Epsilon-trimethyllysine hydroxylase deficiency
disease diseaseOn this page
Also known as autism, susceptibility to, X-linked 6, X-linked recessiveAUTSX6TMLHED
Summary
Epsilon-trimethyllysine hydroxylase deficiency (MONDO:0010469) is a disease with 2 cohort genes.
At a glance
- Cohort genes: 2
- ClinVar variants: 17
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | epsilon-trimethyllysine hydroxylase deficiency |
| Mondo ID | MONDO:0010469 |
| OMIM | 300872 |
| UMLS | C3550875 |
| MedGen | 763789 |
| Is cancer (heuristic) | no |
Also known as: autism, susceptibility to, X-linked 6, X-linked recessive · AUTSX6 · epsilon-trimethyllysine hydroxylase deficiency · TMLHED
Data availability: 17 ClinVar variants · 2 GenCC gene-disease records.
Disease family
Classification path: disease susceptibility › inherited disease susceptibility › autism, susceptiblity to › epsilon-trimethyllysine hydroxylase deficiency
Related subtypes (25): autism, susceptibility to, X-linked 1, autism, susceptibility to, X-linked 2, autism, susceptibility to, X-linked 3, autism, susceptibility to, X-linked 4, autism, susceptibility to, X-linked 5, intellectual developmental disorder with autism and speech delay, autism, susceptibility to, 8, autism, susceptibility to, 3, autism, susceptibility to, 6, autism, susceptibility to, 7, autism, susceptibility to, 11, autism, susceptibility to, 12, autism, susceptibility to, 13, autism, susceptibility to, 9, autism, susceptibility to, 10, autism, susceptibility to, 15, autism, susceptibility to, 16, autism, susceptibility to, 17, intellectual developmental disorder with autism and macrocephaly, autism, susceptibility to, 19, autism, susceptibility to, 20, autism, susceptibility to, 14a, autism, susceptibility to, 14b, autism, susceptibility to, 1, autism, susceptibility to, 4
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
17 retrieved; paginated sample, class counts are floors:
11 uncertain significance, 2 likely pathogenic, 2 risk factor, 1 pathogenic, 1 conflicting classifications of pathogenicity
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 225231 | NM_018196.4(TMLHE):c.961_962del (p.Ile321fs) | TMLHE | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1299348 | NM_018196.4(TMLHE):c.638+2del | TMLHE | Likely pathogenic | no assertion criteria provided |
| 4845897 | NM_018196.4(TMLHE):c.224G>A (p.Trp75Ter) | TMLHE | Likely pathogenic | criteria provided, single submitter |
| 31938 | NC_000023.11:g.(155524633_155545096)_(155545276_155612791)del | SPRY3 | risk factor | no assertion criteria provided |
| 225229 | NM_018196.4(TMLHE):c.730G>C (p.Asp244His) | TMLHE | risk factor | no assertion criteria provided |
| 372796 | NM_018196.4(TMLHE):c.359-2A>G | TMLHE | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1342626 | NM_018196.4(TMLHE):c.638+83_995+2127del | TMLHE | Uncertain significance | criteria provided, single submitter |
| 1685178 | NM_018196.4(TMLHE):c.158G>A (p.Trp53Ter) | TMLHE | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 1691494 | NM_018196.4(TMLHE):c.491C>T (p.Ser164Leu) | TMLHE | Uncertain significance | criteria provided, single submitter |
| 1709697 | NM_018196.4(TMLHE):c.523G>A (p.Glu175Lys) | TMLHE | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 225228 | NM_018196.4(TMLHE):c.229C>T (p.Arg77Ter) | TMLHE | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 225230 | NM_018196.4(TMLHE):c.1107G>T (p.Glu369Asp) | TMLHE | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 3382623 | NM_018196.4(TMLHE):c.995+2T>C | TMLHE | Uncertain significance | criteria provided, single submitter |
| 4081954 | NM_018196.4(TMLHE):c.639-10_758+10del | TMLHE | Uncertain significance | no assertion criteria provided |
