Pelizaeus-Merzbacher spectrum disorder

Summary

Pelizaeus-Merzbacher spectrum disorder (MONDO:0010714) is a disease (an umbrella term covering 5 Mondo subtypes) caused by PLP1 (GenCC Definitive), with 8 cohort genes and 9 clinical trials. Top therapeutic interventions include elranatamab.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: PLP1 (GenCC Definitive)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 8
• ClinVar variants: 170
• Phenotypes (HPO): 32
• Clinical trials: 9

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.25	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.13	Germany	Validated
Point prevalence	1-9 / 1 000 000	0.35	United States	Not yet validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0000505	Visual impairment	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0001531	Failure to thrive in infancy	Very frequent (80-99%)
HP:0001622	Premature birth	Very frequent (80-99%)
HP:0002120	Cerebral cortical atrophy	Very frequent (80-99%)
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0002808	Kyphosis	Very frequent (80-99%)
HP:0004326	Cachexia	Very frequent (80-99%)
HP:0100022	Abnormality of movement	Very frequent (80-99%)
HP:0000079	Abnormality of the urinary system	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000649	Abnormality of visual evoked potentials	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001266	Choreoathetosis	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002607	Bowel incontinence	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0100026	Arteriovenous malformation	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Pelizaeus-Merzbacher spectrum disorder
Mondo ID	MONDO:0010714
MeSH	D020371
OMIM	312080
Orphanet	702
DOID	DOID:3210
ICD-11	1313582105
NCIT	C75487
SNOMED CT	64855000
UMLS	C0205711
MedGen	61440
GARD	0004265
MedDRA	10067610
Is cancer (heuristic)	no

Also known as: diffuse familial brain sclerosis · HLD1 · Pelizaeus Merzbacher disease · Pelizaeus-Merzbacher brain sclerosis · Pelizaeus-Merzbacher disease · Pelizaeus-Merzbacher disease, X-linked recessive · Pelizaeus-Merzbacher spectrum disorder · PMD · Sudanophilic leukodystrophy, Paelizeus-Merzbacher type · sudanophilic leukodystrophy, Paelizeus-Merzbacher type

Data availability: 170 ClinVar variants · 4 GenCC gene-disease records · 31 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › Pelizaeus-Merzbacher spectrum disorder

Related subtypes (64): Alexander disease, cerebrotendinous xanthomatosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, dermatoleukodystrophy, Krabbe disease, Sjogren-Larsson syndrome, Canavan disease, hereditary spastic paraplegia 2, megalencephalic leukoencephalopathy with subcortical cysts, ribose-5-P isomerase deficiency, hypomyelinating leukodystrophy 5, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, hypomyelinating leukodystrophy 6, cystic leukoencephalopathy without megalencephaly, sterol carrier protein 2 deficiency, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, hypomyelination with brain stem and spinal cord involvement and leg spasticity, leukoencephalopathy with mild cerebellar ataxia and white matter edema, progressive encephalopathy with leukodystrophy due to DECR deficiency, hypomyelinating leukodystrophy 9, multiple mitochondrial dysfunctions syndrome 4, hypomyelinating leukodystrophy 10, hypomyelinating leukodystrophy 12, hypomyelinating leukodystrophy 13, leukoencephalopathy with bilateral anterior temporal lobe cysts, progressive cavitating leukoencephalopathy, Pelizaeus-Merzbacher-like disease, CADDS, adrenoleukodystrophy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Aicardi-Goutieres syndrome, metachromatic leukodystrophy, peroxisome biogenesis disorder, unknown leukodystrophy, ravine syndrome, leukodystrophy, hypomyelinating, 22, leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, leukodystrophy, hypomyelinating, 18, leukodystrophy, hypomyelinating, 19, transient infantile, spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, leukodystrophy, hypomyelinating, 14, leukodystrophy, hypomyelinating, 20, early-onset calcifying leukoencephalopathy-skeletal dysplasia, c11orf73-related autosomal recessive hypomyelinating leukodystrophy, alkaline ceramidase 3 deficiency, leukodystrophy, hypomyelinating, 15, leukodystrophy, hypomyelinating, 16, leukodystrophy, hypomyelinating, 17, POLR-related leukodystrophy, leukoencephalopathy, diffuse hereditary, with spheroids 1, leukoencephalopathy with vanishing white matter, leukodystrophy, hypomyelinating, 24, leukodystrophy, childhood-onset, remitting, leukodystrophy, hypomyelinating, 25, leukodystrophy, hypomyelinating, 26, with chondrodysplasia, adult-onset progressive leukoencephalopathy-early-onset deafness, leukoencephalopathy, porphyria-related, episodic memory defect leukoencephalopathy, leukodystrophy, hypomyelinating, 28, leukodystrophy, demyelinating, adult-onset, leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy, leukoencephalopathy without lacunae, adult-onset, AARS1-related leukoencephalopathy

