Thyroid hormone metabolism, abnormal, 2

Summary

Thyroid hormone metabolism, abnormal, 2 (MONDO:0030839) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thyroid hormone metabolism, abnormal, 2
Mondo ID	MONDO:0030839
OMIM	619855
UMLS	C5676976
MedGen	1812066
Is cancer (heuristic)	no

Also known as: THMA2 · thyroid hormone metabolism, abnormal, 2

Data availability: 2 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › thyroid hormone metabolism, abnormal › thyroid hormone metabolism, abnormal, 2

Related subtypes (2): thyroid hormone metabolism, abnormal 1, thyroid hormone metabolism, abnormal, 3

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

2 retrieved; paginated sample, class counts are floors:

2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1686838	NM_000792.7(DIO1):c.282C>A (p.Asn94Lys)	DIO1	Pathogenic	no assertion criteria provided
1686839	NM_000792.7(DIO1):c.603G>A (p.Met201Ile)	DIO1	Pathogenic	no assertion criteria provided

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
DIDO1	Moderate	Autosomal dominant	thyroid hormone metabolism, abnormal, 2
DIO1	Moderate	Autosomal dominant	thyroid hormone metabolism, abnormal, 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
DIDO1	HGNC:2680	ENSG00000101191	Q9BTC0	Death-inducer obliterator 1	gencc,clinvar
DIO1	HGNC:2883	ENSG00000211452	P49895	Type I iodothyronine deiodinase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DIDO1	Death-inducer obliterator 1	Putative transcription factor, weakly pro-apoptotic when overexpressed.
DIO1	Type I iodothyronine deiodinase	Plays a crucial role in the metabolism of thyroid hormones (TH) and has specific roles in TH activation and inactivation by deiodination.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DIDO1	Transcription factor	no		Znf_PHD, TFIIS_cen_dom, Znf_FYVE_PHD
DIO1	Enzyme (other)	yes	1.21.99.4	Iodothyronine_deiodinase, Iodothyronine_deiodinase_AS, Iodothyronine_deiodinase_I/III

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
buccal mucosa cell	1
right uterine tube	1
sural nerve	1
liver	1
nephron tubule	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DIDO1	282	ubiquitous	marker	buccal mucosa cell, sural nerve, right uterine tube
DIO1	169	tissue_specific	yes	right lobe of thyroid gland, nephron tubule, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DIDO1	3,155
DIO1	329

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DIDO1	Q9BTC0	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DIO1	P49895

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Regulation of thyroid hormone activity	1	1903.3×	0.003	DIO1
Metabolism of amine-derived hormones	1	815.7×	0.004	DIO1
Thyroxine biosynthesis	1	407.9×	0.005	DIO1
Meiotic synapsis	1	70.5×	0.021	DIDO1
Metabolism of amino acids and derivatives	1	33.8×	0.035	DIO1
Metabolism	1	5.8×	0.165	DIO1

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
thyroid hormone catabolic process	1	2808.7×	0.003	DIO1
thyroid hormone metabolic process	1	702.2×	0.004	DIO1
hormone biosynthetic process	1	702.2×	0.004	DIO1
thyroid hormone generation	1	495.6×	0.004	DIO1
amino acid metabolic process	1	401.2×	0.004	DIO1
DNA-templated transcription	1	112.3×	0.010	DIDO1
apoptotic signaling pathway	1	112.3×	0.010	DIDO1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	DIDO1

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DIDO1	0	0
DIO1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DIO1	1.21.99.4	thyroxine 5’-deiodinase

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	DIO1
E	Difficult family or no structure, no drug	1	DIDO1

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)
DIDO1	0	—
DIO1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.