| 450888 | NM_018196.4(TMLHE):c.794C>T (p.Thr265Ile) | TMLHE | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 828134 | NM_018196.4(TMLHE):c.6G>T (p.Trp2Cys) | TMLHE | Uncertain significance | no assertion criteria provided |
| 982862 | NM_018196.4(TMLHE):c.278G>A (p.Arg93His) | TMLHE | Uncertain significance | 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 |
|---|---|---|---|---|
| TMLHE | Limited | Unknown | epsilon-trimethyllysine hydroxylase deficiency | 2 |
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 |
|---|---|---|---|---|---|
| TMLHE | HGNC:18308 | ENSG00000185973 | Q9NVH6 | Trimethyllysine dioxygenase, mitochondrial | gencc,clinvar |
| SPRY3 | HGNC:11271 | ENSG00000168939 | O43610 | Protein sprouty homolog 3 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| TMLHE | Trimethyllysine dioxygenase, mitochondrial | Converts trimethyllysine (TML) into hydroxytrimethyllysine (HTML). |
| SPRY3 | Protein sprouty homolog 3 | Inhibits neurite branching, arbor length and neurite complexity. |
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) |
|---|---|---|---|---|
| TMLHE | Enzyme (other) | yes | 1.14.11.8 | TauD/TfdA-like, GBBH-like_N, Trimethyllysine_dOase |
| SPRY3 | Other/Unknown | no | Sprouty, Sprouty_domain |
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 |
|---|---|
| hindlimb stylopod muscle | 1 |
| muscle of leg | 1 |
| skeletal muscle tissue | 1 |
| cortical plate | 1 |
| male germ line stem cell (sensu Vertebrata) in testis | 1 |
| pancreatic ductal cell | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| TMLHE | 136 | ubiquitous | marker | skeletal muscle tissue, hindlimb stylopod muscle, muscle of leg |
| SPRY3 | 162 | broad | yes | pancreatic ductal cell, male germ line stem cell (sensu Vertebrata) in testis, cortical plate |
Protein interactions among cohort
Intra-cohort edges: 1.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| TMLHE | 1,629 |
| SPRY3 | 734 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| SPRY3 | TMLHE | string_interaction |
Structural data
PDB: 0 · AlphaFold-only: 2 · No structure: 0
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| TMLHE | Q9NVH6 | 89.10 |
| SPRY3 | O43610 | 63.71 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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 |
|---|---|---|---|---|
| Carnitine synthesis | 1 | 2855.0× | 4e-04 | TMLHE |
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 |
|---|---|---|---|---|
| negative regulation of neuron projection arborization | 1 | 8426.0× | 9e-04 | SPRY3 |
| carnitine biosynthetic process | 1 | 1685.2× | 0.002 | TMLHE |
| negative regulation of fibroblast growth factor receptor signaling pathway | 1 | 526.6× | 0.005 | SPRY3 |
| animal organ development | 1 | 366.4× | 0.005 | SPRY3 |
| negative regulation of Ras protein signal transduction | 1 | 337.0× | 0.005 | SPRY3 |
| negative regulation of MAPK cascade | 1 | 150.5× | 0.009 | SPRY3 |
| negative regulation of ERK1 and ERK2 cascade | 1 | 108.0× | 0.011 | SPRY3 |
| nervous system development | 1 | 23.0× | 0.043 | SPRY3 |
Therapeutics
Drug target analysis
Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2
Druggability breadth: 0 of 2 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 |
|---|---|---|
| TMLHE | 0 | 0 |
| SPRY3 | 0 | 0 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 1.
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| TMLHE | 1.14.11.8 | trimethyllysine dioxygenase |
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
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 | TMLHE |
| E | Difficult family or no structure, no drug | 1 | SPRY3 |
Undrugged target profiles
2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| TMLHE | 0 | — |
| SPRY3 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.