PHOX2B
protein-codingpaired like homeobox 2B, the group of PRD class homeoboxes and pseudogenes
Gene summary
The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription factor involved in the development of several major noradrenergic neuron populations and the determination of neurotransmitter phenotype. The gene product is linked to enhancement of second messenger-mediated activation of the dopamine beta-hydroylase, c-fos promoters and several enhancers, including cyclic amp-response element and serum-response element. Expansion of a 20 amino acid polyalanine tract in this protein by 5-13 aa has been associated with congenital central hypoventilation syndrome. [provided by RefSeq, Jul 2016]
- PMX2B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0800026
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0700041
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0800026
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0800026
Submitter: ClinGen
Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of the autonomic nervous system characterized by an altered chemosensory response to hypercapnia and hypoxia, typically most pronounced during sleep and reported to be associated with neuroblastoma. PHOX2B was first reported in relation to autosomal dominant congenital central hypoventilation syndrome (CCHS) in 2003 (Amiel et al., PMID: 12640453). PHOX2B encodes a highly conserved paired box homeodomain transcription factor, characterized by two polyalanine repeats of 9 and 20 residues in the C-terminal region. There are two types of PHOX2B mutations associated with CCHS: Polyalanine repeat mutations (PARMs) and nonpolyalanine repeat mutations (NPARMs). PARMs are in-frame nucleotide duplications inside the 20 alanine stretch, leading to expansions from +5 to +13 alanine residues, and are detected in about 90% CCHS patients. NPARMs include missense, nonsense and frameshift mutations, leading to different aberrant C-terminal of the protein, and are detected in about 8% CCHS patients. In MONDO, an assertion has been made for two disease entities: central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (CCHS, MONDO:0800026) and Haddad syndrome (MONDO:0020493). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism(s) (PARM versus NPARMS) AND phenotypic variability underlying the two disease entities. PHENOTYPIC VARIABILITY includes that PHOX2B PARMs are mainly associated with isolated CCHS and lower rate of Hirschsprung disease; whereas PHOX2B NPARMs are associated with Haddad syndrome including a much higher rate of Hirschsprung disease and more frequent neuroblastoma. Therefore, we have split curations for the disease entities, PHOX2B PARMs-CCHS which is being curated here; PHOX2B NPARMs-Haddad syndrome (neuroblastoma, Hirschsprung disease in CCHS syndrome, susceptibility to) which has been curated separately. The mechanism for CCHS disease is unclear and could involve dominant-negative effect or toxic gain of function, and disrupted transcription activity of PHOX2B protein in cells is associated with disease (PMID: 15888479, 16249188). Four PARM variants reported in more than 200 probands in three publications (PMIDs:12640453, 15657873,15121777) 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 association is also supported by experimental evidence. (5 points, PMIDs: 9374403, 10360575, 12640453, 18198276). Mice heterozygous for the CCHS-causing expanded alanine tract in the Phox2b gene had irregular breathing, did not respond to an increase in CO2, and died soon after birth from central apnea. In summary, PHOX2B-PARM is definitively associated with autosomal dominant CCHS syndrome. This has been repeatedly demonstrated in the research and clinical diagnostic settings, and has been upheld over time. Only 2 CCHS patients harboring a polyalanine tract expansion were diagnosed with ganglioneuroma, suggesting limited association between PHOX2B PARMs and tumors of the sympathetic nervous system.