Subtypes (5): Pelizaeus-Merzbacher disease, connatal form, Pelizaeus-Merzbacher disease, classic form, Pelizaeus-Merzbacher disease, transitional form, Pelizaeus-Merzbacher disease in female carriers, null syndrome

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

170 retrieved; paginated sample, class counts are floors:

73 likely pathogenic, 34 pathogenic, 33 uncertain significance, 15 pathogenic/likely pathogenic, 10 conflicting classifications of pathogenicity, 3 benign/likely benign, 1 not provided, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1077188	Single allele	BEX2	Pathogenic	criteria provided, single submitter
11078	NC_000023.11:g.(?103776506)(103799000_104817980)del	FAM199X	Pathogenic	no assertion criteria provided
635342	NM_020435.4(GJC2):c.591dup (p.His198fs)	GJC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11093	NC_000023.11:g.(103477300_103776506)_(104039333_104817980)dup	LOC130068514	Pathogenic	no assertion criteria provided
1028820	NM_000533.5(PLP1):c.21T>A (p.Cys7Ter)	PLP1	Pathogenic	criteria provided, single submitter
11075	NM_000533.5(PLP1):c.44C>T (p.Pro15Leu)	PLP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11076	NM_000533.5(PLP1):c.467C>T (p.Thr156Ile)	PLP1	Pathogenic	no assertion criteria provided
11079	NM_000533.5(PLP1):c.544A>C (p.Thr182Pro)	PLP1	Pathogenic	no assertion criteria provided
11082	NM_000533.5(PLP1):c.220G>A (p.Gly74Arg)	PLP1	Pathogenic	no assertion criteria provided
11099	NM_000533.5(PLP1):c.169G>T (p.Asp57Tyr)	PLP1	Pathogenic	no assertion criteria provided
1344466	NM_000533.5(PLP1):c.442C>T (p.His148Tyr)	PLP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1878514	NM_000533.5(PLP1):c.754del (p.Val252fs)	PLP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209183	NM_000533.5(PLP1):c.1A>G (p.Met1Val)	PLP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2581156	NM_000533.5(PLP1):c.454-1G>A	PLP1	Pathogenic	criteria provided, multiple submitters, no conflicts
265417	NM_000533.5(PLP1):c.607G>A (p.Asp203Asn)	PLP1	Pathogenic	criteria provided, multiple submitters, no conflicts
290425	NM_000533.5(PLP1):c.453G>A (p.Lys151=)	PLP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3252098	NM_000533.5(PLP1):c.380_392del (p.Arg127fs)	PLP1	Pathogenic	criteria provided, single submitter
3252099	NM_000533.5(PLP1):c.406_422del (p.Glu136fs)	PLP1	Pathogenic	criteria provided, single submitter
3255418	NM_000533.5(PLP1):c.282del (p.Gly95fs)	PLP1	Pathogenic	criteria provided, single submitter
3255419	NM_000533.5(PLP1):c.2T>A (p.Met1Lys)	PLP1	Pathogenic	criteria provided, single submitter
3255431	NM_000533.5(PLP1):c.454-1G>T	PLP1	Pathogenic	criteria provided, single submitter
3255432	NM_000533.5(PLP1):c.454-2A>G	PLP1	Pathogenic	criteria provided, single submitter
3255440	NM_000533.5(PLP1):c.613del (p.Arg205fs)	PLP1	Pathogenic	criteria provided, single submitter
3255448	NM_000533.5(PLP1):c.676T>C (p.Ser226Pro)	PLP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3255449	NM_000533.5(PLP1):c.697-2A>C	PLP1	Pathogenic	criteria provided, single submitter
3255452	NM_000533.5(PLP1):c.728C>T (p.Ala243Val)	PLP1	Pathogenic	criteria provided, single submitter
3340088	NC_000023.11:g.(?103776942)(103790556_?)dup	PLP1	Pathogenic	criteria provided, single submitter
3375465	NM_000533.5(PLP1):c.622+1G>A	PLP1	Pathogenic	criteria provided, single submitter
397513	NM_000533.5(PLP1):c.175G>T (p.Glu59Ter)	PLP1	Pathogenic	criteria provided, single submitter
431701	NM_000533.5(PLP1):c.384_393del (p.Gln129fs)	PLP1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 17 · 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
PLP1	Definitive	X-linked	Pelizaeus-Merzbacher spectrum disorder	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLP1	Orphanet:280210	Pelizaeus-Merzbacher disease, connatal form
PLP1	Orphanet:280219	Pelizaeus-Merzbacher disease, classic form
PLP1	Orphanet:280224	Pelizaeus-Merzbacher disease, transitional form
PLP1	Orphanet:280229	Pelizaeus-Merzbacher disease in female carriers
PLP1	Orphanet:280234	Null syndrome
PLP1	Orphanet:599376	Hypomyelination of early myelinating structures
PLP1	Orphanet:99015	Spastic paraplegia type 2
GJC2	Orphanet:280282	Pelizaeus-Merzbacher-like disease due to GJC2 mutation
GJC2	Orphanet:320401	Autosomal recessive spastic paraplegia type 44
GJC2	Orphanet:568051	GJC2-related late-onset primary lymphedema
PRF1	Orphanet:391343	Fatal post-viral neurodegenerative disorder
PRF1	Orphanet:540	Familial hemophagocytic lymphohistiocytosis
PRF1	Orphanet:88	Idiopathic aplastic anemia
RAG1	Orphanet:157949	Combined immunodeficiency with granulomatosis
RAG1	Orphanet:231154	Combined immunodeficiency due to partial RAG1 deficiency
RAG1	Orphanet:331206	Severe combined immunodeficiency due to complete RAG1/2 deficiency
RAG1	Orphanet:39041	Omenn syndrome

