Familial thyroid dyshormonogenesis

Summary

Familial thyroid dyshormonogenesis (MONDO:0010132) is a disease (an umbrella term covering 6 Mondo subtypes) with 6 cohort genes. The dominant Reactome pathway is Thyroxine biosynthesis (5 cohort genes).

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 19
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	2.67	Worldwide	Validated
Point prevalence	1-9 / 100 000	4	Europe	Validated
Annual incidence	1-9 / 100 000	4	Finland	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0002925	Elevated circulating thyroid-stimulating hormone concentration	Very frequent (80-99%)
HP:0031507	Decreased circulating thyroxine level	Very frequent (80-99%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0000270	Delayed cranial suture closure	Frequent (30-79%)
HP:0000851	Congenital hypothyroidism	Frequent (30-79%)
HP:0000853	Goiter	Frequent (30-79%)
HP:0001537	Umbilical hernia	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0004491	Large posterior fontanelle	Frequent (30-79%)
HP:0005930	Abnormality of epiphysis morphology	Frequent (30-79%)
HP:0006579	Prolonged neonatal jaundice	Frequent (30-79%)
HP:0008263	Thyroid defect in oxidation and organification of iodide	Frequent (30-79%)
HP:0008828	Delayed proximal femoral epiphyseal ossification	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0000158	Macroglossia	Occasional (5-29%)
HP:0000282	Facial edema	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001662	Bradycardia	Occasional (5-29%)
HP:0002045	Hypothermia	Occasional (5-29%)
HP:0003265	Neonatal hyperbilirubinemia	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0025482	Positive perchlorate discharge test	Occasional (5-29%)
HP:0025483	Abnormal circulating thyroglobulin concentration	Occasional (5-29%)
HP:0031219	Reduced radioactive iodine uptake	Occasional (5-29%)
HP:0031220	Increased radioactive iodine uptake	Occasional (5-29%)
HP:0011437	Maternal autoimmune disease	Excluded (0%)
HP:0000407	Sensorineural hearing impairment	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial thyroid dyshormonogenesis
Mondo ID	MONDO:0010132
MeSH	C564766
OMIM	274400
Orphanet	95716
DOID	DOID:0112183
NCIT	C121751
SNOMED CT	718183003
UMLS	C4273748
MedGen	903446
GARD	0016843
Is cancer (heuristic)	no

Also known as: dyshormonogenesis · nongoitrous hyperthyrotropinemia · thyroid dyshormonogenesis

Data availability: 19 ClinVar variants · 6 GenCC gene-disease records.

Disease family

An umbrella term covering 6 Mondo subtypes.

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

Related subtypes (7): hypothyroidism, congenital, nongoitrous, Pendred syndrome, transient congenital hypothyroidism, permanent congenital hypothyroidism, idiopathic congenital hypothyroidism, Kocher-debre-Semelaigne syndrome, hypothyroidism due to iodide transport defect

Subtypes (6): thyroid dyshormonogenesis 2A, thyroid dyshormonogenesis 3, thyroid dyshormonogenesis 4, thyroid dyshormonogenesis 5, 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

19 retrieved; paginated sample, class counts are floors:

8 pathogenic/likely pathogenic, 7 conflicting classifications of pathogenicity, 2 pathogenic, 1 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065943	NM_001363711.2(DUOX2):c.3693+1G>T	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
225342	NM_001363711.2(DUOX2):c.1462G>A (p.Gly488Arg)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279800	NM_001363711.2(DUOX2):c.602dup (p.Gln202fs)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
287079	NM_001363711.2(DUOX2):c.1588A>T (p.Lys530Ter)	DUOX2	Pathogenic	criteria provided, multiple submitters, no conflicts
4063	NM_001363711.2(DUOX2):c.2056C>T (p.Gln686Ter)	DUOX2	Pathogenic	criteria provided, multiple submitters, no conflicts
4064	NM_001363711.2(DUOX2):c.2524C>T (p.Arg842Ter)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
932342	NM_001363711.2(DUOX2):c.3328C>T (p.Arg1110Ter)	DUOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225344	NM_207581.4(DUOXA2):c.413dup (p.Tyr138Ter)	DUOXA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
444	NM_207581.4(DUOXA2):c.738C>G (p.Tyr246Ter)	DUOXA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3779594	NM_001363711.2(DUOX2):c.1891C>T (p.Gln631Ter)	DUOX2	Likely pathogenic	criteria provided, single submitter
189228	NM_001363711.2(DUOX2):c.3847+2T>C	DUOX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316133	NM_001363711.2(DUOX2):c.4637A>G (p.Glu1546Gly)	DUOX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316175	NM_001363711.2(DUOX2):c.1825C>T (p.Pro609Ser)	DUOX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4065	NM_001363711.2(DUOX2):c.1126C>T (p.Arg376Trp)	DUOX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
617815	NM_001363711.2(DUOX2):c.2654G>T (p.Arg885Leu)	DUOX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
631732	NM_001363711.2(DUOX2):c.3155G>A (p.Cys1052Tyr)	DUOX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
888352	NM_001363711.2(DUOX2):c.598G>A (p.Gly200Arg)	DUOX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2506342	NM_001363711.2(DUOX2):c.3940G>A (p.Glu1314Lys)	DUOX2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 7 · 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
SLC5A5	Definitive	Autosomal recessive	thyroid dyshormonogenesis 1	5
DUOXA2	Strong	Autosomal recessive	thyroid dyshormonogenesis 5	4
IYD	Strong	Autosomal recessive	thyroid dyshormonogenesis 4	3
TG	Strong	Autosomal recessive	thyroid dyshormonogenesis 3	4
TPO	Strong	Autosomal recessive	thyroid dyshormonogenesis 2A	3

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
SLC5A5	Orphanet:95716	Familial thyroid dyshormonogenesis
TG	Orphanet:95716	Familial thyroid dyshormonogenesis
TPO	Orphanet:95716	Familial thyroid dyshormonogenesis
IYD	Orphanet:95716	Familial thyroid dyshormonogenesis

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

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	gencc,clinvar
SLC5A5	HGNC:11040	ENSG00000105641	Q92911	Sodium/iodide cotransporter	gencc
TG	HGNC:11764	ENSG00000042832	P01266	Thyroglobulin	gencc
TPO	HGNC:12015	ENSG00000115705	P07202	Thyroid peroxidase	gencc
IYD	HGNC:21071	ENSG00000009765	Q6PHW0	Iodotyrosine deiodinase 1	gencc

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.
SLC5A5	Sodium/iodide cotransporter	Sodium:iodide symporter that mediates the transport of iodide into the thyroid gland.
TG	Thyroglobulin	Acts as a substrate for the production of iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3).
TPO	Thyroid peroxidase	Iodination and coupling of the hormonogenic tyrosines in thyroglobulin to yield the thyroid hormones T(3) and T(4).
IYD	Iodotyrosine deiodinase 1	Catalyzes the dehalogenation of halotyrosines such as 3-bromo-L-tyrosine, 3-chloro-L-tyrosine, 3-iodo-L-tyrosine and 3,5-diiodo-L-tyrosine.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 3 · 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
Complement	1	44.7×	0.067
Enzyme (other)	2	4.0×	0.125
Other/Unknown	3	0.9×	0.758

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
SLC5A5	Other/Unknown	no		Na/solute_symporter, Na/solute_symporter_CS, SLC5A5
TG	Other/Unknown	no		Thyroglobulin_1, CarbesteraseB, Tyr-kin_ephrin_A/B_rcpt-like
TPO	Complement	yes	1.11.1.8	EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, EGF
IYD	Enzyme (other)	yes	1.21.1.1	Nitroreductase-like, Nitroreductase, Nitroreductase/BluB

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left lobe of thyroid gland	3
right lobe of thyroid gland	3
thyroid gland	3
gall bladder	2
nasal cavity epithelium	2
palpebral conjunctiva	1
pancreatic ductal cell	1
mucosa of stomach	1
olfactory bulb	1
type B pancreatic 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
SLC5A5	85	tissue_specific	marker	olfactory bulb, type B pancreatic cell, mucosa of stomach
TG	169	tissue_specific	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
TPO	132	tissue_specific	marker	left lobe of thyroid gland, thyroid gland, right lobe of thyroid gland
IYD	130	tissue_specific	marker	right lobe of thyroid gland, thyroid gland, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 13.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IYD	2,104
DUOX2	1,639
TG	1,493
SLC5A5	1,306
TPO	1,074
DUOXA2	633

Intra-cohort edges

A	B	Sources
DUOX2	DUOXA2	intact, string_interaction
DUOX2	IYD	string_interaction
DUOX2	SLC5A5	string_interaction
DUOXA2	IYD	string_interaction
DUOXA2	SLC5A5	string_interaction
DUOXA2	TG	string_interaction
DUOXA2	TPO	string_interaction
IYD	SLC5A5	string_interaction
IYD	TG	string_interaction
IYD	TPO	string_interaction
SLC5A5	TG	string_interaction
SLC5A5	TPO	string_interaction
TG	TPO	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TG	P01266	3
IYD	Q6PHW0	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DUOX2	Q9NRD8	84.37
TPO	P07202	84.00
DUOXA2	Q1HG44	83.29
SLC5A5	Q92911	81.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 6 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Thyroxine biosynthesis	5	815.7×	2e-14	DUOX2, DUOXA2, SLC5A5, TPO, IYD
Metabolism of amine-derived hormones	2	652.6×	2e-05	SLC5A5, IYD
Defective SLC5A5 causes thyroid dyshormonogenesis 1 (TDH1)	1	2284.0×	0.002	SLC5A5
SLC-mediated transport of inorganic anions	1	1142.0×	0.003	SLC5A5
Metabolism of amino acids and derivatives	2	27.0×	0.005	SLC5A5, IYD
Organic anion transport by SLC5/17/25 transporters	1	285.5×	0.008	SLC5A5
SLC transporter disorders	1	40.8×	0.045	SLC5A5
Disorders of transmembrane transporters	1	27.9×	0.055	SLC5A5
R-HSA-425393	1	25.9×	0.055	SLC5A5
Metabolism	2	4.7×	0.081	SLC5A5, IYD
SLC-mediated transmembrane transport	1	11.8×	0.097	SLC5A5
Transport of small molecules	1	5.0×	0.199	SLC5A5
Disease	1	2.6×	0.328	SLC5A5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 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 generation	4	660.9×	4e-10	DUOX2, SLC5A5, TG, TPO
hormone biosynthetic process	3	702.2×	1e-07	DUOX2, TG, TPO
iodide transport	2	802.5×	3e-05	SLC5A5, TG
positive regulation of cell motility	2	255.3×	2e-04	DUOX2, DUOXA2
hydrogen peroxide catabolic process	2	224.7×	2e-04	DUOX2, TPO
iodide transmembrane transport	1	1404.3×	0.003	SLC5A5
cellular response to Thyroid stimulating hormone	1	1404.3×	0.003	SLC5A5
regulation of thyroid hormone generation	1	1404.3×	0.003	DUOXA2
response to oxidative stress	2	43.5×	0.003	DUOX2, TPO
cuticle development	1	936.2×	0.004	DUOX2
obsolete tyrosine metabolic process	1	702.2×	0.004	IYD
positive regulation of hydrogen peroxide biosynthetic process	1	702.2×	0.004	DUOXA2
hydrogen peroxide metabolic process	1	702.2×	0.004	DUOXA2
cellular response to gonadotropin stimulus	1	468.1×	0.005	SLC5A5
thyroid hormone metabolic process	1	234.1×	0.009	IYD
hydrogen peroxide biosynthetic process	1	234.1×	0.009	DUOX2
cellular response to forskolin	1	187.2×	0.011	SLC5A5
embryonic hemopoiesis	1	165.2×	0.012	TPO
regulation of myelination	1	147.8×	0.012	TG
superoxide anion generation	1	112.3×	0.016	DUOX2
thyroid gland development	1	90.6×	0.018	TG
positive regulation of wound healing	1	87.8×	0.018	DUOX2
response to cAMP	1	85.1×	0.018	DUOX2
cellular response to cAMP	1	48.4×	0.030	SLC5A5
sodium ion transport	1	45.3×	0.031	SLC5A5
defense response	1	36.0×	0.037	DUOX2
transport across blood-brain barrier	1	29.9×	0.043	SLC5A5
regulation of inflammatory response	1	28.1×	0.044	DUOXA2
protein maturation	1	27.3×	0.044	DUOXA2
monoatomic ion transport	1	26.0×	0.044	SLC5A5

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 2 of 6 evidence-associated genes (33%) 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
TPO	PROPYLTHIOURACIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TPO	3	4
DUOX2	0	0
DUOXA2	0	0
SLC5A5	0	0
TG	0	0
IYD	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PROPYLTHIOURACIL	4	TPO
MITIPERSTAT	2	TPO
PF-06282999	1	TPO

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
TPO	12	Binding:12
DUOX2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DUOX2	1.6.3.1	NAD(P)H oxidase (H2O2-forming)
TPO	1.11.1.8, 3.6.1.52	iodide peroxidase, diphosphoinositol-polyphosphate diphosphatase
IYD	1.21.1.1	iodotyrosine deiodinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
PROPYLTHIOURACIL	4	TPO
MITIPERSTAT	2	TPO
PF-06282999	1	TPO

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TPO
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	IYD
D	Druggable family + AlphaFold only, no drug	1	DUOX2
E	Difficult family or no structure, no drug	3	DUOXA2, SLC5A5, TG

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC5A5	0	TPO
TG	0	TPO
IYD	0	TPO
DUOX2	1	—
DUOXA2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.