Thyroid hormone metabolism, abnormal 1

Summary

Thyroid hormone metabolism, abnormal 1 (MONDO:0800046) is a disease caused by SECISBP2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: SECISBP2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 13
• Phenotypes (HPO): 18

Clinical features

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0002925	Elevated circulating thyroid-stimulating hormone concentration	Frequent (30-79%)
HP:0031506	Increased circulating thyroxine level	Frequent (30-79%)
HP:0032210	Decreased circulating free T3	Frequent (30-79%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000736	Short attention span	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001513	Obesity	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0003162	Fasting hypoglycemia	Occasional (5-29%)
HP:0003391	Gowers sign	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0008994	Proximal muscle weakness in lower limbs	Occasional (5-29%)
HP:0009053	Distal lower limb muscle weakness	Occasional (5-29%)
HP:0012548	Fatty replacement of skeletal muscle	Occasional (5-29%)
HP:0031903	Abnormal circulating selenium concentration	Occasional (5-29%)
HP:0040214	Abnormal circulating insulin concentration	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	thyroid hormone metabolism, abnormal 1
Mondo ID	MONDO:0800046
MeSH	C566454
OMIM	609698
Orphanet	171706
UMLS	C5676891
MedGen	1801974
GARD	0017068
Is cancer (heuristic)	no

Also known as: short stature-delayed bone age due to thyroid hormone metabolism deficiency · THMA1 · thyroid hormone metabolism, abnormal

Data availability: 13 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › hereditary endocrine growth disease › permanent congenital hypothyroidism › peripheral hypothyroidism › thyroid hormone metabolism, abnormal 1

Related subtypes (1): peripheral resistance to thyroid hormones

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

13 retrieved; paginated sample, class counts are floors:

8 pathogenic, 3 uncertain significance, 1 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323572	NM_024077.5(SECISBP2):c.358C>T (p.Arg120Ter)	SECISBP2	Pathogenic	criteria provided, single submitter
1703052	NM_024077.5(SECISBP2):c.2308C>T (p.Arg770Ter)	SECISBP2	Pathogenic	criteria provided, single submitter
2581403	NM_024077.5(SECISBP2):c.1156_1159del (p.Glu386fs)	SECISBP2	Pathogenic	criteria provided, single submitter
2582503	NM_024077.5(SECISBP2):c.1089+2T>C	SECISBP2	Pathogenic	criteria provided, single submitter
2920	NM_024077.5(SECISBP2):c.1312A>T (p.Lys438Ter)	SECISBP2	Pathogenic	no assertion criteria provided
2921	NM_024077.5(SECISBP2):c.1212+29G>A	SECISBP2	Pathogenic	no assertion criteria provided
638567	NM_024077.5(SECISBP2):c.800dup (p.Gly268_Glu269insTer)	SECISBP2	Pathogenic	no assertion criteria provided
217868	NC_000019.10:g.45478610G>C	TRU-TCA1-1	Pathogenic	no assertion criteria provided
1120062	NM_024077.5(SECISBP2):c.182+1G>A	SECISBP2	Likely pathogenic	criteria provided, single submitter
2919	NM_024077.5(SECISBP2):c.1619G>A (p.Arg540Gln)	SECISBP2	Conflicting classifications of pathogenicity	no assertion criteria provided
1028292	NM_024077.5(SECISBP2):c.137C>G (p.Ser46Cys)	SECISBP2	Uncertain significance	criteria provided, single submitter
2435802	NM_024077.5(SECISBP2):c.1775C>T (p.Ser592Leu)	SECISBP2	Uncertain significance	criteria provided, single submitter
2580226	NM_024077.5(SECISBP2):c.2320A>T (p.Lys774Ter)	SECISBP2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
SECISBP2	Strong	Autosomal recessive	thyroid hormone metabolism, abnormal 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SECISBP2	Orphanet:171706	Short stature-delayed bone age due to thyroid hormone metabolism deficiency

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
SECISBP2	HGNC:30972	ENSG00000187742	Q96T21	Selenocysteine insertion sequence-binding protein 2	gencc,clinvar
TRU-TCA1-1	HGNC:12348			tRNA-SeC (anticodon TCA) 1-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SECISBP2	Selenocysteine insertion sequence-binding protein 2	mRNA-binding protein that binds to the SECIS (selenocysteine insertion sequence) element present in the 3’-UTR of mRNAs encoding selenoproteins and facilitates the incorporation of the rare amino acid selenocysteine.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SECISBP2	Other/Unknown	no		Ribosomal_eL8/eL30/eS12/Gad45, Ribosomal_eL30-like_sf, SECISBP2
TRU-TCA1-1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

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	1

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
secondary oocyte	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SECISBP2	280	ubiquitous	marker	secondary oocyte, sperm, oocyte
TRU-TCA1-1

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SECISBP2	2,096
TRU-TCA1-1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SECISBP2	Q96T21	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Selenoamino acid metabolism	1	196.9×	0.017	SECISBP2
Selenocysteine synthesis	1	120.2×	0.017	SECISBP2
Metabolism of amino acids and derivatives	1	67.6×	0.020	SECISBP2
Metabolism	1	11.6×	0.086	SECISBP2

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
forebrain neuron development	1	2407.4×	0.001	SECISBP2
selenocysteine incorporation	1	1872.4×	0.001	SECISBP2
negative regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1	1872.4×	0.001	SECISBP2
striatum development	1	1123.5×	0.001	SECISBP2
RNA catabolic process	1	455.5×	0.003	SECISBP2
mRNA stabilization	1	366.4×	0.003	SECISBP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
SECISBP2	0	0
TRU-TCA1-1	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	2	SECISBP2, TRU-TCA1-1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SECISBP2	0	—
TRU-TCA1-1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.