Brain-lung-thyroid syndrome

Summary

Brain-lung-thyroid syndrome (MONDO:0012593) is a disease caused by NKX2-1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NKX2-1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 101
• Phenotypes (HPO): 60

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

60 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000820	Abnormality of the thyroid gland	Very frequent (80-99%)
HP:0000707	Abnormality of the nervous system	Frequent (30-79%)
HP:0000851	Congenital hypothyroidism	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001266	Choreoathetosis	Frequent (30-79%)
HP:0002072	Chorea	Frequent (30-79%)
HP:0002086	Abnormality of the respiratory system	Frequent (30-79%)
HP:0002098	Respiratory distress	Frequent (30-79%)
HP:0002643	Neonatal respiratory distress	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0001671	Abnormal cardiac septum morphology	Occasional (5-29%)
HP:0002080	Intention tremor	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002186	Apraxia	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002311	Incoordination	Occasional (5-29%)
HP:0002312	Clumsiness	Occasional (5-29%)
HP:0002925	Elevated circulating thyroid-stimulating hormone concentration	Occasional (5-29%)
HP:0004305	Involuntary movements	Occasional (5-29%)
HP:0006530	Abnormal pulmonary interstitial morphology	Occasional (5-29%)
HP:0006532	Recurrent pneumonia	Occasional (5-29%)
HP:0008188	Thyroid dysgenesis	Occasional (5-29%)
HP:0008223	Compensated hypothyroidism	Occasional (5-29%)
HP:0011780	Thyroid hemiagenesis	Occasional (5-29%)
HP:0000021	Megacystis	Very rare (<1-4%)
HP:0000047	Hypospadias	Very rare (<1-4%)
HP:0000076	Vesicoureteral reflux	Very rare (<1-4%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0000465	Webbed neck	Very rare (<1-4%)
HP:0000668	Hypodontia	Very rare (<1-4%)
HP:0000722	Compulsive behaviors	Very rare (<1-4%)
HP:0000736	Short attention span	Very rare (<1-4%)
HP:0000752	Hyperactivity	Very rare (<1-4%)
HP:0000829	Hypoparathyroidism	Very rare (<1-4%)
HP:0001274	Agenesis of corpus callosum	Very rare (<1-4%)
HP:0001655	Patent foramen ovale	Very rare (<1-4%)
HP:0001955	Unexplained fevers	Very rare (<1-4%)
HP:0001999	Abnormal facial shape	Very rare (<1-4%)
HP:0002099	Asthma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	brain-lung-thyroid syndrome
Mondo ID	MONDO:0012593
MeSH	C567034
OMIM	610978
Orphanet	209905
ICD-11	809856670
SNOMED CT	719098007
UMLS	C1970269
MedGen	369694
GARD	0012163
Is cancer (heuristic)	no

Also known as: BLT syndrome · brain-lung-thyroid syndrome · CAHTP · choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction · choreoathetosis, hypothyroidism, and neonatal respiratory distress · choreoathetosis-hypothyroidism-neonatal respiratory distress · choreoathetosis-hypothyroidism-neonatal respiratory distress syndrome

Data availability: 101 ClinVar variants · 4 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › brain-lung-thyroid syndrome

Related subtypes (53): cerebellar ataxia, chronic tic disorder, choreatic disease, extrapyramidal and movement disease, benign shuddering attacks, transient tic disorder, essential tremor, lingual-facial-buccal dyskinesia, kuru, inherited Creutzfeldt-Jakob disease, Tourette syndrome, clonic hemifacial spasm, Huntington disease, multiple system atrophy, spinal muscular atrophy-progressive myoclonic epilepsy syndrome, benign paroxysmal tonic upgaze of childhood with ataxia, hereditary geniospasm, tremor-nystagmus-duodenal ulcer syndrome, arthrogryposis, Lafora disease, Unverricht-Lundborg syndrome, neuronal intranuclear inclusion disease, Huntington disease-like 3, myoclonus, familial, proximal myopathy with extrapyramidal signs, progressive myoclonic epilepsy type 7, progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome, progressive non-fluent aphasia, opsoclonus-myoclonus syndrome, isolated facial myokymia, primary orthostatic tremor, familial congenital mirror movements, neuroacanthocytosis, behavioral variant of frontotemporal dementia, frontotemporal dementia with motor neuron disease, hyperekplexia, intellectual disability-hyperkinetic movement-truncal ataxia syndrome, neurodegeneration with brain iron accumulation, Huntington disease-like syndrome due to C9ORF72 expansions, variably protease-sensitive prionopathy, corticobasal syndrome, sensorineural hearing loss-early graying-essential tremor syndrome, progressive supranuclear palsy, Sandifer syndrome, psychogenic movement disorders, epilepsy with myoclonic absences, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome, childhood-onset benign chorea with striatal involvement, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, PRRT2-associated paroxysmal movement disorder, SLC6A3-related dopamine transporter deficiency syndrome, dyskinesia with orofacial involvement, autosomal dominant, complex movement disorder with or without neurodevelopmental features

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

101 retrieved; paginated sample, class counts are floors:

26 pathogenic, 24 likely pathogenic, 19 uncertain significance, 12 pathogenic/likely pathogenic, 9 conflicting classifications of pathogenicity, 7 benign, 2 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1204589	NM_001079668.3(NKX2-1):c.727C>T (p.Arg243Cys)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326865	NM_001079668.3(NKX2-1):c.338dup (p.Tyr116fs)	NKX2-1	Pathogenic	criteria provided, single submitter
1712809	NM_001079668.3(NKX2-1):c.612C>A (p.Tyr204Ter)	NKX2-1	Pathogenic	criteria provided, multiple submitters, no conflicts
1801521	NM_001079668.3(NKX2-1):c.626G>C (p.Arg209Pro)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2013969	NM_001079668.3(NKX2-1):c.474del (p.Phe158fs)	NKX2-1	Pathogenic	criteria provided, multiple submitters, no conflicts
217884	NM_001079668.3(NKX2-1):c.524C>A (p.Ser175Ter)	NKX2-1	Pathogenic	criteria provided, multiple submitters, no conflicts
2444045	NM_001079668.3(NKX2-1):c.464-9C>A	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506907	NM_001079668.3(NKX2-1):c.216del (p.Arg72fs)	NKX2-1	Pathogenic	criteria provided, single submitter
2506917	NM_001079668.3(NKX2-1):c.583del (p.Arg195fs)	NKX2-1	Pathogenic	criteria provided, single submitter
2506918	NM_001079668.3(NKX2-1):c.1045dup (p.His349fs)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506928	NM_001079668.3(NKX2-1):c.650C>A (p.Ser217Ter)	NKX2-1	Pathogenic	criteria provided, multiple submitters, no conflicts
2506933	NM_001079668.3(NKX2-1):c.711C>G (p.Ile237Met)	NKX2-1	Pathogenic	criteria provided, single submitter
2506934	NM_001079668.3(NKX2-1):c.622C>T (p.Arg208Ter)	NKX2-1	Pathogenic	criteria provided, single submitter
2506937	NM_001079668.3(NKX2-1):c.423del (p.Gly142fs)	NKX2-1	Pathogenic	criteria provided, single submitter
2506939	NM_001079668.3(NKX2-1):c.647del (p.Leu216fs)	NKX2-1	Pathogenic	criteria provided, single submitter
2506942	NM_001079668.3(NKX2-1):c.336_345del (p.Val113fs)	NKX2-1	Pathogenic	criteria provided, single submitter
2506943	NM_001079668.3(NKX2-1):c.196del (p.Ala66fs)	NKX2-1	Pathogenic	criteria provided, single submitter
3075710	NM_001079668.3(NKX2-1):c.512_576del (p.Gly171fs)	NKX2-1	Pathogenic	criteria provided, single submitter
3576568	NM_001079668.3(NKX2-1):c.572G>T (p.Arg191Leu)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4813540	NM_001079668.3(NKX2-1):c.1080_1084dup (p.His362fs)	NKX2-1	Pathogenic	criteria provided, single submitter
504417	NM_001079668.3(NKX2-1):c.664G>T (p.Glu222Ter)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
521215	NM_001079668.3(NKX2-1):c.617T>A (p.Leu206Gln)	NKX2-1	Pathogenic	criteria provided, multiple submitters, no conflicts
635557	NC_000014.9:g.(?36516072)(36520130_?)del	NKX2-1	Pathogenic	criteria provided, single submitter
803017	NM_001079668.3(NKX2-1):c.267dup (p.His90fs)	NKX2-1	Pathogenic	criteria provided, multiple submitters, no conflicts
807109	NM_001079668.3(NKX2-1):c.344del (p.Gly115fs)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
870856	NM_001079668.3(NKX2-1):c.432C>A (p.Tyr144Ter)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8974	NM_001079668.3(NKX2-1):c.713G>T (p.Trp238Leu)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8976	NM_001079668.3(NKX2-1):c.703G>T (p.Val235Phe)	NKX2-1	Pathogenic	no assertion criteria provided
8977	NM_001079668.3(NKX2-1):c.672_673dup (p.Ala225fs)	NKX2-1	Pathogenic	no assertion criteria provided
8979	NM_001079668.3(NKX2-1):c.613G>T (p.Glu205Ter)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 4 · 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
NKX2-1	Definitive	Autosomal dominant	brain-lung-thyroid syndrome	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NKX2-1	Orphanet:1429	Benign hereditary chorea
NKX2-1	Orphanet:146	Differentiated thyroid carcinoma
NKX2-1	Orphanet:209905	Brain-lung-thyroid syndrome
NKX2-1	Orphanet:95713	Athyreosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NKX2-1	HGNC:11825	ENSG00000136352	P43699	Homeobox protein Nkx-2.1	gencc,clinvar
SFTA3	HGNC:18387	ENSG00000229415	P0C7M3	Surfactant-associated protein 3	clinvar
PSMB11	HGNC:31963	ENSG00000222028	A5LHX3	Proteasome subunit beta type-11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NKX2-1	Homeobox protein Nkx-2.1	Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor.
SFTA3	Surfactant-associated protein 3	Putative surfactant protein.
PSMB11	Proteasome subunit beta type-11	The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NKX2-1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
SFTA3	Other/Unknown	no
PSMB11	Other/Unknown	no		Pept_T1A_subB, Proteasome_sua/b, Proteasome_bsu_CS

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
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
colonic epithelium	1
cortical plate	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NKX2-1	101	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
SFTA3	107	tissue_specific	marker	right lobe of thyroid gland, thyroid gland, left lobe of thyroid gland
PSMB11	1	tissue_specific	marker	colonic epithelium, ventricular zone, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NKX2-1	2,403
PSMB11	1,101
SFTA3	604

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NKX2-1	P43699	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PSMB11	A5LHX3	80.90
SFTA3	P0C7M3	61.17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 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 CSF2RB causes SMDP5	1	815.7×	0.002	SFTA3
Defective CSF2RA causes SMDP4	1	815.7×	0.002	SFTA3
Surfactant metabolism	1	184.2×	0.007	SFTA3
Proteasome assembly	1	102.0×	0.010	PSMB11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
developmental induction	1	2808.7×	0.007	NKX2-1
cerebral cortex GABAergic interneuron differentiation	1	1872.4×	0.007	NKX2-1
CD8-positive, alpha-beta T cell differentiation	1	1872.4×	0.007	PSMB11
globus pallidus development	1	1123.5×	0.007	NKX2-1
forebrain neuron fate commitment	1	1123.5×	0.007	NKX2-1
club cell differentiation	1	1123.5×	0.007	NKX2-1
forebrain dorsal/ventral pattern formation	1	702.2×	0.007	NKX2-1
lung saccule development	1	702.2×	0.007	NKX2-1
type II pneumocyte differentiation	1	702.2×	0.007	NKX2-1
anatomical structure formation involved in morphogenesis	1	624.1×	0.007	NKX2-1
cerebral cortex cell migration	1	510.7×	0.007	NKX2-1
interneuron migration	1	510.7×	0.007	NKX2-1
Leydig cell differentiation	1	401.2×	0.008	NKX2-1
positive regulation of circadian rhythm	1	401.2×	0.008	NKX2-1
hypothalamus development	1	351.1×	0.009	NKX2-1
epithelial tube branching involved in lung morphogenesis	1	280.9×	0.010	NKX2-1
pituitary gland development	1	216.1×	0.012	NKX2-1
endoderm development	1	208.1×	0.012	NKX2-1
thyroid gland development	1	181.2×	0.013	NKX2-1
response to hormone	1	144.0×	0.014	NKX2-1
oligodendrocyte differentiation	1	140.4×	0.014	NKX2-1
negative regulation of epithelial to mesenchymal transition	1	137.0×	0.014	NKX2-1
T cell differentiation in thymus	1	137.0×	0.014	PSMB11
forebrain development	1	117.0×	0.016	NKX2-1
phospholipid metabolic process	1	114.6×	0.016	NKX2-1
rhythmic process	1	83.8×	0.021	NKX2-1
hippocampus development	1	77.0×	0.021	NKX2-1
wound healing	1	75.9×	0.021	SFTA3
lung development	1	66.1×	0.023	NKX2-1
locomotory behavior	1	59.8×	0.025	NKX2-1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
PSMB11	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSMB11	5	4
NKX2-1	0	0
SFTA3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BORTEZOMIB	4	PSMB11
CARFILZOMIB	4	PSMB11
IXAZOMIB	3	PSMB11
MARIZOMIB	3	PSMB11
OPROZOMIB	2	PSMB11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSMB11	168	Binding:159, ADMET:6, Functional:3

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PSMB11	168

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

5 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)
BORTEZOMIB	4	PSMB11
CARFILZOMIB	4	PSMB11
IXAZOMIB	3	PSMB11
MARIZOMIB	3	PSMB11
OPROZOMIB	2	PSMB11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSMB11
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	NKX2-1, SFTA3

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)
NKX2-1	0	—
SFTA3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.