Thyroid dyshormonogenesis 4

Summary

Thyroid dyshormonogenesis 4 (MONDO:0010136) is a disease caused by IYD (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: IYD (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thyroid dyshormonogenesis 4
Mondo ID	MONDO:0010136
MeSH	C562770
OMIM	274800
DOID	DOID:0112188
SNOMED CT	17885001
UMLS	C0342195
MedGen	87429
GARD	0018191
Is cancer (heuristic)	no

Also known as: familial thyroid dyshormonogenesis caused by mutation in IYD · hypothyroidism, congenital, due to dyshormonogenesis, 4 · IYD familial thyroid dyshormonogenesis · TDH4 · thyroid dyshormonogenesis 4 · thyroid dyshormonogenesis type 4 · thyroid hormonogenesis, genetic defect in, 4

Data availability: 12 ClinVar variants · 2 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 4

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

12 retrieved; paginated sample, class counts are floors:

6 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2577213	NM_203395.3(IYD):c.835C>T (p.Arg279Cys)	IYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
740	NM_203395.3(IYD):c.658G>A (p.Ala220Thr)	IYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593218	NM_203395.3(IYD):c.293_306del (p.Asn98fs)	IYD	Likely pathogenic	criteria provided, single submitter
3593219	NM_203395.3(IYD):c.523_524insTT (p.Lys175fs)	IYD	Likely pathogenic	criteria provided, single submitter
3593220	NM_203395.3(IYD):c.567del (p.Ile190fs)	IYD	Likely pathogenic	criteria provided, single submitter
3593221	NM_203395.3(IYD):c.736C>T (p.Arg246Ter)	IYD	Likely pathogenic	criteria provided, single submitter
737	NM_203395.3(IYD):c.301C>T (p.Arg101Trp)	IYD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
739	NM_203395.3(IYD):c.347T>C (p.Ile116Thr)	IYD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2239895	NM_203395.3(IYD):c.624del (p.Val209fs)	IYD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
738	NM_203395.3(IYD):c.315_317del (p.Phe105_Ile106delinsLeu)	IYD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
257584	NM_203395.3(IYD):c.687+1305T>C	IYD	Benign	criteria provided, multiple submitters, no conflicts
355674	NM_203395.3(IYD):c.323A>G (p.Asn108Ser)	IYD	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
IYD	Strong	Autosomal recessive	thyroid dyshormonogenesis 4	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IYD	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
IYD	HGNC:21071	ENSG00000009765	Q6PHW0	Iodotyrosine deiodinase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IYD	Enzyme (other)	yes	1.21.1.1	Nitroreductase-like, Nitroreductase, Nitroreductase/BluB

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
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IYD	130	tissue_specific	marker	right lobe of thyroid gland, thyroid gland, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IYD	2,104

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IYD	Q6PHW0	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Metabolism of amine-derived hormones	1	1631.4×	0.002	IYD
Thyroxine biosynthesis	1	815.7×	0.002	IYD
Metabolism of amino acids and derivatives	1	67.6×	0.020	IYD
Metabolism	1	11.6×	0.086	IYD

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
obsolete tyrosine metabolic process	1	4213.0×	5e-04	IYD
thyroid hormone metabolic process	1	1404.3×	7e-04	IYD

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
IYD	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IYD	1.21.1.1	iodotyrosine deiodinase

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	1	IYD
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
IYD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.