Tremor, hereditary essential, 6

Summary

Tremor, hereditary essential, 6 (MONDO:0030027) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	tremor, hereditary essential, 6
Mondo ID	MONDO:0030027
OMIM	618866
DOID	DOID:0081295
UMLS	C5394329
MedGen	1711112
Is cancer (heuristic)	no

Also known as: ETM6 · TREMOR, HEREDITARY ESSENTIAL, 6 · tremor, hereditary essential, 6

Data availability: 3 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › essential tremor › tremor, hereditary essential, 6

Related subtypes (5): tremor, hereditary essential, 1, tremor, hereditary essential, 2, tremor, hereditary essential, 3, tremor, hereditary essential, 4, tremor, hereditary essential, 5

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

3 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
4075314	NM_001291415.2(KDM6A):c.2366C>T (p.Thr789Ile)	KDM6A	Pathogenic	no assertion criteria provided
691867	NM_001364012.2:c.-164GGC[(66_517)]	NOTCH2NLC	Pathogenic	no assertion criteria provided
1300174	NM_000334.4(SCN4A):c.4679C>T (p.Pro1560Leu)	GH-LCR	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KDM6A	Orphanet:2322	Kabuki syndrome
NOTCH2NLC	Orphanet:2289	Neuronal intranuclear inclusion disease
NOTCH2NLC	Orphanet:98897	Oculopharyngodistal myopathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KDM6A	HGNC:12637	ENSG00000147050	O15550	Lysine-specific demethylase 6A	clinvar
NOTCH2NLC	HGNC:53924	ENSG00000286219	P0DPK4	Notch homolog 2 N-terminal-like protein C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KDM6A	Lysine-specific demethylase 6A	Histone demethylase that specifically demethylates ‘Lys-27’ of histone H3, thereby playing a central role in histone code.
NOTCH2NLC	Notch homolog 2 N-terminal-like protein C	Human-specific protein that promotes neural progenitor proliferation and evolutionary expansion of the brain neocortex by regulating the Notch signaling pathway.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KDM6A	Enzyme (other)	yes	1.14.11.68	JmjC_dom, TPR-like_helical_dom_sf, TPR_rpt
NOTCH2NLC	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow cell	1
oocyte	1
secondary oocyte	1
left testis	1
lower esophagus mucosa	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KDM6A	286	ubiquitous	yes	secondary oocyte, oocyte, bone marrow cell
NOTCH2NLC	134	ubiquitous	marker	lower esophagus mucosa, left testis, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KDM6A	8,825
NOTCH2NLC	668

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KDM6A	O15550	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NOTCH2NLC	P0DPK4	80.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Expression of NOTCH2NL genes	1	1142.0×	0.015	NOTCH2NLC
Maternal to zygotic transition (MZT)	1	356.9×	0.019	KDM6A
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	219.6×	0.019	NOTCH2NLC
Activation of HOX genes during differentiation	1	219.6×	0.019	KDM6A
Formation of WDR5-containing histone-modifying complexes	1	132.8×	0.022	KDM6A
HDMs demethylate histones	1	114.2×	0.022	KDM6A
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	107.7×	0.022	KDM6A
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	98.5×	0.022	KDM6A
Chromatin modifications during the maternal to zygotic transition (MZT)	1	81.6×	0.022	KDM6A
Epigenetic regulation by WDR5-containing histone modifying complexes	1	77.2×	0.022	KDM6A
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	45.7×	0.032	KDM6A
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.032	KDM6A
Chromatin organization	1	40.8×	0.032	KDM6A
Chromatin modifying enzymes	1	36.1×	0.032	KDM6A
Epigenetic regulation of gene expression	1	35.7×	0.032	KDM6A
Gene expression (Transcription)	1	8.9×	0.116	KDM6A
Developmental Biology	1	7.2×	0.134	KDM6A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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 Notch signaling pathway	1	175.5×	0.027	NOTCH2NLC
cerebral cortex development	1	102.8×	0.027	NOTCH2NLC
Notch signaling pathway	1	70.8×	0.027	NOTCH2NLC
regulation of gene expression	1	41.7×	0.027	KDM6A
heart development	1	39.4×	0.027	KDM6A
chromatin remodeling	1	36.5×	0.027	KDM6A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
KDM6A	DEFERIPRONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KDM6A	1	4
NOTCH2NLC	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DEFERIPRONE	4	KDM6A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KDM6A	40	Binding:36, Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KDM6A	1.14.11.68	[histone H3]-trimethyl-L-lysine27 demethylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
DEFERIPRONE	4	KDM6A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KDM6A
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	NOTCH2NLC

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)
NOTCH2NLC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.