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLP1	HGNC:9086	ENSG00000123560	P60201	Myelin proteolipid protein	gencc,clinvar
RAB9B	HGNC:14090	ENSG00000123570	Q9NP90	Ras-related protein Rab-9B	clinvar
GJC2	HGNC:17494	ENSG00000198835	Q5T442	Gap junction gamma-2 protein	clinvar
FAM199X	HGNC:25195	ENSG00000123575	Q6PEV8	Protein FAM199X	clinvar
H2BW1	HGNC:27252	ENSG00000123569	Q7Z2G1	Histone H2B type W-T	clinvar
BEX2	HGNC:30933	ENSG00000133134	Q9BXY8	Protein BEX2	clinvar
PRF1	HGNC:9360	ENSG00000180644	P14222	Perforin-1	clinvar
RAG1	HGNC:9831	ENSG00000166349	P15918	V(D)J recombination-activating protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLP1	Myelin proteolipid protein	This is the major myelin protein from the central nervous system.
RAB9B	Ras-related protein Rab-9B	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.
GJC2	Gap junction gamma-2 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
H2BW1	Histone H2B type W-T	Atypical histone H2B that can form nucleosomes structurally and dynamically indistinguishable from those containing conventional H2B.
BEX2	Protein BEX2	Regulator of mitochondrial apoptosis and G1 cell cycle in breast cancer.
PRF1	Perforin-1	Pore-forming protein that plays a key role in granzyme-mediated programmed cell death, and in defense against virus-infected or neoplastic cells.
RAG1	V(D)J recombination-activating protein 1	Catalytic component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 5 · Druggable fraction: 0.12

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
Complement	1	33.5×	0.088
Transcription factor	2	2.1×	0.377
Other/Unknown	5	1.1×	0.496

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLP1	Other/Unknown	no		Myelin_PLP, Myelin_PLP_CS
RAB9B	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
GJC2	Other/Unknown	no		Connexin, Connexin_N, Connexin_CS
FAM199X	Other/Unknown	no		FAM199X_fam
H2BW1	Other/Unknown	no		Histone_H2B, H2A/H2B/H3, Histone-fold
BEX2	Transcription factor	no		BEX, TF_A-like/BEX
PRF1	Complement	yes		C2_dom, MACPF_CS, MACPF
RAG1	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS

Expression context

Cohort genes with no expression data: 0.

4 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)	1
broad (>20)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
inferior vagus X ganglion	2
Brodmann (1909) area 23	2
endothelial cell	2
male germ line stem cell (sensu Vertebrata) in testis	2
corpus callosum	1
middle frontal gyrus	1
left ventricle myocardium	1
C1 segment of cervical spinal cord	1
spinal cord	1
corpus epididymis	1
lateral nuclear group of thalamus	1
oviduct epithelium	1
cortical plate	1
right testis	1
pons	1
blood	1
granulocyte	1
spleen	1
buccal mucosa cell	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLP1	250	broad	marker	corpus callosum, middle frontal gyrus, inferior vagus X ganglion
RAB9B	207	broad	yes	left ventricle myocardium, Brodmann (1909) area 23, endothelial cell
GJC2	181	tissue_specific	yes	C1 segment of cervical spinal cord, spinal cord, inferior vagus X ganglion
FAM199X	264	ubiquitous	yes	oviduct epithelium, corpus epididymis, lateral nuclear group of thalamus
H2BW1	13		yes	male germ line stem cell (sensu Vertebrata) in testis, cortical plate, right testis
BEX2	249	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, pons
PRF1	220	broad	marker	granulocyte, blood, spleen
RAG1	164	broad	marker	thymus, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAG1	3,549
PRF1	3,299
H2BW1	1,746
RAB9B	1,320
BEX2	1,124
GJC2	638
FAM199X	595
PLP1	157

Structural data

PDB: 3 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
H2BW1	Q7Z2G1	2
PLP1	P60201	1
RAB9B	Q9NP90	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRF1	P14222	91.01
RAG1	P15918	81.68
BEX2	Q9BXY8	68.93
GJC2	Q5T442	68.50
FAM199X	Q6PEV8	57.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 8 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RHOBTB3 ATPase cycle	1	285.5×	0.031	RAB9B
Nuclear events stimulated by ALK signaling in cancer	1	81.6×	0.031	PRF1
Interleukin-7 signaling	1	79.3×	0.031	RAG1
Gap junction assembly	1	73.2×	0.031	GJC2
Retrograde transport at the Trans-Golgi-Network	1	54.9×	0.033	RAB9B
RAB geranylgeranylation	1	43.3×	0.034	RAB9B
MAPK6/MAPK4 signaling	1	34.0×	0.036	RAG1
RAB GEFs exchange GTP for GDP on RABs	1	31.0×	0.036	RAB9B
Neutrophil degranulation	1	5.8×	0.162	RAB9B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of killing of cells of another organism	1	2808.7×	0.015	PRF1
pre-B cell allelic exclusion	1	936.2×	0.015	RAG1
immune response to tumor cell	1	936.2×	0.015	PRF1
cell communication by electrical coupling	1	702.2×	0.015	GJC2
regulation of behavioral fear response	1	702.2×	0.015	RAG1
axon ensheathment	1	468.1×	0.018	PLP1
V(D)J recombination	1	351.1×	0.018	RAG1
granzyme-mediated programmed cell death signaling pathway	1	351.1×	0.018	PRF1
protein import	1	280.9×	0.018	PRF1
negative regulation of thymocyte apoptotic process	1	280.9×	0.018	RAG1
immunological synapse formation	1	216.1×	0.018	PRF1
defense response to tumor cell	1	216.1×	0.018	PRF1
protein transmembrane transport	1	216.1×	0.018	PRF1
T cell mediated cytotoxicity	1	187.2×	0.018	PRF1
astrocyte development	1	187.2×	0.018	PLP1
central nervous system myelination	1	165.2×	0.018	PLP1
Rab protein signal transduction	1	165.2×	0.018	RAB9B
plasma membrane repair	1	96.8×	0.030	PRF1
T cell homeostasis	1	75.9×	0.031	RAG1
positive regulation of T cell differentiation	1	75.9×	0.031	RAG1
axon development	1	75.9×	0.031	PLP1
long-chain fatty acid biosynthetic process	1	73.9×	0.031	PLP1
ceramide biosynthetic process	1	70.2×	0.031	PRF1
T cell differentiation in thymus	1	68.5×	0.031	RAG1
substantia nigra development	1	61.1×	0.033	PLP1
DNA recombination	1	56.2×	0.033	RAG1
thymus development	1	56.2×	0.033	RAG1
apoptotic process	2	9.6×	0.033	BEX2, PRF1
cellular defense response	1	53.0×	0.034	PRF1
visual learning	1	51.1×	0.034	RAG1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 8 evidence-associated genes (12%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLP1	0	0
RAB9B	0	0
GJC2	0	0
FAM199X	0	0
H2BW1	0	0
BEX2	0	0
PRF1	0	0
RAG1	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
PRF1	34	Binding:34

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; 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	PRF1
E	Difficult family or no structure, no drug	7	PLP1, RAB9B, GJC2, FAM199X, H2BW1, BEX2, RAG1

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)
PLP1	0	—
RAB9B	0	—
GJC2	0	—
FAM199X	0	—
H2BW1	0	—
BEX2	0	—
PRF1	34	—
RAG1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE1	3
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07382739	PHASE2	RECRUITING	A Phase 2 Study of Radiotherapy-induced Immune Priming to Enhance Elranatamab (Elra) in Relapsed Refractory Multiple Myeloma (RRMM) With Extramedullary Disease (EMD) and Paramedullary Disease (PMD) PRIME-EMD-PMD
NCT02254863	PHASE1	RECRUITING	UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells
NCT06150716	PHASE1	RECRUITING	Orbit Study: A Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Intrathecally Administered ION356 in Participants With Pelizaeus Merzbacher Disease (PMD)
NCT01005004	PHASE1	COMPLETED	Study of Human Central Nervous System (CNS) Stem Cells Transplantation in Pelizaeus-Merzbacher Disease (PMD) Subjects
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT05659901	Not specified	RECRUITING	Rocket Study: A Study to Characterize Biomarkers and Disease Progression in Participants With Pelizaeus-Merzbacher Disease
NCT01391637	Not specified	COMPLETED	Long-Term Follow-Up Study of Human Stem Cells Transplanted in Subjects With Connatal Pelizaeus-Merzbacher Disease (PMD)
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ELRANATAMAB	4	1