Leukodystrophy, hypomyelinating, 16

Summary

Leukodystrophy, hypomyelinating, 16 (MONDO:0054791) is a disease caused by TMEM106B (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TMEM106B (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	leukodystrophy, hypomyelinating, 16
Mondo ID	MONDO:0054791
OMIM	617964
DOID	DOID:0070405
UMLS	C4693779
MedGen	1631337
GARD	0025976
Is cancer (heuristic)	no

Also known as: HLD16 · leukodystrophy, hypomyelinating, 16

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

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › leukodystrophy, hypomyelinating, 16

Related subtypes (64): Alexander disease, cerebrotendinous xanthomatosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, dermatoleukodystrophy, Krabbe disease, Sjogren-Larsson syndrome, Canavan disease, Pelizaeus-Merzbacher spectrum disorder, 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, 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

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:

7 uncertain significance, 4 benign, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3772686	NM_001134232.2(TMEM106B):c.754G>C (p.Asp252His)	TMEM106B	Pathogenic	criteria provided, single submitter
523236	NM_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn)	TMEM106B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028107	NM_001134232.2(TMEM106B):c.55G>C (p.Asp19His)	TMEM106B	Uncertain significance	criteria provided, single submitter
1806032	NM_001134232.2(TMEM106B):c.523G>A (p.Val175Ile)	TMEM106B	Uncertain significance	criteria provided, single submitter
2229552	NM_001134232.2(TMEM106B):c.464A>G (p.Asn155Ser)	TMEM106B	Uncertain significance	criteria provided, multiple submitters, no conflicts
2437108	NM_001134232.2(TMEM106B):c.697A>G (p.Thr233Ala)	TMEM106B	Uncertain significance	criteria provided, single submitter
2585394	NM_001134232.2(TMEM106B):c.167G>T (p.Arg56Ile)	TMEM106B	Uncertain significance	criteria provided, single submitter
3341382	NM_001134232.2(TMEM106B):c.322C>G (p.Leu108Val)	TMEM106B	Uncertain significance	criteria provided, single submitter
4076258	NM_001134232.2(TMEM106B):c.595G>A (p.Val199Ile)	TMEM106B	Uncertain significance	criteria provided, single submitter
1168238	NM_001134232.2(TMEM106B):c.554C>G (p.Thr185Ser)	TMEM106B	Benign	criteria provided, multiple submitters, no conflicts
1168270	NM_001134232.2(TMEM106B):c.687-11A>G	TMEM106B	Benign	criteria provided, multiple submitters, no conflicts
1342220	NM_001134232.2(TMEM106B):c.442-44_442-43insGTTT	TMEM106B	Benign	criteria provided, single submitter
1342221	NM_001134232.2(TMEM106B):c.686+29T>A	TMEM106B	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
TMEM106B	Strong	Autosomal dominant	leukodystrophy, hypomyelinating, 16	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM106B	Orphanet:100069	Semantic dementia
TMEM106B	Orphanet:100070	Progressive non-fluent aphasia
TMEM106B	Orphanet:275864	Behavioral variant of frontotemporal dementia

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
TMEM106B	HGNC:22407	ENSG00000106460	Q9NUM4	Transmembrane protein 106B	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM106B	Transmembrane protein 106B	In neurons, involved in the transport of late endosomes/lysosomes.

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)
TMEM106B	Other/Unknown	no		TMEM106, TMEM106_C, TMEM106_N

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
caput epididymis	1
cauda epididymis	1
corpus epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM106B	286	ubiquitous	marker	caput epididymis, corpus epididymis, cauda epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TMEM106B	1,449

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TMEM106B	Q9NUM4	29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
regulation of lysosome organization	1	2808.7×	0.003	TMEM106B
lysosomal protein catabolic process	1	1053.2×	0.003	TMEM106B
positive regulation of dendrite development	1	991.3×	0.003	TMEM106B
lysosomal transport	1	702.2×	0.003	TMEM106B
lysosomal lumen acidification	1	674.1×	0.003	TMEM106B
lysosome localization	1	526.6×	0.003	TMEM106B
neuron cellular homeostasis	1	455.5×	0.003	TMEM106B
dendrite morphogenesis	1	432.1×	0.003	TMEM106B
lysosome organization	1	306.4×	0.003	TMEM106B

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
TMEM106B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	TMEM106B

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)
TMEM106B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.