Thyroid hemiagenesis

Summary

Thyroid hemiagenesis (MONDO:0019860) is a disease with 5 cohort genes.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide)
• Cohort genes: 5
• ClinVar variants: 9
• Phenotypes (HPO): 27

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	25	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0011780	Thyroid hemiagenesis	Obligate (100%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001537	Umbilical hernia	Very frequent (80-99%)
HP:0002019	Constipation	Very frequent (80-99%)
HP:0003270	Abdominal distention	Very frequent (80-99%)
HP:0008191	Thyroid agenesis	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0100786	Hypersomnia	Very frequent (80-99%)
HP:0000158	Macroglossia	Very frequent (80-99%)
HP:0000239	Large fontanelles	Very frequent (80-99%)
HP:0000271	Abnormality of the face	Very frequent (80-99%)
HP:0000280	Coarse facial features	Very frequent (80-99%)
HP:0000952	Jaundice	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0000854	Thyroid adenoma	Frequent (30-79%)
HP:0000872	Hashimoto thyroiditis	Frequent (30-79%)
HP:0002925	Elevated circulating thyroid-stimulating hormone concentration	Frequent (30-79%)
HP:0011788	Increased circulating free T3	Frequent (30-79%)
HP:0025379	Anti-thyroid peroxidase antibody positivity	Frequent (30-79%)
HP:0025388	Thyroid nodule	Frequent (30-79%)
HP:0032069	Anti-thyroglobulin antibody positivity	Frequent (30-79%)
HP:0000843	Hyperparathyroidism	Occasional (5-29%)
HP:0002895	Papillary thyroid carcinoma	Occasional (5-29%)
HP:0100647	Graves disease	Occasional (5-29%)
HP:0002865	Medullary thyroid carcinoma	Very rare (<1-4%)
HP:0006731	Follicular thyroid carcinoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	thyroid hemiagenesis
Mondo ID	MONDO:0019860
Orphanet	95719
ICD-11	872920513
SNOMED CT	715734006
UMLS	C4023190
MedGen	868785
GARD	0016844
Is cancer (heuristic)	no

Data availability: 9 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › thyroid gland disorder › inherited thyroid metabolism disease › thyroid hormone resistance syndrome › generalized resistance to thyroid hormone › thyroid hemiagenesis

Related subtypes (5): thyroid hormone resistance, generalized, autosomal dominant, thyroid hormone resistance, generalized, autosomal recessive, thyroid ectopia, athyreosis, thyroid hypoplasia

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

9 retrieved; paginated sample, class counts are floors:

9 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
369982	GRCh37/hg19 11p15.2(chr11:14504463-14909461)x1	CYP2R1	Likely pathogenic	no assertion criteria provided
369983	GRCh37/hg19 11p15.2(chr11:14657389-14918308)x1	CYP2R1	Likely pathogenic	no assertion criteria provided
369989	GRCh37/hg19 2p21(chr2:45453858-45455897)x3	LINC01121	Likely pathogenic	no assertion criteria provided
369990	GRCh37/hg19 2p21(chr2:45454554-45457111)x3	LINC01121	Likely pathogenic	no assertion criteria provided
369988	GRCh37/hg19 17q21.1(chr17:38146929-38153473)x1	PSMD3	Likely pathogenic	no assertion criteria provided
369984	GRCh37/hg19 14q23.1(chr14:58737402-58884615)x1	TOMM20L	Likely pathogenic	no assertion criteria provided
369985	GRCh37/hg19 14q23.1(chr14:58737402-58891576)x1	TOMM20L	Likely pathogenic	no assertion criteria provided
369986	GRCh37/hg19 15q22.2(chr15:62128861-62340126)x1	VPS13C	Likely pathogenic	no assertion criteria provided
369987	GRCh37/hg19 15q22.2(chr15:62155282-62332980)x1	VPS13C	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP2R1	Orphanet:289157	Hypocalcemic vitamin D-dependent rickets
VPS13C	Orphanet:2828	Young-onset Parkinson disease

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYP2R1	HGNC:20580	ENSG00000186104	Q6VVX0	Vitamin D 25-hydroxylase	clinvar
VPS13C	HGNC:23594	ENSG00000129003	Q709C8	Intermembrane lipid transfer protein VPS13C	clinvar
TOMM20L	HGNC:33752	ENSG00000196860	Q6UXN7	TOMM20-like protein 1	clinvar
LINC01121	HGNC:49266	ENSG00000205054		long intergenic non-protein coding RNA 1121	clinvar
PSMD3	HGNC:9560	ENSG00000108344	O43242	26S proteasome non-ATPase regulatory subunit 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP2R1	Vitamin D 25-hydroxylase	A cytochrome P450 monooxygenase involved in activation of vitamin D precursors.
VPS13C	Intermembrane lipid transfer protein VPS13C	Mediates the transfer of lipids between membranes at organelle contact sites.
PSMD3	26S proteasome non-ATPase regulatory subunit 3	Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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	2.4×	0.353
Other/Unknown	4	1.4×	0.353

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYP2R1	Enzyme (other)	yes	1.14.14.24	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
VPS13C	Other/Unknown	no		VPS13_VAB, VPS13, VPS13_N
TOMM20L	Other/Unknown	no		MAS20, MAS20_rcpt_metazoan, Tom20_dom_sf
LINC01121	Other/Unknown	no
PSMD3	Other/Unknown	no		PCI_dom, TPR-like_helical_dom_sf, PSMD3_C

