PHOX2B

Chr 4AD

paired like homeobox 2B

Also known as: CCHS, NBLST2, NBPhox, PMX2B

NCBI Gene: 8929 ENSG00000109132 UniProt: Q99453

This gene encodes a transcription factor that regulates the development of noradrenergic neurons and determines neurotransmitter phenotype in the nervous system. Mutations cause congenital central hypoventilation syndrome (often with Hirschsprung disease) and predispose to neuroblastoma, following autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.94, LOEUF 0.34), and congenital central hypoventilation syndrome typically presents in the neonatal period with life-threatening respiratory control abnormalities.

Summary from RefSeq, OMIM, UniProt

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Primary Disease Associations & Inheritance

{Neuroblastoma, susceptibility to, 2}MIM #613013

Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung diseaseMIM #209880

Neuroblastoma with Hirschsprung diseaseMIM #613013

UniProtNeuroblastoma 2

Active trials

Pubs (1 yr)

P/LP submissions

P/LP missense

0.34

LOEUF· LoF intol.

Multiple*

Mechanism· G2P

Clinical Summary— PHOX2B

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Gene-Disease Validity (ClinGen)

Haddad syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

46 unique Pathogenic / Likely Pathogenic· 292 VUS of 500 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — PHOX2B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.34LOEUF

pLI 0.938

Z-score 2.75

OE 0.00 (0.00–0.34)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

2.08Z-score

OE missense 0.55 (0.46–0.65)

93 obs / 169.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.00 (0.00–0.34)

0≤0.351.4

Missense OE0.55 (0.46–0.65)

0≤0.61.4

Synonymous OE1.17

0≤1.21.6

LoF obs/exp: 0 / 8.8Missense obs/exp: 93 / 169.3Syn Z: -1.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePHOX2B-related neuroblastoma with Hirschsprung diseaseLOFAD

definitivePHOX2B-related central hypoventilation syndrome, congenital, with or without Hirschsprung diseaseDNAD

0.4190th %ile

GOF

0.2895th %ile

LOF

0.87top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 41% of P/LP variants are LoF · LOEUF 0.34

DN1 literature citation

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNWe propose that CCHS is partially caused by a dominant-negative effect of expanded PHOX2B due to the retention of the wild-type protein in pathogenic aggregates.PMID:22307522

GOFThe apparent phenotypic differences between mice carrying a loss-of-function mutation of Phox2b and CCHS patients indicates that PHOX2B mutations found in CCHS patients, all of which can produce proteins with intact DNA-binding domains, are gain-of-function mutations that alter rather than abolish pPMID:15150159

LOFHaploinsufficiency for Phox2b in mice causes dilated pupils and atrophy of the ciliary ganglion: mechanistic insights into human congenital central hypoventilation syndrome.PMID:15150159

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.