Thyroid dyshormonogenesis 6

Summary

Thyroid dyshormonogenesis 6 (MONDO:0011792) is a disease caused by DUOX2 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: DUOX2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 370
• Phenotypes (HPO): 21
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0000853	Goiter	Frequent (30-79%)
HP:0002925	Elevated circulating thyroid-stimulating hormone concentration	Frequent (30-79%)
HP:0008263	Thyroid defect in oxidation and organification of iodide	Frequent (30-79%)
HP:0025484	Increased circulating thyroglobulin concentration	Frequent (30-79%)
HP:0031507	Decreased circulating thyroxine level	Frequent (30-79%)
HP:0000158	Macroglossia	Occasional (5-29%)
HP:0001070	Mottled pigmentation	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0001615	Hoarse cry	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0006579	Prolonged neonatal jaundice	Occasional (5-29%)
HP:0011437	Maternal autoimmune disease	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0031169	Postterm pregnancy	Occasional (5-29%)
HP:0031221	Abnormal radioactive iodine uptake test result	Occasional (5-29%)
HP:0100786	Hypersomnia	Occasional (5-29%)
HP:0000969	Edema	Very rare (<1-4%)
HP:0001252	Hypotonia	Very rare (<1-4%)
HP:0002045	Hypothermia	Very rare (<1-4%)
HP:0005990	Thyroid hypoplasia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	thyroid dyshormonogenesis 6
Mondo ID	MONDO:0011792
MeSH	C564608
OMIM	607200
Orphanet	226316
DOID	DOID:0112189
UMLS	C1846632
MedGen	375935
GARD	0018193
Is cancer (heuristic)	no

Also known as: DUOX2 familial thyroid dyshormonogenesis · familial thyroid dyshormonogenesis caused by mutation in DUOX2 · TDH6 · thyroid dyshormonogenesis 6 · thyroid dyshormonogenesis type 6

Data availability: 370 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 6

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

370 retrieved; paginated sample, class counts are floors:

125 uncertain significance, 105 conflicting classifications of pathogenicity, 46 likely pathogenic, 35 pathogenic/likely pathogenic, 26 pathogenic, 15 benign, 14 benign/likely benign, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027400	NM_001363711.2(DUOX2):c.605_621del (p.Gln202fs)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065943	NM_001363711.2(DUOX2):c.3693+1G>T	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071547	NM_001363711.2(DUOX2):c.2101C>T (p.Arg701Ter)	DUOX2	Pathogenic	criteria provided, multiple submitters, no conflicts
1210930	NM_001363711.2(DUOX2):c.4552G>A (p.Gly1518Ser)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322789	NM_001363711.2(DUOX2):c.2921+2T>C	DUOX2	Pathogenic	criteria provided, single submitter
1322790	NM_001363711.2(DUOX2):c.2000del (p.Leu667fs)	DUOX2	Pathogenic	criteria provided, multiple submitters, no conflicts
1324306	NM_001363711.2(DUOX2):c.2635G>A (p.Glu879Lys)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339190	NM_001363711.2(DUOX2):c.3033C>A (p.Tyr1011Ter)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1404956	NM_001363711.2(DUOX2):c.1153C>T (p.Gln385Ter)	DUOX2	Pathogenic	criteria provided, multiple submitters, no conflicts
1414720	NM_001363711.2(DUOX2):c.1606C>T (p.Arg536Ter)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1415646	NM_001363711.2(DUOX2):c.1461_1462delinsCA (p.Gly488Arg)	DUOX2	Pathogenic	criteria provided, multiple submitters, no conflicts
1452632	NM_001363711.2(DUOX2):c.3751del (p.Leu1251fs)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454477	NM_001363711.2(DUOX2):c.4524+1dup	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454809	NM_001363711.2(DUOX2):c.1741C>T (p.Gln581Ter)	DUOX2	Pathogenic	criteria provided, multiple submitters, no conflicts
1456312	NM_001363711.2(DUOX2):c.1873C>T (p.Arg625Ter)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457928	NM_001363711.2(DUOX2):c.2335-1G>C	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458737	NM_001363711.2(DUOX2):c.2654G>A (p.Arg885Gln)	DUOX2	Pathogenic	criteria provided, multiple submitters, no conflicts
1687299	NM_001363711.2(DUOX2):c.790del (p.Leu264fs)	DUOX2	Pathogenic	criteria provided, single submitter
1803440	NM_001363711.2(DUOX2):c.3061C>T (p.Arg1021Ter)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189229	NM_001363711.2(DUOX2):c.2895_2898del (p.Phe966fs)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1906787	NM_001363711.2(DUOX2):c.4152del (p.Gly1386fs)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1956595	NM_001363711.2(DUOX2):c.3134_3135del (p.Val1045fs)	DUOX2	Pathogenic	criteria provided, multiple submitters, no conflicts
225342	NM_001363711.2(DUOX2):c.1462G>A (p.Gly488Arg)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225343	NM_001363711.2(DUOX2):c.2653C>T (p.Arg885Ter)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2267170	NM_001363711.2(DUOX2):c.1395_1396del (p.Gln466fs)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2581533	NM_001363711.2(DUOX2):c.2428G>T (p.Glu810Ter)	DUOX2	Pathogenic	criteria provided, multiple submitters, no conflicts
2627482	NM_001363711.2(DUOX2):c.457C>T (p.Gln153Ter)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2636778	NM_001363711.2(DUOX2):c.3076C>T (p.Gln1026Ter)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2689071	NM_001363711.2(DUOX2):c.1708C>T (p.Gln570Ter)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2701361	NM_001363711.2(DUOX2):c.2413G>T (p.Glu805Ter)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
DUOX2	Definitive	Autosomal recessive	thyroid dyshormonogenesis 6	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DUOX2	Orphanet:226316	Genetic transient congenital hypothyroidism
DUOX2	Orphanet:95716	Familial thyroid dyshormonogenesis
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
DUOX2	HGNC:13273	ENSG00000140279	Q9NRD8	Dual oxidase 2	gencc,clinvar
DUOXA2	HGNC:32698	ENSG00000140274	Q1HG44	Dual oxidase maturation factor 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DUOX2	Dual oxidase 2	Generates hydrogen peroxide which is required for the activity of thyroid peroxidase/TPO and lactoperoxidase/LPO.
DUOXA2	Dual oxidase maturation factor 2	Required for the maturation and transport of functional DUOX2 from the endoplasmic reticulum to the plasma membrane.

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)
DUOX2	Enzyme (other)	yes	1.6.3.1	EF_hand_dom, Haem_peroxidase_sf, EF-hand-dom_pair
DUOXA2	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	2
nasal cavity epithelium	2
palpebral conjunctiva	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DUOX2	191	tissue_specific	marker	gall bladder, nasal cavity epithelium, palpebral conjunctiva
DUOXA2	121	tissue_specific	marker	pancreatic ductal cell, nasal cavity epithelium, gall bladder

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DUOX2	1,639
DUOXA2	633

Intra-cohort edges

A	B	Sources
DUOX2	DUOXA2	intact, string_interaction

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DUOX2	Q9NRD8	84.37
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	DUOX2, DUOXA2

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 cell motility	2	766.0×	3e-05	DUOX2, DUOXA2
regulation of thyroid hormone generation	1	4213.0×	0.002	DUOXA2
cuticle development	1	2808.7×	0.002	DUOX2
positive regulation of hydrogen peroxide biosynthetic process	1	2106.5×	0.002	DUOXA2
hydrogen peroxide metabolic process	1	2106.5×	0.002	DUOXA2
hormone biosynthetic process	1	702.2×	0.004	DUOX2
hydrogen peroxide biosynthetic process	1	702.2×	0.004	DUOX2
thyroid hormone generation	1	495.6×	0.005	DUOX2
superoxide anion generation	1	337.0×	0.006	DUOX2
hydrogen peroxide catabolic process	1	337.0×	0.006	DUOX2
positive regulation of wound healing	1	263.3×	0.007	DUOX2
response to cAMP	1	255.3×	0.007	DUOX2
defense response	1	108.0×	0.014	DUOX2
regulation of inflammatory response	1	84.3×	0.016	DUOXA2
protein maturation	1	81.8×	0.016	DUOXA2
response to virus	1	72.0×	0.017	DUOX2
response to oxidative stress	1	65.3×	0.017	DUOX2
cytokine-mediated signaling pathway	1	65.3×	0.017	DUOX2
intracellular protein localization	1	52.3×	0.020	DUOXA2
protein transport	1	21.9×	0.045	DUOXA2

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
DUOX2	0	0
DUOXA2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DUOX2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DUOX2	1.6.3.1	NAD(P)H oxidase (H2O2-forming)

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	DUOX2
E	Difficult family or no structure, no drug	1	DUOXA2

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)
DUOX2	1	—
DUOXA2	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