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	2
calcaneal tendon	2
male germ line stem cell (sensu Vertebrata) in testis	2
male germ cell	1
sperm	1
epithelium of nasopharynx	1
upper leg skin	1
testis	1
tendon	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYP2R1	252	ubiquitous	marker	sperm, male germ cell, left testis
VPS13C	291	ubiquitous	marker	calcaneal tendon, upper leg skin, epithelium of nasopharynx
TOMM20L	131	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, left testis, testis
LINC01121	131	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon, tendon
PSMD3	291	ubiquitous	marker	gastrocnemius, muscle of leg, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSMD3	3,788
VPS13C	2,056
CYP2R1	1,609
TOMM20L	824
LINC01121	0

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSMD3	O43242	118
CYP2R1	Q6VVX0	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TOMM20L	Q6UXN7	81.08
VPS13C	Q709C8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 71. Enrichment computed across 5 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CYP27B1 causes VDDR1B	1	5710.0×	0.012	CYP2R1
Vitamins	1	951.7×	0.017	CYP2R1
Vitamin D (calciferol) metabolism	1	439.2×	0.017	CYP2R1
Regulation of activated PAK-2p34 by proteasome mediated degradation	1	139.3×	0.017	PSMD3
Regulation of ornithine decarboxylase (ODC)	1	135.9×	0.017	PSMD3
Vpu mediated degradation of CD4	1	132.8×	0.017	PSMD3
Autodegradation of the E3 ubiquitin ligase COP1	1	132.8×	0.017	PSMD3
Ubiquitin-dependent degradation of Cyclin D	1	132.8×	0.017	PSMD3
Cross-presentation of soluble exogenous antigens (endosomes)	1	126.9×	0.017	PSMD3
Vif-mediated degradation of APOBEC3G	1	126.9×	0.017	PSMD3
AUF1 (hnRNP D0) binds and destabilizes mRNA	1	124.1×	0.017	PSMD3
Degradation of AXIN	1	124.1×	0.017	PSMD3
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	1	124.1×	0.017	PSMD3
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	1	124.1×	0.017	PSMD3
Hh mutants are degraded by ERAD	1	121.5×	0.017	PSMD3
SCF-beta-TrCP mediated degradation of Emi1	1	119.0×	0.017	PSMD3
Degradation of DVL	1	119.0×	0.017	PSMD3
Negative regulation of NOTCH4 signaling	1	119.0×	0.017	PSMD3
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	1	119.0×	0.017	PSMD3
Regulation of RUNX3 expression and activity	1	116.5×	0.017	PSMD3
Somitogenesis	1	116.5×	0.017	PSMD3
NIK–>noncanonical NF-kB signaling	1	114.2×	0.017	PSMD3
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	114.2×	0.017	PSMD3
Degradation of GLI1 by the proteasome	1	112.0×	0.017	PSMD3
Degradation of GLI2 by the proteasome	1	112.0×	0.017	PSMD3
GLI3 is processed to GLI3R by the proteasome	1	112.0×	0.017	PSMD3
Defective CFTR causes cystic fibrosis	1	109.8×	0.017	PSMD3
Degradation of CRY and PER proteins	1	109.8×	0.017	PSMD3
Dectin-1 mediated noncanonical NF-kB signaling	1	107.7×	0.017	PSMD3
Hedgehog ligand biogenesis	1	105.7×	0.017	PSMD3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to cesium ion	1	4213.0×	0.003	CYP2R1
tRNA import into mitochondrion	1	2106.5×	0.003	TOMM20L
negative regulation of type 2 mitophagy	1	2106.5×	0.003	VPS13C
calcitriol biosynthetic process from calciol	1	1404.3×	0.004	CYP2R1
protein retention in Golgi apparatus	1	842.6×	0.005	VPS13C
vitamin metabolic process	1	702.2×	0.005	CYP2R1
obsolete organic acid metabolic process	1	601.9×	0.005	CYP2R1
vitamin D metabolic process	1	383.0×	0.007	CYP2R1
protein targeting to vacuole	1	324.1×	0.007	VPS13C
Golgi to endosome transport	1	263.3×	0.008	VPS13C
regulation of protein catabolic process	1	210.7×	0.009	PSMD3
protein import into mitochondrial matrix	1	175.5×	0.010	TOMM20L
response to ionizing radiation	1	102.8×	0.016	CYP2R1
protein targeting	1	91.6×	0.016	TOMM20L
lipid transport	1	65.8×	0.021	VPS13C
response to insulin	1	57.7×	0.023	VPS13C
mitochondrion organization	1	38.0×	0.031	VPS13C
xenobiotic metabolic process	1	37.3×	0.031	CYP2R1
ubiquitin-dependent protein catabolic process	1	18.6×	0.058	PSMD3
intracellular protein transport	1	16.2×	0.063	TOMM20L
proteasome-mediated ubiquitin-dependent protein catabolic process	1	13.0×	0.074	PSMD3

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 3

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
CYP2R1	PAZOPANIB
PSMD3	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSMD3	2	4
CYP2R1	1	4
VPS13C	0	0
TOMM20L	0	0
LINC01121	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PAZOPANIB	4	CYP2R1
BORTEZOMIB	4	PSMD3
CARFILZOMIB	4	PSMD3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CYP2R1	183	ADMET:181, Binding:2
PSMD3	27	Binding:27

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP2R1	1.14.14.24	vitamin D 25-hydroxylase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CYP2R1	183

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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)
PAZOPANIB	4	CYP2R1
BORTEZOMIB	4	PSMD3
CARFILZOMIB	4	PSMD3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CYP2R1, PSMD3
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	3	VPS13C, TOMM20L, LINC01121

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VPS13C	0	—
TOMM20L	0	—
LINC01121	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.