Thyroid dyshormonogenesis 1

Summary

Thyroid dyshormonogenesis 1 (MONDO:0020716) is a disease caused by SLC5A5 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Causal gene: SLC5A5 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 118
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thyroid dyshormonogenesis 1
Mondo ID	MONDO:0020716
OMIM	274400
DOID	DOID:0112185
UMLS	C1848805
MedGen	336422
GARD	0018188
Is cancer (heuristic)	no

Also known as: familial thyroid dyshormonogenesis 1 · hypothyroidism, congenital, due to dyshormonogenesis, 1 · iodine accumulation, transport, or trapping defect · TDH1 · thyroid dyshormonogenesis type 1 · thyroid hormonogenesis, genetic defect in, 1

Data availability: 118 ClinVar variants · 4 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 1

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

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

118 retrieved; paginated sample, class counts are floors:

52 uncertain significance, 21 conflicting classifications of pathogenicity, 16 likely pathogenic, 8 pathogenic, 7 likely benign, 6 benign/likely benign, 4 benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2444146	NM_000453.3(SLC5A5):c.1546C>T (p.Arg516Ter)	SLC5A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2633371	NM_000453.3(SLC5A5):c.176T>A (p.Val59Glu)	SLC5A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3000681	NM_000453.3(SLC5A5):c.1340dup (p.Leu449fs)	SLC5A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7664	NM_000453.3(SLC5A5):c.1060A>C (p.Thr354Pro)	SLC5A5	Pathogenic	criteria provided, multiple submitters, no conflicts
7665	NM_000453.3(SLC5A5):c.816C>A (p.Cys272Ter)	SLC5A5	Pathogenic	criteria provided, single submitter
7667	NM_000453.3(SLC5A5):c.1593C>G (p.Tyr531Ter)	SLC5A5	Pathogenic	criteria provided, multiple submitters, no conflicts
7668	NM_000453.3(SLC5A5):c.277G>C (p.Gly93Arg)	SLC5A5	Pathogenic	no assertion criteria provided
7669	NM_000453.3(SLC5A5):c.1628G>A (p.Gly543Glu)	SLC5A5	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
7671	NG_012930.1:g.7540_13728delins431	SLC5A5	Pathogenic	no assertion criteria provided
983276	NM_000453.3(SLC5A5):c.152del (p.Gly51fs)	SLC5A5	Pathogenic	no assertion criteria provided
983277	NM_000453.3(SLC5A5):c.1261G>A (p.Gly421Arg)	SLC5A5	Pathogenic	no assertion criteria provided
2736846	NM_000453.3(SLC5A5):c.371G>A (p.Arg124His)	SLC5A5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3583529	NM_000453.3(SLC5A5):c.357+1G>A	SLC5A5	Likely pathogenic	criteria provided, single submitter
3583530	NM_000453.3(SLC5A5):c.410_414del (p.Tyr137fs)	SLC5A5	Likely pathogenic	criteria provided, single submitter
3583531	NM_000453.3(SLC5A5):c.679del (p.Ser227fs)	SLC5A5	Likely pathogenic	criteria provided, single submitter
3583532	NM_000453.3(SLC5A5):c.699-2A>G	SLC5A5	Likely pathogenic	criteria provided, single submitter
3583533	NM_000453.3(SLC5A5):c.969+1G>A	SLC5A5	Likely pathogenic	criteria provided, single submitter
3583534	NM_000453.3(SLC5A5):c.970-9_970dup	SLC5A5	Likely pathogenic	criteria provided, single submitter
3583535	NM_000453.3(SLC5A5):c.970-7_980delinsA	SLC5A5	Likely pathogenic	criteria provided, single submitter
3583536	NM_000453.3(SLC5A5):c.1242+2T>G	SLC5A5	Likely pathogenic	criteria provided, single submitter
3583537	NM_000453.3(SLC5A5):c.1459_1460del (p.Val488fs)	SLC5A5	Likely pathogenic	criteria provided, single submitter
3583538	NM_000453.3(SLC5A5):c.1605_1618del (p.Thr536fs)	SLC5A5	Likely pathogenic	criteria provided, single submitter
3583539	NM_000453.3(SLC5A5):c.1767+1G>C	SLC5A5	Likely pathogenic	criteria provided, single submitter
3583540	NM_000453.3(SLC5A5):c.1768-1G>C	SLC5A5	Likely pathogenic	criteria provided, single submitter
4845885	NM_000453.3(SLC5A5):c.1651+2T>A	SLC5A5	Likely pathogenic	criteria provided, single submitter
7666	NM_000453.3(SLC5A5):c.799C>G (p.Gln267Glu)	SLC5A5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
917859	NM_000453.3(SLC5A5):c.794A>G (p.Gln265Arg)	SLC5A5	Likely pathogenic	no assertion criteria provided
256200	NM_000453.3(SLC5A5):c.839+11C>T	SLC5A5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328534	NM_000453.3(SLC5A5):c.330C>T (p.Tyr110=)	SLC5A5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
SLC5A5	Definitive	Autosomal recessive	thyroid dyshormonogenesis 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC5A5	Orphanet:95716	Familial thyroid dyshormonogenesis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC5A5	HGNC:11040	ENSG00000105641	Q92911	Sodium/iodide cotransporter	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC5A5	Sodium/iodide cotransporter	Sodium:iodide symporter that mediates the transport of iodide into the thyroid gland.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC5A5	Other/Unknown	no		Na/solute_symporter, Na/solute_symporter_CS, SLC5A5

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
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
SLC5A5	85	tissue_specific	marker	olfactory bulb, type B pancreatic cell, mucosa of stomach

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC5A5	1,306

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC5A5	Q92911	81.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC5A5 causes thyroid dyshormonogenesis 1 (TDH1)	1	11420.0×	0.001	SLC5A5
SLC-mediated transport of inorganic anions	1	5710.0×	0.001	SLC5A5
Metabolism of amine-derived hormones	1	1631.4×	0.002	SLC5A5
Organic anion transport by SLC5/17/25 transporters	1	1427.5×	0.002	SLC5A5
Thyroxine biosynthesis	1	815.7×	0.003	SLC5A5
SLC transporter disorders	1	203.9×	0.011	SLC5A5
Disorders of transmembrane transporters	1	139.3×	0.013	SLC5A5
R-HSA-425393	1	129.8×	0.013	SLC5A5
Metabolism of amino acids and derivatives	1	67.6×	0.021	SLC5A5
SLC-mediated transmembrane transport	1	59.2×	0.022	SLC5A5
Transport of small molecules	1	25.1×	0.047	SLC5A5
Disease	1	13.1×	0.083	SLC5A5
Metabolism	1	11.6×	0.086	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
iodide transmembrane transport	1	8426.0×	6e-04	SLC5A5
cellular response to Thyroid stimulating hormone	1	8426.0×	6e-04	SLC5A5
cellular response to gonadotropin stimulus	1	2808.7×	0.001	SLC5A5
iodide transport	1	2407.4×	0.001	SLC5A5
cellular response to forskolin	1	1123.5×	0.002	SLC5A5
thyroid hormone generation	1	991.3×	0.002	SLC5A5
cellular response to cAMP	1	290.6×	0.005	SLC5A5
sodium ion transport	1	271.8×	0.005	SLC5A5
transport across blood-brain barrier	1	179.3×	0.006	SLC5A5
monoatomic ion transport	1	156.0×	0.006	SLC5A5

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
SLC5A5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	SLC5A5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC5A5	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