thyroid dyshormonogenesis 2A

Summary

thyroid dyshormonogenesis 2A (MONDO:0010133) is a disease caused by TPO (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: TPO (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 186
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thyroid dyshormonogenesis 2A
Mondo ID	MONDO:0010133
MeSH	C563206
OMIM	274500
DOID	DOID:0112186
NCIT	C121750
SNOMED CT	124204003
UMLS	C1291299
MedGen	226940
GARD	0018189
Is cancer (heuristic)	no

Also known as: familial thyroid dyshormonogenesis caused by mutation in TPO · hypothyroidism, congenital, due to dyshormonogenesis, 2A · TDH2A · thyroid dyshormonogenesis 2A · thyroid dyshormonogenesis type 2A · thyroid hormonogenesis, genetic defect in, 2A · TPO familial thyroid dyshormonogenesis

Data availability: 186 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 2A

Related subtypes (5): 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

186 retrieved; paginated sample, class counts are floors:

52 uncertain significance, 47 conflicting classifications of pathogenicity, 29 likely pathogenic, 22 pathogenic, 18 benign, 13 pathogenic/likely pathogenic, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1333570	NM_001206744.2(TPO):c.1786G>T (p.Glu596Ter)	LALTOP	Pathogenic	criteria provided, multiple submitters, no conflicts
2664755	NM_001206744.2(TPO):c.2619G>A (p.Trp873Ter)	LALTOP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584393	NM_001206744.2(TPO):c.2314_2332del (p.Tyr772fs)	LALTOP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4042	NM_001206744.2(TPO):c.1618C>T (p.Arg540Ter)	LALTOP	Pathogenic	criteria provided, multiple submitters, no conflicts
4046	NM_001206744.2(TPO):c.2395G>A (p.Glu799Lys)	LALTOP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4047	NM_001206744.2(TPO):c.2421dup (p.Cys808fs)	LALTOP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4048	NM_001206744.2(TPO):c.1943G>A (p.Arg648Gln)	LALTOP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4049	NM_001206744.2(TPO):c.2512del (p.Cys838fs)	LALTOP	Pathogenic	no assertion criteria provided
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
1028337	NM_001206744.2(TPO):c.214C>T (p.Gln72Ter)	TPO	Pathogenic	criteria provided, single submitter
1064772	NM_001206744.2(TPO):c.1477G>A (p.Gly493Ser)	TPO	Pathogenic	criteria provided, multiple submitters, no conflicts
1254323	NM_001206744.2(TPO):c.2578G>A (p.Gly860Arg)	TPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323705	NM_001206744.2(TPO):c.31_50dup (p.Glu17fs)	TPO	Pathogenic	criteria provided, multiple submitters, no conflicts
1701830	NM_001206744.2(TPO):c.265C>T (p.Arg89Ter)	TPO	Pathogenic	criteria provided, multiple submitters, no conflicts
2581320	NM_001206744.2(TPO):c.2492T>G (p.Leu831Ter)	TPO	Pathogenic	criteria provided, multiple submitters, no conflicts
2734126	NM_001206744.2(TPO):c.670_672del (p.Asp224del)	TPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734130	NM_001206744.2(TPO):c.1993C>T (p.Arg665Trp)	TPO	Pathogenic	criteria provided, multiple submitters, no conflicts
2896074	NM_001206744.2(TPO):c.2688C>A (p.Cys896Ter)	TPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2979940	NM_001206744.2(TPO):c.2044C>T (p.Gln682Ter)	TPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3002279	NM_001206744.2(TPO):c.1039G>T (p.Glu347Ter)	TPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584382	NM_001206744.2(TPO):c.796C>T (p.Gln266Ter)	TPO	Pathogenic	criteria provided, single submitter
3584385	NM_001206744.2(TPO):c.1336del (p.Gln446fs)	TPO	Pathogenic	criteria provided, single submitter
3584392	NM_001206744.2(TPO):c.2141del (p.Phe714fs)	TPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3769373	NM_001206744.2(TPO):c.875C>T (p.Ser292Phe)	TPO	Pathogenic	criteria provided, single submitter
4043	NM_001206744.2(TPO):c.1339A>T (p.Ile447Phe)	TPO	Pathogenic	no assertion criteria provided
4044	NM_001206744.2(TPO):c.1357T>G (p.Tyr453Asp)	TPO	Pathogenic	criteria provided, multiple submitters, no conflicts
4045	NM_001206744.2(TPO):c.1768G>A (p.Gly590Ser)	TPO	Pathogenic	no assertion criteria provided
4052	NM_001206744.2(TPO):c.1496del (p.Pro499fs)	TPO	Pathogenic	no assertion criteria provided
4054	NM_001206744.2(TPO):c.1955dup (p.Phe653fs)	TPO	Pathogenic	criteria provided, single submitter

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
TPO	Strong	Autosomal recessive	thyroid dyshormonogenesis 2A	3

Orphanet rare-disease linkage (cohort genes)

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

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TPO	HGNC:12015	ENSG00000115705	P07202	Thyroid peroxidase	gencc,clinvar
LALTOP	HGNC:58132	ENSG00000228613		lung cancer associated lncRNA targeting TOP2A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPO	Thyroid peroxidase	Iodination and coupling of the hormonogenic tyrosines in thyroglobulin to yield the thyroid hormones T(3) and T(4).

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
Complement	1	134.0×	0.015
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TPO	Complement	yes	1.11.1.8	EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, EGF
LALTOP	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left lobe of thyroid gland	2
right lobe of thyroid gland	2
thyroid gland	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPO	132	tissue_specific	marker	left lobe of thyroid gland, thyroid gland, right lobe of thyroid gland
LALTOP	108		yes	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPO	1,074
LALTOP	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TPO	P07202	84.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Thyroxine biosynthesis	1	815.7×	0.001	TPO

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
hormone biosynthetic process	1	1404.3×	0.002	TPO
thyroid hormone generation	1	991.3×	0.002	TPO
embryonic hemopoiesis	1	991.3×	0.002	TPO
hydrogen peroxide catabolic process	1	674.1×	0.002	TPO
response to oxidative stress	1	130.6×	0.008	TPO

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
LALTOP	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): 1.

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

Symbol	Assays	Type breakdown
TPO	12	Binding:12

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TPO	1.11.1.8, 3.6.1.52	iodide peroxidase, diphosphoinositol-polyphosphate diphosphatase

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

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

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)
LALTOP	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