Inheritance Pattern: AD
Disease ID:MONDO:0020493
Submitter: ClinGen
Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of the autonomic nervous system characterized by an altered chemosensory response to hypercapnia and hypoxia, typically most pronounced during sleep. PHOX2B was first reported in relation to autosomal dominant congenital central hypoventilation syndrome (CCHS) in 2003 (Amiel et al., PMID: 12640453). PHOX2B encodes a highly conserved paired box homeodomain transcription factor, characterized by two polyalanine repeats of 9 and 20 residues in the C-terminal region. There are two types of PHOX2B mutations associated with CCHS: Polyalanine repeat mutations (PARMs) and nonpolyalanine repeat mutations (NPARMs). PARMs are in-frame nucleotide duplications inside the 20 alanine stretch, leading to expansions from +5 to +13 alanine residues, and are detected in about 90% CCHS patients. NPARMs include missense, nonsense and frameshift mutations, leading to different aberrant C-terminal of the protein, and are detected in about 8% CCHS patients. In MONDO, an assertion has been made for two disease entities: congenital central hypoventilation syndrome (CCHS) associated with PARMs and Haddad syndrome (CCHS occurs concurrently with Hirschsprung disease) associated with NPARMs demonstrating different molecular mechanisms. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism(s) AND phenotypic variability underlying the two disease entities. For phenotypic variability, PHOX2B PARMs are mainly associated with isolated CCHS; whereas PHOX2B NPARMs are associated with Haddad syndrome including a much higher rate of Hirschsprung disease and more frequent neuroblastoma. The estimated incidence of neuroblastoma in patients with NPARMs is 50% compared to 1% among patients with PARMs (Berry-Kravis et al., 2006 PMID: 16888290). Therefore, we have split curations for the disease entities, PHOX2B PARMs-CCHS; PHOX2B NPARMs-Haddad syndrome (neuroblastoma, Hirschsprung disease in CCHS syndrome, susceptibility to) being curated here. Six variants (missense, nonsense, frameshift, deletion) that have been reported in 9 probands in five publications (PMIDs:12640453, 15657873, 29543228, 29696799, 17637745) are included in this curation. This gene-disease association is also supported by function studies (PMIDs: 17637745, 15888479). In summary, PHOX2B-NPARM is definitively associated with autosomal dominant Haddad syndrome (neuroblastoma, Hirschsprung disease in CCHS syndrome, susceptibility to). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0800026
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0700041
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0800026
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0020493
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008852
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Gastrointestinal; Neurologic; Oncologic
Intervention: Neurologic; Oncologic
Rationale: In Central hypoventilation syndrome, congenital, early recognition and interventions to support ventilation (as well as avoidance of exacerbating factors) can reduce morbidity and mortality; In Neuroblastoma, susceptibility to, 2 and Neuroblastoma with Hirschsprung disease, surveillance and/or awareness of cancer risk (involving the sympathetic nervous system) may allow early diagnosis and treatment of tumors, which may reduce morbidity and mortality
Comments: Individuals are also at risk of additional autonomic nervous system anomalies including Hirschsprung disease
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PHOX2B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003924.4. 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 | 2 | 399 | 401 | |||
| missense | 2 | 7 | 718 | 22 | 3 | 752 |
| nonsense | 9 | 3 | 6 | 18 | ||
| start loss | 2 | 2 | ||||
| frameshift | 24 | 14 | 6 | 44 | ||
| splice donor/acceptor (+/-2bp) | 4 | 1 | 1 | 6 | ||
| Total | 35 | 28 | 735 | 422 | 3 | 1223 |
Highest pathogenic variant AF is 0.000036587022
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003915.2 | 3 | MANE Select | |
| Ensembl | ENSP00000226382.2 | 3 | MANE Select | |
| Ensembl | ENSP00000801893.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| phox2bb | Danio rerio | Structure: enteric nervous system Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Neural Crest Differentiation
- Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways
Biological Process
- neuron migration
- regulation of respiratory gaseous exchange by neurological system process
- noradrenergic neuron differentiation
- noradrenergic neuron development
- brainstem development
Molecular Function
- RNA polymerase II regulatory region sequence-specific DNA binding
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
Cellular Component
- nuclear chromatin
- nucleus
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000226382
- Coding exons
- 3
- Length
- 4889
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.08 | 93 | 169 | 0.549 | 0.00000760 | 1988 |
| Missense (PolyPhen) | 12 | 44.162 | 0.27173 | 536 | ||
| Synonymous | -1.11 | 85 | 72.9 | 1.17 | 0.00000346 | 666 |
| Loss of Function | 2.75 | 0 | 8.80 | 0.00 | 3.76e-7 | 102 |
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 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in the development of several major noradrenergic neuron populations, including the locus coeruleus. Transcription factor which could determine a neurotransmitter phenotype in vertebrates. Enhances second-messenger-mediated activation of the dopamine beta-hydrolase and c-fos promoters, and of several enhancers including cAMP-response element and serum- response element.;
- Disease
- DISEASE: Neuroblastoma 2 (NBLST2) [MIM:613013]: A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system. {ECO:0000305|PubMed:15024693}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.281
Intolerance Scores
- LoFtool
- 0.0467
- RVIS EVS
- 0.13
- RVIS percentile EVS
- 62.74
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.626
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |