central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

Summary

central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (MONDO:0800026) is a disease caused by PHOX2B (GenCC Definitive), with 2 cohort genes and 13 clinical trials. Top therapeutic interventions include desogestrel and medronate disodium.

At a glance

• Prevalence: 1-9 / 1 000 000 (France) [Orphanet-validated]
• Causal gene: PHOX2B (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 31
• Phenotypes (HPO): 10
• Clinical trials: 13

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.5	France	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002270	Abnormality of the autonomic nervous system	Very frequent (80-99%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0002251	Aganglionic megacolon	Occasional (5-29%)
HP:0003005	Ganglioneuroma	Occasional (5-29%)
HP:0003006	Neuroblastoma	Occasional (5-29%)
HP:0006747	Ganglioneuroblastoma	Occasional (5-29%)
HP:0100006	Neoplasm of the central nervous system	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease
Mondo ID	MONDO:0800026
OMIM	209880
Orphanet	661
DOID	DOID:0060731
ICD-11	1750742010
NCIT	C98889
SNOMED CT	230499002
UMLS	C5562075
MedGen	1794285
GARD	0008535
MedDRA	10007982, 10066131
Is cancer (heuristic)	no

Also known as: autonomic control, congenital failure of · CCHS · central hypoventilation syndrome, congenital · congenital central alveolar hypoventilation syndrome · congenital central hypoventilation · congenital central hypoventilation syndrome · congenital failure of autonomic control · congenital Ondine curse · idiopathic congenital central alveolar hypoventilation · Ondine curse · Ondine curse (formerly) · Ondine curse, congenital · Ondine syndrome · Ondine’s curse (formerly) · primary alveolar hypoventilation

Data availability: 31 ClinVar variants · 5 GenCC gene-disease records · 11 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › autonomic nervous system disorder › central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

Related subtypes (12): idiopathic peripheral autonomic neuropathy, autonomic neuropathy, autonomic nervous system neoplasm, Frey syndrome, harlequin syndrome, chronic hiccup, pure autonomic failure, baroreflex failure, autonomic dysreflexia, dysautonomia, sympathetic nervous system disorder, parasympathetic nervous system disorder

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

31 retrieved; paginated sample, class counts are floors:

