Thyroid dyshormonogenesis 5

Summary

Thyroid dyshormonogenesis 5 (MONDO:0010137) is a disease caused by DUOXA2 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: DUOXA2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 34
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thyroid dyshormonogenesis 5
Mondo ID	MONDO:0010137
MeSH	C562771
OMIM	274900
DOID	DOID:0112184
SNOMED CT	63127008
UMLS	C0342196
MedGen	87430
GARD	0018192
Is cancer (heuristic)	no

Also known as: DUOXA2 familial thyroid dyshormonogenesis · familial thyroid dyshormonogenesis caused by mutation in DUOXA2 · hypothyroidism, congenital, due to dyshormonogenesis, 5 · TDH5 · thyroid dyshormonogenesis 5 · thyroid dyshormonogenesis type 5 · thyroid hormonogenesis, genetic defect in, 5

Data availability: 34 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › thyroid gland disorder › hypothyroidism › congenital hypothyroidism › familial thyroid dyshormonogenesis › thyroid dyshormonogenesis 5

Related subtypes (5): thyroid dyshormonogenesis 2A, thyroid dyshormonogenesis 3, thyroid dyshormonogenesis 4, thyroid dyshormonogenesis 6, thyroid dyshormonogenesis 1

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

34 retrieved; paginated sample, class counts are floors:

16 likely pathogenic, 8 pathogenic, 5 benign, 3 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
3366765	NC_000015.9:g.(?45406523)(45410620_?)del	DUOXA1	Pathogenic	criteria provided, single submitter
1806167	NM_207581.4(DUOXA2):c.298del (p.Arg100fs)	DUOXA2	Pathogenic	criteria provided, single submitter
225344	NM_207581.4(DUOXA2):c.413dup (p.Tyr138Ter)	DUOXA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2581549	NM_207581.4(DUOXA2):c.573G>A (p.Trp191Ter)	DUOXA2	Pathogenic	criteria provided, single submitter
3577206	NM_207581.4(DUOXA2):c.37C>T (p.Gln13Ter)	DUOXA2	Pathogenic	criteria provided, single submitter
3577207	NM_207581.4(DUOXA2):c.136del (p.Arg46fs)	DUOXA2	Pathogenic	criteria provided, single submitter
444	NM_207581.4(DUOXA2):c.738C>G (p.Tyr246Ter)	DUOXA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
547935	NM_207581.4(DUOXA2):c.414C>G (p.Tyr138Ter)	DUOXA2	Pathogenic	criteria provided, single submitter
917857	NM_207581.4(DUOXA2):c.501C>A (p.Cys167Ter)	DUOXA2	Pathogenic	no assertion criteria provided
972709	NM_207581.4(DUOXA2):c.604G>A (p.Ala202Thr)	DUOXA2	Pathogenic	no assertion criteria provided
974896	NM_207581.4(DUOXA2):c.95dup (p.Leu32fs)	DUOXA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3577220	NM_207581.4(DUOXA2):c.770-19_780del	DUOXA1	Likely pathogenic	criteria provided, single submitter
3577221	NM_207581.4(DUOXA2):c.860del (p.Lys287fs)	DUOXA1	Likely pathogenic	criteria provided, single submitter
1705348	NM_207581.4(DUOXA2):c.228G>T (p.Trp76Cys)	DUOXA2	Likely pathogenic	criteria provided, single submitter
3383175	NM_207581.4(DUOXA2):c.113_119del (p.Phe38fs)	DUOXA2	Likely pathogenic	criteria provided, single submitter
3577205	NM_207581.4(DUOXA2):c.1A>G (p.Met1Val)	DUOXA2	Likely pathogenic	criteria provided, single submitter
3577208	NM_207581.4(DUOXA2):c.147+1G>T	DUOXA2	Likely pathogenic	criteria provided, single submitter
3577209	NM_207581.4(DUOXA2):c.205+1G>A	DUOXA2	Likely pathogenic	criteria provided, single submitter
3577210	NM_207581.4(DUOXA2):c.205+1G>T	DUOXA2	Likely pathogenic	criteria provided, single submitter
3577211	NM_207581.4(DUOXA2):c.340+1G>A	DUOXA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3577212	NM_207581.4(DUOXA2):c.382G>T (p.Glu128Ter)	DUOXA2	Likely pathogenic	criteria provided, single submitter
3577213	NM_207581.4(DUOXA2):c.396G>A (p.Trp132Ter)	DUOXA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3577214	NM_207581.4(DUOXA2):c.465_466dup (p.Tyr156fs)	DUOXA2	Likely pathogenic	criteria provided, single submitter
3577215	NM_207581.4(DUOXA2):c.611T>C (p.Leu204Pro)	DUOXA2	Likely pathogenic	criteria provided, single submitter
3577216	NM_207581.4(DUOXA2):c.753G>A (p.Trp251Ter)	DUOXA2	Likely pathogenic	criteria provided, single submitter
3577217	NM_207581.4(DUOXA2):c.768del (p.Gly257fs)	DUOXA2	Likely pathogenic	criteria provided, single submitter
3577219	NM_207581.4(DUOXA2):c.769+2T>A	DUOXA2	Likely pathogenic	criteria provided, single submitter
1701924	NM_207581.4(DUOXA2):c.228G>C (p.Trp76Cys)	DUOXA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265105	NM_207581.4(DUOXA2):c.205+2T>C	DUOXA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
263302	NM_207581.4(DUOXA2):c.298C>G (p.Arg100Gly)	DUOXA2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
DUOXA2	Strong	Autosomal recessive	thyroid dyshormonogenesis 5	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DUOXA2	Orphanet:95716	Familial thyroid dyshormonogenesis

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
DUOXA2	HGNC:32698	ENSG00000140274	Q1HG44	Dual oxidase maturation factor 2	gencc,clinvar
DUOXA1	HGNC:26507	ENSG00000140254	Q1HG43	Dual oxidase maturation factor 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DUOXA2	Dual oxidase maturation factor 2	Required for the maturation and transport of functional DUOX2 from the endoplasmic reticulum to the plasma membrane.
DUOXA1	Dual oxidase maturation factor 1	Required for the maturation and transport of functional DUOX1 from the endoplasmic reticulum to the plasma membrane.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DUOXA2	Other/Unknown	no		Dual_oxidase_maturation_fac
DUOXA1	Other/Unknown	no		Dual_oxidase_maturation_fac

Expression context

Cohort genes with no expression data: 0.

2 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)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gall bladder	1
nasal cavity epithelium	1
pancreatic ductal cell	1
left lobe of thyroid gland	1
lower esophagus mucosa	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DUOXA2	121	tissue_specific	marker	pancreatic ductal cell, nasal cavity epithelium, gall bladder
DUOXA1	181	tissue_specific	marker	lower esophagus mucosa, right lobe of thyroid gland, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DUOXA2	633
DUOXA1	515

Intra-cohort edges

A	B	Sources
DUOXA1	DUOXA2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DUOXA1	Q1HG43	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DUOXA2	Q1HG44	83.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Thyroxine biosynthesis	2	815.7×	1e-06	DUOXA2, DUOXA1

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
regulation of thyroid hormone generation	2	8426.0×	6e-08	DUOXA2, DUOXA1
positive regulation of hydrogen peroxide biosynthetic process	2	4213.0×	1e-07	DUOXA2, DUOXA1
hydrogen peroxide metabolic process	2	4213.0×	1e-07	DUOXA2, DUOXA1
regulation of inflammatory response	2	168.5×	8e-05	DUOXA2, DUOXA1
intracellular protein localization	2	104.7×	2e-04	DUOXA2, DUOXA1
protein transport	2	43.9×	8e-04	DUOXA2, DUOXA1
positive regulation of cell motility	1	383.0×	0.003	DUOXA2
positive regulation of neuron differentiation	1	99.1×	0.011	DUOXA1
protein maturation	1	81.8×	0.012	DUOXA2

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
DUOXA2	0	0
DUOXA1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	2	DUOXA2, DUOXA1

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)
DUOXA2	0	—
DUOXA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns