Congenital hypothyroidism

disease

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Also known as congenital goitrecongenital iodine deficiency syndromecretinismfoetal iodine deficiency syndrome

Summary

Congenital hypothyroidism (MONDO:0018612) is a disease (an umbrella term covering 8 Mondo subtypes) caused by SLC26A7 (GenCC Strong), with 24 cohort genes and 24 clinical trials. The dominant Reactome pathway is Thyroxine biosynthesis (6 cohort genes). Top therapeutic interventions include levothyroxine and thyroid.

At a glance

Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
Causal gene: SLC26A7 (GenCC Strong)
Umbrella term: 8 Mondo subtypes
Cohort genes: 24
ClinVar variants: 81
Clinical trials: 24

Clinical features

Epidemiology

Prevalence records

47 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Europe	Validated
Prevalence at birth	1-5 / 10 000	38	Europe	Validated
Annual incidence	6-9 / 10 000	97.0873	Brazil	Validated
Prevalence at birth	1-5 / 10 000	10	France	Validated
Prevalence at birth	1-5 / 10 000	45.5	Italy	Validated
Prevalence at birth	6-9 / 10 000	57	Greece	Validated
Prevalence at birth	1-5 / 10 000	55.5	Cyprus	Validated
Prevalence at birth	1-5 / 10 000	15.5	Latvia	Validated
Prevalence at birth	1-5 / 10 000	49.1	China	Validated
Prevalence at birth	1-5 / 10 000	30.2	Germany	Validated
Prevalence at birth	1-5 / 10 000	29.4	Denmark	Validated
Prevalence at birth	1-5 / 10 000	25	Poland	Validated
Prevalence at birth	1-5 / 10 000	35	Estonia	Validated
Prevalence at birth	1-5 / 10 000	54.8	Lebanon	Validated
Prevalence at birth	>1 / 1000	150	Iran, Islamic Republic of	Validated
Prevalence at birth	1-5 / 10 000	43	Turkey	Validated
Prevalence at birth	1-5 / 10 000	35.4	Australia	Validated
Prevalence at birth	6-9 / 10 000	63.7	United Arab Emirates	Validated
Prevalence at birth	6-9 / 10 000	76.9	Bangladesh	Validated
Prevalence at birth	6-9 / 10 000	62.5	Pakistan	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital hypothyroidism
Mondo ID	MONDO:0018612
MeSH	D003409
Orphanet	442
DOID	DOID:0050328
ICD-11	602450215
NCIT	C26734
SNOMED CT	190268003, 217710005
UMLS	C0010308
MedGen	41344
GARD	0001487
MedDRA	10010510
Is cancer (heuristic)	no

Also known as: congenital goitre · congenital hypothyroidism · congenital iodine deficiency syndrome · cretinism · foetal iodine deficiency syndrome

Data availability: 81 ClinVar variants · 6 GenCC gene-disease records.

Disease family

An umbrella term covering 8 Mondo subtypes.

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

Related subtypes (5): postsurgical hypothyroidism, iodine hypothyroidism, myxedema, myxedema coma, myxedema heart disease

Subtypes (8): hypothyroidism, congenital, nongoitrous, familial thyroid dyshormonogenesis, Pendred syndrome, transient congenital hypothyroidism, permanent congenital hypothyroidism, idiopathic congenital hypothyroidism, Kocher-debre-Semelaigne syndrome, hypothyroidism due to iodide transport defect

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

81 retrieved; paginated sample, class counts are floors:

22 uncertain significance, 17 pathogenic, 16 conflicting classifications of pathogenicity, 12 pathogenic/likely pathogenic, 10 likely pathogenic, 2 benign, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
189229	NM_001363711.2(DUOX2):c.2895_2898del (p.Phe966fs)	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
3031356	NM_001363711.2(DUOX2):c.618dup (p.Pro207fs)	DUOX2	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
1333570	NM_001206744.2(TPO):c.1786G>T (p.Glu596Ter)	LALTOP	Pathogenic	criteria provided, multiple submitters, no conflicts
4050	NM_001206744.2(TPO):c.2268dup (p.Glu757Ter)	LALTOP	Pathogenic	criteria provided, multiple submitters, no conflicts
4053	NM_001206744.2(TPO):c.1978C>G (p.Gln660Glu)	LALTOP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
988652	NM_003466.4(PAX8):c.658C>T (p.Arg220Ter)	LOC126806316	Pathogenic	no assertion criteria provided
988648	NM_003466.4(PAX8):c.101T>A (p.Ile34Asn)	PAX8	Pathogenic	no assertion criteria provided
988649	NM_003466.4(PAX8):c.397C>T (p.Arg133Trp)	PAX8	Pathogenic	no assertion criteria provided
7670	NM_000453.3(SLC5A5):c.1183G>A (p.Gly395Arg)	SLC5A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028100	NM_003235.5(TG):c.475C>T (p.Arg159Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12691	NM_003235.5(TG):c.4588C>T (p.Arg1530Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
12695	NM_003235.5(TG):c.886C>T (p.Arg296Ter)	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
12706	NM_003235.5(TG):c.638+1G>A	TG	Pathogenic	no assertion criteria provided
2434134	NM_003235.5(TG):c.2311C>T (p.Gln771Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595243	NM_003235.5(TG):c.115G>T (p.Glu39Ter)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
684547	NM_003235.5(TG):c.5686+1G>T	TG	Pathogenic	criteria provided, multiple submitters, no conflicts
988639	NM_003235.5(TG):c.6701C>A (p.Ala2234Asp)	TG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
988641	NM_003235.5(TG):c.649dup (p.Ala217fs)	TG	Pathogenic	no assertion criteria provided
988644	NM_003235.5(TG):c.2234dup (p.Leu746fs)	TG	Pathogenic	criteria provided, single submitter
1323705	NM_001206744.2(TPO):c.31_50dup (p.Glu17fs)	TPO	Pathogenic	criteria provided, multiple submitters, no conflicts
4044	NM_001206744.2(TPO):c.1357T>G (p.Tyr453Asp)	TPO	Pathogenic	criteria provided, multiple submitters, no conflicts
988647	NM_001206744.2(TPO):c.866T>C (p.Phe289Ser)	TPO	Pathogenic	no assertion criteria provided
4812824	NM_000369.5(TSHR):c.497del (p.Thr165_Ser166insTer)	TSHR	Pathogenic	criteria provided, single submitter
6439	NM_000369.5(TSHR):c.1637G>A (p.Trp546Ter)	TSHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225505	NM_000369.5(TSHR):c.1349G>A (p.Arg450His)	TSHR-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6444	NM_000369.5(TSHR):c.1170T>G (p.Cys390Trp)	TSHR-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
586965	NM_030773.4(TUBB1):c.318C>G (p.Tyr106Ter)	TUBB1	Pathogenic	no assertion criteria provided
1120118	NM_001363711.2(DUOX2):c.3416-1G>A	DUOX2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 39 · 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
NKX2-1	Definitive	Autosomal dominant	NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction	9
SLC26A7	Strong	Autosomal recessive	congenital hypothyroidism	2
DUOXA1	Moderate	Semidominant	congenital hypothyroidism
TTF1	Moderate	Autosomal dominant	congenital hypothyroidism
DUOX1	Limited	Unknown	congenital hypothyroidism
TTF2	Limited	Autosomal dominant	congenital hypothyroidism

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NKX2-1	Orphanet:1429	Benign hereditary chorea
NKX2-1	Orphanet:146	Differentiated thyroid carcinoma
NKX2-1	Orphanet:209905	Brain-lung-thyroid syndrome
NKX2-1	Orphanet:95713	Athyreosis
SLC5A5	Orphanet:95716	Familial thyroid dyshormonogenesis
TG	Orphanet:95716	Familial thyroid dyshormonogenesis
TPO	Orphanet:95716	Familial thyroid dyshormonogenesis
TRHR	Orphanet:99832	Resistance to thyrotropin-releasing hormone syndrome
TSHR	Orphanet:424	Familial hyperthyroidism due to mutations in TSH receptor
TSHR	Orphanet:90673	Hypothyroidism due to TSH receptor mutations
TSHR	Orphanet:95713	Athyreosis
TSHR	Orphanet:95720	Thyroid hypoplasia
TSHR	Orphanet:99819	Familial gestational hyperthyroidism
DUOX2	Orphanet:226316	Genetic transient congenital hypothyroidism
DUOX2	Orphanet:95716	Familial thyroid dyshormonogenesis
TUBB1	Orphanet:140957	Autosomal dominant macrothrombocytopenia
GLIS3	Orphanet:79118	Neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidneys syndrome
DUOXA2	Orphanet:95716	Familial thyroid dyshormonogenesis
FOXE1	Orphanet:1226	Bamforth-Lazarus syndrome
FOXE1	Orphanet:146	Differentiated thyroid carcinoma
FOXE1	Orphanet:319487	Familial papillary or follicular thyroid carcinoma
FOXE1	Orphanet:95713	Athyreosis
LHX3	Orphanet:226307	Hypothyroidism due to deficient transcription factors involved in pituitary development or function
LHX3	Orphanet:231720	Non-acquired combined pituitary hormone deficiency-sensorineural hearing loss-spine abnormalities syndrome
OTX2	Orphanet:178364	Syndromic microphthalmia type 5
OTX2	Orphanet:3157	Septo-optic dysplasia spectrum
OTX2	Orphanet:35612	Nanophthalmos
OTX2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
OTX2	Orphanet:98938	Colobomatous microphthalmia
OTX2	Orphanet:990	Agnathia-holoprosencephaly-situs inversus syndrome
OTX2	Orphanet:99001	Butterfly-shaped pigment dystrophy
PAX8	Orphanet:146	Differentiated thyroid carcinoma
PAX8	Orphanet:95712	Thyroid ectopia
PAX8	Orphanet:95713	Athyreosis
PAX8	Orphanet:95720	Thyroid hypoplasia
SLC26A4	Orphanet:705	Pendred syndrome
SLC26A4	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
SLC26A4	Orphanet:95713	Athyreosis
SLC26A4	Orphanet:95720	Thyroid hypoplasia

Cohort genes → proteins

24 cohort genes, 21 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	24

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC26A7	HGNC:14467	ENSG00000147606	Q8TE54	Anion exchange transporter	gencc,clinvar
NKX2-1	HGNC:11825	ENSG00000136352	P43699	Homeobox protein Nkx-2.1	gencc
TTF1	HGNC:12397	ENSG00000125482	Q15361	Transcription termination factor 1	gencc
TTF2	HGNC:12398	ENSG00000116830	Q9UNY4	Transcription termination factor 2	gencc
DUOXA1	HGNC:26507	ENSG00000140254	Q1HG43	Dual oxidase maturation factor 1	gencc
DUOX1	HGNC:3062	ENSG00000137857	Q9NRD9	Dual oxidase 1	gencc
SLC5A5	HGNC:11040	ENSG00000105641	Q92911	Sodium/iodide cotransporter	clinvar
TBL1X	HGNC:11585	ENSG00000101849	O60907	F-box-like/WD repeat-containing protein TBL1X	clinvar
TG	HGNC:11764	ENSG00000042832	P01266	Thyroglobulin	clinvar
TPO	HGNC:12015	ENSG00000115705	P07202	Thyroid peroxidase	clinvar
TRHR	HGNC:12299	ENSG00000174417	P34981	Thyrotropin-releasing hormone receptor	clinvar
TSHR	HGNC:12373	ENSG00000165409	P16473	Thyrotropin receptor	clinvar
DUOX2	HGNC:13273	ENSG00000140279	Q9NRD8	Dual oxidase 2	clinvar
TUBB1	HGNC:16257	ENSG00000101162	Q9H4B7	Tubulin beta-1 chain	clinvar
GLIS3	HGNC:28510	ENSG00000107249	Q8NEA6	Zinc finger protein GLIS3	clinvar
DUOXA2	HGNC:32698	ENSG00000140274	Q1HG44	Dual oxidase maturation factor 2	clinvar
FOXE1	HGNC:3806	ENSG00000178919	O00358	Forkhead box protein E1	clinvar
PAX8-AS1	HGNC:49271	ENSG00000189223		PAX8 antisense RNA 1	clinvar
LALTOP	HGNC:58132	ENSG00000228613		lung cancer associated lncRNA targeting TOP2A	clinvar
TSHR-AS1	HGNC:58172	ENSG00000284959		TSHR antisense RNA 1	clinvar
LHX3	HGNC:6595	ENSG00000107187	Q9UBR4	LIM/homeobox protein Lhx3	clinvar
OTX2	HGNC:8522	ENSG00000165588	P32243	Homeobox protein OTX2	clinvar
PAX8	HGNC:8622	ENSG00000125618	Q06710	Paired box protein Pax-8	clinvar
SLC26A4	HGNC:8818	ENSG00000091137	O43511	Pendrin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC26A7	Anion exchange transporter	Acts as an anion channel mediating the transport of chloride, sulfate and oxalate ions.
NKX2-1	Homeobox protein Nkx-2.1	Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor.
TTF1	Transcription termination factor 1	Multifunctional nucleolar protein that terminates ribosomal gene transcription, mediates replication fork arrest and regulates RNA polymerase I transcription on chromatin.
TTF2	Transcription termination factor 2	DsDNA-dependent ATPase which acts as a transcription termination factor by coupling ATP hydrolysis with removal of RNA polymerase II from the DNA template.
DUOXA1	Dual oxidase maturation factor 1	Required for the maturation and transport of functional DUOX1 from the endoplasmic reticulum to the plasma membrane.
DUOX1	Dual oxidase 1	Generates hydrogen peroxide (H2O2) which is required for the activity of thyroid peroxidase/TPO and lactoperoxidase/LPO.
SLC5A5	Sodium/iodide cotransporter	Sodium:iodide symporter that mediates the transport of iodide into the thyroid gland.
TBL1X	F-box-like/WD repeat-containing protein TBL1X	F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units.
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).
TRHR	Thyrotropin-releasing hormone receptor	Receptor for thyrotropin-releasing hormone (TRH).
TSHR	Thyrotropin receptor	Receptor for the thyroid-stimulating hormone (TSH) or thyrotropin.
DUOX2	Dual oxidase 2	Generates hydrogen peroxide which is required for the activity of thyroid peroxidase/TPO and lactoperoxidase/LPO.
TUBB1	Tubulin beta-1 chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
GLIS3	Zinc finger protein GLIS3	Acts both as a repressor and an activator of transcription.
DUOXA2	Dual oxidase maturation factor 2	Required for the maturation and transport of functional DUOX2 from the endoplasmic reticulum to the plasma membrane.
FOXE1	Forkhead box protein E1	Transcription factor that binds consensus sites on a variety of gene promoters and activate their transcription.
LHX3	LIM/homeobox protein Lhx3	Transcription factor.
OTX2	Homeobox protein OTX2	Transcription factor probably involved in the development of the brain and the sense organs.
PAX8	Paired box protein Pax-8	Transcription factor for the thyroid-specific expression of the genes exclusively expressed in the thyroid cell type, maintaining the functional differentiation of such cells.
SLC26A4	Pendrin	Sodium-independent transporter of chloride and iodide.

Protein-family classification

Druggable: 6 · Difficult: 8 · Unknown: 10 · Druggable fraction: 0.25

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
Transcription factor	7	2.4×	0.142
Complement	1	11.2×	0.301
Transporter	1	3.2×	0.467
GPCR	2	2.0×	0.467
Enzyme (other)	2	1.0×	0.849
Scaffold/PPI	1	0.7×	0.888
Other/Unknown	10	0.8×	0.945

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC26A7	Other/Unknown	no		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom
NKX2-1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
TTF1	Other/Unknown	no		SANT/Myb, TTF1-like
TTF2	Transcription factor	no		SNF2_N, Helicase_C-like, DNA/RNA_helicase_DEAH_CS
DUOXA1	Other/Unknown	no		Dual_oxidase_maturation_fac
DUOX1	Enzyme (other)	yes	1.6.3.1	EF_hand_dom, Haem_peroxidase_sf, EF-hand-dom_pair
SLC5A5	Other/Unknown	no		Na/solute_symporter, Na/solute_symporter_CS, SLC5A5
TBL1X	Scaffold/PPI	no		WD40_rpt, LisH, Quinoprotein_ADH-like_sf
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
TRHR	GPCR	yes		GPCR_Rhodpsn, TRH_rcpt_1, GPCR_Rhodpsn_7TM
TSHR	GPCR	yes		GPCR_Rhodpsn, Gphrmn_rcpt_fam, TSH_rcpt
DUOX2	Enzyme (other)	yes	1.6.3.1	EF_hand_dom, Haem_peroxidase_sf, EF-hand-dom_pair
TUBB1	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
GLIS3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
DUOXA2	Other/Unknown	no		Dual_oxidase_maturation_fac
FOXE1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
PAX8-AS1	Other/Unknown	no
LALTOP	Other/Unknown	no
TSHR-AS1	Other/Unknown	no
LHX3	Transcription factor	no		HD, Znf_LIM, Homeodomain-like_sf
OTX2	Transcription factor	no		HD, Otx2_TF, Otx_TF
PAX8	Transcription factor	no		Paired_dom, Homeodomain-like_sf, Pax2_C
SLC26A4	Transporter	yes		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom

Expression context

Cohort genes with no expression data: 0.

21 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)	24
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of thyroid gland	13
left lobe of thyroid gland	10
thyroid gland	10
buccal mucosa cell	2
oocyte	2
lower esophagus mucosa	2
male germ line stem cell (sensu Vertebrata) in testis	2
gall bladder	2
nasal cavity epithelium	2
palpebral conjunctiva	2
pancreatic ductal cell	2
trabecular bone tissue	1
adrenal tissue	1
colonic epithelium	1
sural nerve	1
tongue squamous epithelium	1
mucosa of stomach	1
olfactory bulb	1
type B pancreatic cell	1
cauda epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC26A7	178	tissue_specific	marker	thyroid gland, right lobe of thyroid gland, left lobe of thyroid gland
NKX2-1	101	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
TTF1	287	ubiquitous	marker	buccal mucosa cell, trabecular bone tissue, oocyte
TTF2	229	ubiquitous	marker	sural nerve, adrenal tissue, colonic epithelium
DUOXA1	181	tissue_specific	marker	lower esophagus mucosa, right lobe of thyroid gland, left lobe of thyroid gland
DUOX1	213	broad	marker	tongue squamous epithelium, lower esophagus mucosa, right lobe of thyroid gland
SLC5A5	85	tissue_specific	marker	olfactory bulb, type B pancreatic cell, mucosa of stomach
TBL1X	280	ubiquitous	marker	cauda epididymis, seminal vesicle, corpus epididymis
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
TRHR	22		yes	male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon, metanephric glomerulus
TSHR	169	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
DUOX2	191	tissue_specific	marker	gall bladder, nasal cavity epithelium, palpebral conjunctiva
TUBB1	140	tissue_specific	marker	monocyte, mononuclear cell, leukocyte
GLIS3	213	ubiquitous	marker	buccal mucosa cell, epithelial cell of pancreas, pancreatic ductal cell
DUOXA2	121	tissue_specific	marker	pancreatic ductal cell, nasal cavity epithelium, gall bladder
FOXE1	94	tissue_specific	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
PAX8-AS1	212	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, metanephros cortex
LALTOP	108		yes	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
TSHR-AS1	134		marker	male germ line stem cell (sensu Vertebrata) in testis, right lobe of thyroid gland, thyroid gland
LHX3	22	tissue_specific	yes	pituitary gland, diaphragm, adenohypophysis
OTX2	62	broad	marker	secondary oocyte, oocyte, pigmented layer of retina
PAX8	242	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
SLC26A4	190	tissue_specific	marker	palpebral conjunctiva, right lobe of thyroid gland, thyroid gland

Protein interactions among cohort

Intra-cohort edges: 49.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBL1X	6,393
TUBB1	4,106
TTF2	2,689
NKX2-1	2,403
OTX2	2,368
PAX8	1,994
DUOX1	1,762
GLIS3	1,717
TSHR	1,672
LHX3	1,661

Intra-cohort edges

A	B	Sources
DUOX1	DUOXA1	intact, string_interaction
DUOX1	DUOXA2	string_interaction
DUOX2	DUOXA1	string_interaction
DUOX2	DUOXA2	intact, string_interaction
DUOX2	SLC26A4	string_interaction
DUOX2	SLC5A5	string_interaction
DUOXA1	DUOXA2	string_interaction
DUOXA1	SLC26A4	string_interaction
DUOXA1	SLC26A7	string_interaction
DUOXA1	SLC5A5	string_interaction
DUOXA2	FOXE1	string_interaction
DUOXA2	SLC26A4	string_interaction
DUOXA2	SLC26A7	string_interaction
DUOXA2	SLC5A5	string_interaction
DUOXA2	TG	string_interaction
DUOXA2	TPO	string_interaction
DUOXA2	TSHR	string_interaction
FOXE1	NKX2-1	string_interaction
FOXE1	PAX8	string_interaction
FOXE1	SLC26A4	string_interaction
FOXE1	SLC5A5	string_interaction
FOXE1	TG	string_interaction
FOXE1	TPO	intact, string_interaction
FOXE1	TSHR	string_interaction
NKX2-1	PAX8	biogrid_interaction, string_interaction
NKX2-1	SLC5A5	string_interaction
NKX2-1	TG	string_interaction
NKX2-1	TPO	string_interaction
NKX2-1	TSHR	string_interaction
PAX8	SLC5A5	string_interaction
PAX8	TG	string_interaction
PAX8	TPO	string_interaction
PAX8	TSHR	string_interaction
SLC26A4	SLC5A5	string_interaction
SLC26A4	TG	string_interaction
SLC26A4	TPO	string_interaction
SLC26A4	TSHR	string_interaction
SLC26A7	SLC5A5	string_interaction
SLC26A7	TSHR	string_interaction
SLC5A5	TG	string_interaction
SLC5A5	TPO	string_interaction
SLC5A5	TRHR	string_interaction
SLC5A5	TSHR	string_interaction
TBL1X	TPO	string_interaction
TG	TPO	string_interaction
TG	TSHR	string_interaction
TG	TTF1	string_interaction
TPO	TSHR	string_interaction
TRHR	TSHR	string_interaction

Structural data

PDB: 9 · AlphaFold-only: 12 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TSHR	P16473	9
TRHR	P34981	4
TBL1X	O60907	3
TG	P01266	3
SLC26A7	Q8TE54	2
NKX2-1	P43699	2
DUOXA1	Q1HG43	2
DUOX1	Q9NRD9	2
PAX8	Q06710	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TUBB1	Q9H4B7	90.92
DUOX2	Q9NRD8	84.37
TPO	P07202	84.00
DUOXA2	Q1HG44	83.29
SLC26A4	O43511	82.72
SLC5A5	Q92911	81.54
LHX3	Q9UBR4	68.68
TTF2	Q9UNY4	62.70
FOXE1	O00358	62.02
OTX2	P32243	60.99
TTF1	Q15361	57.99
GLIS3	Q8NEA6	49.95

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 165. Enrichment computed across 24 evidence-associated genes (16 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 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Thyroxine biosynthesis	6	305.9×	1e-12	SLC5A5, TPO, DUOX2, DUOXA1, DUOX1, DUOXA2
Inorganic anion exchange by SLC26 transporters	2	158.6×	0.005	SLC26A7, SLC26A4
R-HSA-425393	3	24.3×	0.013	SLC26A7, SLC5A5, SLC26A4
Defective SLC26A4 causes Pendred syndrome (PDS)	1	713.8×	0.039	SLC26A4
Defective SLC5A5 causes thyroid dyshormonogenesis 1 (TDH1)	1	713.8×	0.039	SLC5A5
HCMV Infection	2	40.8×	0.039	TBL1X, TUBB1
SLC-mediated transport of inorganic anions	1	356.9×	0.051	SLC5A5
SLC transporter disorders	2	25.5×	0.051	SLC5A5, SLC26A4
SLC-mediated transmembrane transport	3	11.1×	0.051	SLC26A7, SLC5A5, SLC26A4
Disorders of transmembrane transporters	2	17.4×	0.094	SLC5A5, SLC26A4
Metabolism of amine-derived hormones	1	102.0×	0.102	SLC5A5
Loss of MECP2 binding ability to the NCoR/SMRT complex	1	102.0×	0.102	TBL1X
Organic anion transport by SLC5/17/25 transporters	1	89.2×	0.102	SLC5A5
Loss of function of MECP2 in Rett syndrome	1	89.2×	0.102	TBL1X
Pervasive developmental disorders	1	89.2×	0.102	TBL1X
Disorders of Developmental Biology	1	89.2×	0.102	TBL1X
Disorders of Nervous System Development	1	89.2×	0.102	TBL1X
Formation of intermediate mesoderm	1	89.2×	0.102	PAX8
Formation of the posterior neural plate	1	71.4×	0.121	OTX2
Formation of the anterior neural plate	1	64.9×	0.125	OTX2
Hormone ligand-binding receptors	1	59.5×	0.125	TSHR
HCMV Early Events	2	10.1×	0.125	TBL1X, TUBB1
R-HSA-1368082	1	44.6×	0.149	TBL1X
Formation of the nephric duct	1	39.6×	0.149	PAX8
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	34.0×	0.149	TUBB1
Transport of connexons to the plasma membrane	1	34.0×	0.149	TUBB1
Gap junction trafficking and regulation	1	29.7×	0.149	TUBB1
Gap junction trafficking	1	29.7×	0.149	TUBB1
Post-chaperonin tubulin folding pathway	1	29.7×	0.149	TUBB1
BMAL1:CLOCK,NPAS2 activates circadian expression	1	26.4×	0.149	TBL1X

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 21 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	7	330.4×	5e-15	SLC26A7, SLC5A5, TG, TPO, DUOX2, DUOX1, FOXE1
iodide transport	4	458.6×	6e-09	SLC26A7, SLC5A5, TG, SLC26A4
thyroid gland development	5	129.4×	2e-08	TG, NKX2-1, TUBB1, FOXE1, PAX8
hormone biosynthetic process	4	267.5×	4e-08	TG, TPO, DUOX2, DUOX1
regulation of thyroid hormone generation	2	802.5×	5e-05	DUOXA1, DUOXA2
positive regulation of cell motility	3	109.4×	8e-05	DUOX2, DUOX1, DUOXA2
hydrogen peroxide catabolic process	3	96.3×	1e-04	TPO, DUOX2, DUOX1
cuticle development	2	535.0×	1e-04	DUOX2, DUOX1
positive regulation of hydrogen peroxide biosynthetic process	2	401.2×	2e-04	DUOXA1, DUOXA2
hydrogen peroxide metabolic process	2	401.2×	2e-04	DUOXA1, DUOXA2
cellular response to gonadotropin stimulus	2	267.5×	4e-04	SLC5A5, PAX8
positive regulation of DNA-templated transcription	6	8.0×	0.001	TBL1X, NKX2-1, FOXE1, LHX3, OTX2, PAX8
DNA-templated transcription termination	2	145.9×	0.001	TTF1, TTF2
hydrogen peroxide biosynthetic process	2	133.8×	0.001	DUOX2, DUOX1
sulfate transmembrane transport	2	114.6×	0.002	SLC26A7, SLC26A4
monoatomic ion transport	3	22.3×	0.004	SLC26A7, SLC5A5, SLC26A4
superoxide anion generation	2	64.2×	0.005	DUOX2, DUOX1
response to oxidative stress	3	18.7×	0.005	TPO, DUOX2, DUOX1
positive regulation of wound healing	2	50.1×	0.007	DUOX2, DUOX1
response to cAMP	2	48.6×	0.007	DUOX2, DUOX1
gluconate transmembrane transport	1	802.5×	0.009	SLC26A7
thyroid-stimulating hormone signaling pathway	1	802.5×	0.009	TSHR
cellular response to thyrotropin-releasing hormone	1	802.5×	0.009	TSHR
regulation of thyroid-stimulating hormone secretion	1	802.5×	0.009	PAX8
regulation of transcription by RNA polymerase II	7	3.9×	0.010	TBL1X, NKX2-1, GLIS3, FOXE1, LHX3, OTX2, PAX8
forebrain development	2	33.4×	0.011	NKX2-1, OTX2
medial motor column neuron differentiation	1	401.2×	0.012	LHX3
developmental induction	1	401.2×	0.012	NKX2-1
pronephric field specification	1	401.2×	0.012	PAX8
prolactin secreting cell differentiation	1	401.2×	0.012	LHX3

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Levothyroxine	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 5 · Undrugged: 19

Druggability breadth: 9 of 24 evidence-associated genes (38%) 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
TRHR	PROTIRELIN
TSHR	LEVOSALBUTAMOL
TUBB1	COLCHICINE
PAX8	SORAFENIB TOSYLATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TSHR	354	4
TUBB1	22	4
PAX8	14	4
TPO	3	4
TRHR	1	4
SLC26A7	0	0
NKX2-1	0	0
TTF1	0	0
TTF2	0	0
DUOXA1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PROPYLTHIOURACIL	4	TPO, TSHR
PROTIRELIN	4	TRHR
LEVOSALBUTAMOL	4	TSHR
PROGESTERONE	4	TSHR
DICLOFENAC SODIUM	4	TSHR
CLOTRIMAZOLE	4	TSHR
DAPSONE	4	TSHR
COLCHICINE	4	TSHR, TUBB1
OXAPROZIN	4	TSHR
BUMETANIDE	4	TSHR
GLIPIZIDE	4	TSHR
CARBAMAZEPINE	4	TSHR
METHYL SALICYLATE	4	TSHR
PHENELZINE	4	TSHR
EDROPHONIUM	4	TSHR
SULFAPHENAZOLE	4	TSHR
AMOXAPINE	4	TSHR
PYRIDOSTIGMINE	4	TSHR
ACETAMINOPHEN	4	TSHR
DICYCLOMINE	4	TSHR
IODIPAMIDE	4	TSHR
TESTOSTERONE PROPIONATE	4	TSHR
TETRABENAZINE	4	TSHR
CELECOXIB	4	TSHR
PROPANTHELINE	4	TSHR
BENOXINATE	4	TSHR
NICARDIPINE HYDROCHLORIDE	4	TSHR
PYRITHIONE ZINC	4	TSHR
GUANABENZ ACETATE	4	TSHR
PROPIOLACTONE	4	TSHR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
TUBB1	1,765	Binding:1723, Functional:36, ADMET:6
SLC26A4	37	Binding:37
TSHR	33	Functional:24, Binding:9
TRHR	15	Binding:12, Functional:3
TPO	12	Binding:12
TBL1X	9	Binding:9
PAX8	3	Functional:3
DUOX1	1	Binding:1
DUOX2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DUOX1	1.6.3.1	NAD(P)H oxidase (H2O2-forming)
TPO	1.11.1.8, 3.6.1.52	iodide peroxidase, diphosphoinositol-polyphosphate diphosphatase
DUOX2	1.6.3.1	NAD(P)H oxidase (H2O2-forming)

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TUBB1	1,765

Pharmacogenomics

Cohort genes with a PharmGKB record: 21; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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, TSHR
PROTIRELIN	4	TRHR
LEVOSALBUTAMOL	4	TSHR
PROGESTERONE	4	TSHR
DICLOFENAC SODIUM	4	TSHR
CLOTRIMAZOLE	4	TSHR
DAPSONE	4	TSHR
COLCHICINE	4	TSHR, TUBB1
OXAPROZIN	4	TSHR
BUMETANIDE	4	TSHR
GLIPIZIDE	4	TSHR
CARBAMAZEPINE	4	TSHR
METHYL SALICYLATE	4	TSHR
PHENELZINE	4	TSHR
EDROPHONIUM	4	TSHR
SULFAPHENAZOLE	4	TSHR
AMOXAPINE	4	TSHR
PYRIDOSTIGMINE	4	TSHR
ACETAMINOPHEN	4	TSHR
DICYCLOMINE	4	TSHR
IODIPAMIDE	4	TSHR
TESTOSTERONE PROPIONATE	4	TSHR
TETRABENAZINE	4	TSHR
CELECOXIB	4	TSHR
PROPANTHELINE	4	TSHR
BENOXINATE	4	TSHR
NICARDIPINE HYDROCHLORIDE	4	TSHR
PYRITHIONE ZINC	4	TSHR
GUANABENZ ACETATE	4	TSHR
PROPIOLACTONE	4	TSHR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	TPO, TRHR, TSHR, TUBB1, PAX8
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	DUOX1
D	Druggable family + AlphaFold only, no drug	2	DUOX2, SLC26A4
E	Difficult family or no structure, no drug	16	SLC26A7, NKX2-1, TTF1, TTF2, DUOXA1, SLC5A5, TBL1X, TG, GLIS3, DUOXA2 (+6 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NKX2-1	0	PAX8, TSHR
SLC5A5	0	TSHR, TPO
TG	0	TPO, TSHR, PAX8
FOXE1	0	PAX8, TSHR
SLC26A7	0	—
TTF1	0	—
TTF2	0	—
DUOXA1	0	—
DUOX1	1	—
TBL1X	9	—
DUOX2	1	—
GLIS3	0	—
DUOXA2	0	—
PAX8-AS1	0	—
LALTOP	0	—
TSHR-AS1	0	—
LHX3	0	—
OTX2	0	—
SLC26A4	37	—

Clinical trials & evidence

Clinical trials

Clinical trials: 24.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	22
PHASE4	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05228184	PHASE4	TERMINATED	Use of Tirosint®-SOL or Tablet Formulations of Levothyroxine in Pediatric Patients With Congenital Hypothyroidism (CH)
NCT05371262	PHASE4	COMPLETED	Influence of Initial Levothyroxine Dose on Neurodevelopmental and Growth Outcomes in Congenital Hypothyroidism
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT06724224	Not specified	RECRUITING	Comparison of Levothyroxine Formulations in the Treatment of Congenital Hypothyroidism
NCT06728735	Not specified	RECRUITING	Role of Next Generation Sequencing in the Etiological Diagnosis of Permanent Congenital Hypothyroidism With in Situ Thyroid
NCT06864039	Not specified	ENROLLING_BY_INVITATION	Quality of Life and Long-term Outcome of Adequately Treated Congenital Hypothyroidism
NCT06864351	Not specified	RECRUITING	Prospective Evaluation of OptiThyDose
NCT07126353	Not specified	NOT_YET_RECRUITING	Metabolic Risk Assessment in Prepubertal Children With Congenital Hypothyroidism
NCT07280104	Not specified	RECRUITING	Infants With Primary Congenital Hypothyroidism and Development
NCT07425028	Not specified	NOT_YET_RECRUITING	Evaluation of an Intensified Systematic Screening for Congenital Hypothyroidism in Premature Newborns
NCT07579988	Not specified	NOT_YET_RECRUITING	Ultrasound Measurement of Thyroid Volume in Term Newborns
NCT00403390	Not specified	COMPLETED	Generic vs. Name-Brand Levothyroxine
NCT00493103	Not specified	COMPLETED	TG Gene Mutations and Congenital Hypothyroidism
NCT00497575	Not specified	COMPLETED	Diagnosis and Follow-up of Patients With Subclinical Hypothyroidism
NCT00505479	Not specified	UNKNOWN	Iodine Status in Pregnant Women and Their Newborns: is Congenital Hypothyroidism Related to Iodine Deficiency in Pregnancy?
NCT01223638	Not specified	WITHDRAWN	The Prevalence of Hearing Loss Among Children With Congenital Hypothyroidism
NCT01349634	Not specified	COMPLETED	The Effects of Iodized Salt on Cognitive Development in Ethiopia
NCT01488721	Not specified	COMPLETED	Clinical Evaluation of NeoPlex4 Assay and NeoPlex System
NCT01916018	Not specified	COMPLETED	Clinical and Genetic Analysis in Congenital Hypothyroidism Due to Thyroid Dysgenesis.
NCT02307175	Not specified	COMPLETED	A Study of 99m Tc Pertechnetate Produced in High Energy Cyclotron in Patients With Thyroid Scan Indication
NCT02374593	Not specified	COMPLETED	Targeted Levothyroxine Dosing in Infants With Congenital Hypothyroidism
NCT04712760	Not specified	UNKNOWN	Congenital Hypothyroidism in Children With Eutopic Gland or Thyroid Hemiagenesis: Predictive Factors for Transient vs Permanent Hypothyroidism.
NCT04734457	Not specified	UNKNOWN	Final Height in Patients With CH Diagnosed by the Screening
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LEVOTHYROXINE	4	7
THYROID	3	1

Cohort genes: SLC26A7, NKX2-1, TTF1, TTF2, DUOXA1, DUOX1, SLC5A5, TBL1X, TG, TPO, TRHR, TSHR, DUOX2, TUBB1, GLIS3, DUOXA2, FOXE1, PAX8-AS1, LALTOP, TSHR-AS1, LHX3, OTX2, PAX8, SLC26A4
Drugs: Levothyroxine, Thyroid