NKX2-1

protein-coding

NK2 homeobox 1, the group of NKL subclass homeoboxes and pseudogenes

Gene summary

This gene encodes a protein initially identified as a thyroid-specific transcription factor. The encoded protein binds to the thyroglobulin promoter and regulates the expression of thyroid-specific genes but has also been shown to regulate the expression of genes involved in morphogenesis. Mutations and deletions in this gene are associated with benign hereditary chorea, choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress, and may be associated with thyroid cancer. Multiple transcript variants encoding different isoforms have been found for this gene. This gene shares the symbol/alias 'TTF1' with another gene, transcription termination factor 1, which plays a role in ribosomal gene transcription. [provided by RefSeq, Feb 2014]

Previous symbols:

NKX2A
BCH
TITF1

MANE transcript

NM_001079668.3

Inheritance

ClinVar variants

P:139U:152B:80

Top phenotype

Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction; Thyroid cancer, nonmedullary 1

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr14:36,516,392-36,521,149

External References & Databases

Ensembl (ENSG00000136352)

Transcript & Mutation Effects

hg38 • Region Span ~4.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunctionDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100520

Submitter: ClinGen

The NKX2-1 gene is located on chromosome 14 at 14q13.3 and encodes the NK2 homeobox 1 protein, a transcription factor that binds and activates thyroid specific genes. NKX2-1 was first reported in relation to autosomal dominant NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction in 1998 (Devriendt et al., 1998, PMID: 9565498). Variants in NKX2-1 have been reported in individuals with the following disease entities: Thyroid cancer, nonmedullary, 1 (MIM: 188550), Chorea, hereditary benign (MIM:118700), Choreoathetosis, hypothyroidism, and neonatal respiratory distress (MIM:610978). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction. At least 9 variants including missense and loss-of-function variants have been reported in a heterozygous state. Evidence supporting this gene-disease relationship include case level and experimental data. Variants in this gene have been reported in at least nine probands from three publications (Gras et al., 2012, PMID: 22832740; Iodice et al., 2019, PMID: 30352709; Parnes et al., 2019, PMID: 30746413) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by mouse models that partially recapitulate the human disease phenotype (Kimura et al., 1996, PMID: 8557195; Pohlenz et al., 2002, PMID: 11854318). In situ hybridization shows the gene is expressed primarily in thyroid, lung epithelium, and areas of the forebrain during embryogenesis, providing more support for the relationship of the gene and disease. In summary, the NKX2-1 gene is definitively associated with autosomal dominant NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 07.26.2022 (SOP Version 9).

NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunctionSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100520

Submitter: PanelApp Australia

brain-lung-thyroid syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012593

Submitter: G2P

choreatic diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0001595

Submitter: Orphanet

brain-lung-thyroid syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012593

Submitter: Labcorp Genetics (formerly Invitae)

brain-lung-thyroid syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012593

Submitter: Genomics England PanelApp

hereditary progressive chorea without dementiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0021011

Submitter: Genomics England PanelApp

brain-lung-thyroid syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012593

Submitter: Orphanet

Clinical Genomic Database (CGD)

Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction; Thyroid cancer, nonmedullary 1AD

Manifestation: Allergy/Immunology/Infectious; Endocrine; Neurologic; Oncologic; Pulmonary

Intervention: Allergy/Immunology/Infectious; Endocrine; Neurologic; Oncologic; Pulmonary

Rationale: Individuals with Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction may have congenital hypothyroidism necessitating thyroxine replacement; Response to levodopa has also been reported; Neonates may require ventilatory support, and may be prone to recurrent respiratory infections, and awareness may allow prophylactic measures, as well as prompt and aggressive treatment of infections; For Thyroid cancer, nonmedullary 1, individuals have been described as being susceptible to nonmedullary thyroid cancer, and awareness may allow early surveillance, diagnosis, and management

Comments: Choreoathetosis, hypothyroidism, and neonatal respiratory distress manifests in the childhood; Thyroid cancer, nonmedullary 4 has been reported as manifesting in adulthood

Refs: 9565498; 10931427; 11854319; 11854318; 11971878; 12891678; 15289765; 15955952; 19176457; 19336474; 22488412; 22825795

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NKX2-1 variants in ClinVar

17 Conditions Cataloged

not providedTotal: 245

Brain-lung-thyroid syndromeTotal: 88

Inborn genetic diseasesTotal: 59

Benign hereditary choreaTotal: 44

not specifiedTotal: 30

NKX2-1-Related DisordersTotal: 27

Interstitial lung disease 2Total: 5

Thyroid cancer, nonmedullary, 1Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001079668.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	65 clinvar	1 clinvar	75
missense	6 clinvar	27 clinvar	137 clinvar	13 clinvar	1 clinvar	184
nonsense	18 clinvar	13 clinvar	2 clinvar			33
start loss	1 clinvar		1 clinvar			2
frameshift	40 clinvar	31 clinvar	1 clinvar			72
splice donor/acceptor (+/-2bp)	3 clinvar		2 clinvar			5
Total	68	71	152	78	2	371

Highest pathogenic variant AF is 0.000002053672

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001079668.3	RefSeq	NP_001073136.1	3	MANE Select
ENST00000354822.7	Ensembl	ENSP00000346879.6	3	MANE Select
NM_003317.4	RefSeq	NP_003308.1	2	Standard
ENST00000498187.6	Ensembl	ENSP00000429607.2	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endoderm Differentiation
Preimplantation Embryo
Tgif disruption of Shh signaling
FOXA2 and FOXA3 transcription factor networks

Biological Process

negative regulation of transcription by RNA polymerase II
neuron migration
phospholipid metabolic process
axon guidance
brain development

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
RNA polymerase II distal enhancer sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
RNA polymerase II regulatory region DNA binding

Cellular Component

nucleus
nucleoplasm
transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000354822
Coding exons: 3
Length: 4753
Individuals with no LoFs: 121082
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 121086
p: 0.0000165

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.81	149	225	0.661	0.0000101	2550
Missense (PolyPhen)		60	107.29	0.55922		1204
Synonymous	-0.913	112	100	1.12	0.00000475	822
Loss of Function	2.61	3	13.2	0.227	5.73e-7	130

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000057	0.000056	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000028	0.000028	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor. Crucial in the maintenance of the thyroid differentiation phenotype. May play a role in lung development and surfactant homeostasis. Forms a regulatory loop with GRHL2 that coordinates lung epithelial cell morphogenesis and differentiation. Activates the transcription of GNRHR and plays a role in enhancing the circadian oscillation of its gene expression. Represses the transcription of the circadian transcriptional repressor NR1D1 (By similarity). {ECO:0000250|UniProtKB:P23441, ECO:0000250|UniProtKB:P50220}.;
Disease: DISEASE: Chorea, hereditary benign (BHC) [MIM:118700]: A rare autosomal dominant movement disorder, defined by early onset in childhood, a stable or non-progressive course of chorea, and no mental deterioration. Chorea is characterized by involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. {ECO:0000269|PubMed:11971878, ECO:0000269|PubMed:15955952, ECO:0000269|PubMed:24453141, ECO:0000269|PubMed:26723978}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (CAHTP) [MIM:610978]: An autosomal dominant disorder that manifests in infancy with neurological disturbances, hypothyroidism, and respiratory problems. It is characterized by movement abnormalities beginning with muscular hypotonia followed by the development of chorea, athetosis, dystonia, ataxia, and dysarthria. {ECO:0000269|PubMed:11854318, ECO:0000269|PubMed:11854319, ECO:0000269|PubMed:15289765, ECO:0000269|PubMed:15955952, ECO:0000269|PubMed:24714694}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Thyroid cancer, non-medullary, 1 (NMTC1) [MIM:188550]: A form of non-medullary thyroid cancer (NMTC), a cancer characterized by tumors originating from the thyroid follicular cells. NMTCs represent approximately 95% of all cases of thyroid cancer and are classified into papillary, follicular, Hurthle cell, and anaplastic neoplasms. {ECO:0000269|PubMed:19176457}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.523

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.928

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium