×	0.011	FA2H
cellular response to manganese ion	1	240.7×	0.011	ATP13A2
positive regulation of ceramide biosynthetic process	1	240.7×	0.011	PLA2G6

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 2 · Undrugged: 8

Druggability breadth: 4 of 10 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COASY	1	2
PLA2G6	1	2
REPS1	0	0
FA2H	0	0
CP	0	0
CRAT	0	0
C19orf12	0	0
DCAF17	0	0
WDR45	0	0
ATP13A2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	COASY
VARESPLADIB	2	PLA2G6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
PLA2G6	47	Binding:47
COASY	10	Binding:10
FA2H	2	Binding:2
CRAT	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FA2H	1.14.18.6	4-hydroxysphinganine ceramide fatty acyl 2-hydroxylase
CP	1.16.3.1	ferroxidase
CRAT	2.3.1.7	carnitine O-acetyltransferase
COASY	2.7.1.24, 2.7.7.3	dephospho-CoA kinase, pantetheine-phosphate adenylyltransferase
PLA2G6	3.1.1.4	phospholipase A2

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 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)
MOLIBRESIB	2	COASY
VARESPLADIB	2	PLA2G6

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	2	COASY, PLA2G6
C	Druggable family + PDB, no drug	2	CP, CRAT
D	Druggable family + AlphaFold only, no drug	1	FA2H
E	Difficult family or no structure, no drug	5	REPS1, C19orf12, DCAF17, WDR45, ATP13A2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
C19orf12	0	PLA2G6
DCAF17	0	COASY
REPS1	0	—
FA2H	2	—
CP	0	—
CRAT	2	—
WDR45	0	—
ATP13A2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05522374	Not specified	RECRUITING	TIRCON International NBIA Registry
NCT06596746	Not specified	RECRUITING	Neurodegenerative Diseases Progression Markers (MARKERS-NDD)
NCT02587858	Not specified	UNKNOWN	NBIAready: Online Collection of Natural History Patient-reported Outcome Measures
NCT05615571	Not specified	COMPLETED	Testing of NBIA Genes: Analysis of Genetic Heterogeneity and Validation of Mitochondrial Markers for Assessing Causality of Sequence Variants.
NCT05696912	Not specified	UNKNOWN	Functional Tests to Resolve Unsolved Rare Diseases. Rares.