8 pathogenic, 7 benign/likely benign, 6 uncertain significance, 4 likely pathogenic, 3 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1757728	NM_003924.4(PHOX2B):c.722_759dup (p.Ala254fs)	LOC110011216	Pathogenic	criteria provided, multiple submitters, no conflicts
2500070	NM_003924.4(PHOX2B):c.775_776insGGCGGCAGCGGCAGCGGCGGC (p.Ala259delinsGlyArgGlnArgGlnArgArgPro)	LOC110011216	Pathogenic	criteria provided, single submitter
452239	NM_003924.4(PHOX2B):c.756_776dup (p.Ala254_Ala260dup)	LOC110011216	Pathogenic	criteria provided, multiple submitters, no conflicts
505021	NM_003924.4(PHOX2B):c.753_767dup (p.Ala256_Ala260dup)	LOC110011216	Pathogenic	criteria provided, multiple submitters, no conflicts
506167	NM_003924.4(PHOX2B):c.729_749dup (p.Ala254_Ala260dup)	LOC110011216	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
986849	NM_003924.4(PHOX2B):c.741_758dup (p.Ala255_Ala260dup)	LOC110011216	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500068	NM_003924.4(PHOX2B):c.778_779insGGCGGCGGCGGCAGCGGCAGCGGCGGCAGC (p.Ala260delinsGlyArgArgArgGlnArgGlnArgArgGlnPro)	PHOX2B	Pathogenic	criteria provided, single submitter
3254839	NM_003924.4(PHOX2B):c.666_667del (p.Ala223fs)	PHOX2B	Pathogenic	criteria provided, single submitter
4813344	NM_003924.4(PHOX2B):c.651_760del (p.Pro218fs)	PHOX2B	Pathogenic	criteria provided, single submitter
987239	NM_003924.4(PHOX2B):c.866dup (p.Pro290fs)	PHOX2B	Pathogenic	criteria provided, multiple submitters, no conflicts
2500234	NM_003924.4(PHOX2B):c.745_746insGGCGGCCGCGGC (p.Ala249delinsGlyArgProArgPro)	LOC110011216	Likely pathogenic	criteria provided, single submitter
2684393	NM_003924.4(PHOX2B):c.609_610delinsA (p.Asn203fs)	PHOX2B	Likely pathogenic	criteria provided, single submitter
3066323	NM_003924.4(PHOX2B):c.344_347dup (p.Phe117fs)	PHOX2B	Likely pathogenic	criteria provided, single submitter
4279623	NM_003924.4(PHOX2B):c.753_791dup (p.Ala266_Gly267insAlaAlaAlaAlaAlaAlaAlaGlyGlyLeuAlaAlaAla)	PHOX2B	Likely pathogenic	criteria provided, single submitter
135034	NM_003924.4(PHOX2B):c.617C>G (p.Pro206Arg)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
406405	NM_003924.4(PHOX2B):c.242-5_242-2dup	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
576023	NM_003924.4(PHOX2B):c.865G>A (p.Gly289Ser)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3590574	NM_003924.4(PHOX2B):c.860T>C (p.Leu287Pro)	PHOX2B	Uncertain significance	criteria provided, single submitter
486029	NM_003924.4(PHOX2B):c.683G>T (p.Gly228Val)	PHOX2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
486033	NM_003924.4(PHOX2B):c.694C>A (p.Pro232Thr)	PHOX2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
646058	NM_003924.4(PHOX2B):c.639CGG[5] (p.Gly217dup)	PHOX2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
658375	NM_003924.4(PHOX2B):c.716G>A (p.Gly239Asp)	PHOX2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
826705	NM_003924.4(PHOX2B):c.691G>A (p.Gly231Ser)	PHOX2B	Uncertain significance	criteria provided, multiple submitters, no conflicts
179366	NM_004316.4(ASCL1):c.151CAG[13] (p.Gln62_Ala63insGln)	ASCL1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
227016	NM_003924.4(PHOX2B):c.741_758del (p.Ala255_Ala260del)	LOC110011216	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
239595	NM_003924.4(PHOX2B):c.765_779del (p.Ala256_Ala260del)	LOC110011216	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
164943	NM_003924.4(PHOX2B):c.870C>A (p.Pro290=)	PHOX2B	Benign	criteria provided, multiple submitters, no conflicts
227014	NM_003924.4(PHOX2B):c.450C>G (p.Arg150=)	PHOX2B	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
227015	NM_003924.4(PHOX2B):c.552C>T (p.Ser184=)	PHOX2B	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
413923	NM_003924.4(PHOX2B):c.642C>T (p.Gly214=)	PHOX2B	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 5 · 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
PHOX2B	Definitive	Autosomal dominant	central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease	9
ASCL1	Moderate	Autosomal dominant	central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ASCL1	Orphanet:99803	Haddad syndrome
PHOX2B	Orphanet:2151	Hirschsprung disease-ganglioneuroblastoma syndrome
PHOX2B	Orphanet:635	Neuroblastoma
PHOX2B	Orphanet:661	Congenital central hypoventilation syndrome
PHOX2B	Orphanet:99803	Haddad syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ASCL1	HGNC:738	ENSG00000139352	P50553	Achaete-scute homolog 1	gencc,clinvar
PHOX2B	HGNC:9143	ENSG00000109132	Q99453	Paired mesoderm homeobox protein 2B	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ASCL1	Achaete-scute homolog 1	Transcription factor that plays a key role in neuronal differentiation: acts as a pioneer transcription factor, accessing closed chromatin to allow other factors to bind and activate neural pathways.
PHOX2B	Paired mesoderm homeobox protein 2B	Involved in the development of several major noradrenergic neuron populations, including the locus coeruleus.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · 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	2	8.3×	0.015

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ASCL1	Transcription factor	no		bHLH_dom, MASH1/Ascl1a-like, HLH_DNA-bd_sf
PHOX2B	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
CA1 field of hippocampus	1
ganglionic eminence	1
ventricular zone	1
buccal mucosa cell	1
dorsal motor nucleus of vagus nerve	1
muscle layer of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ASCL1	143	broad	marker	ganglionic eminence, ventricular zone, CA1 field of hippocampus
PHOX2B	53	tissue_specific	marker	muscle layer of sigmoid colon, buccal mucosa cell, dorsal motor nucleus of vagus nerve

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ASCL1	2,422
PHOX2B	1,215

Intra-cohort edges

A	B	Sources
ASCL1	PHOX2B	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PHOX2B	Q99453	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ASCL1	P50553	68.22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Nuclear Events (kinase and transcription factor activation)	1	346.1×	0.008	ASCL1
NGF-stimulated transcription	1	285.5×	0.008	ASCL1
Signaling by NTRK1 (TRKA)	1	196.9×	0.008	ASCL1
Signaling by NTRKs	1	181.3×	0.008	ASCL1
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.023	ASCL1
Signal Transduction	1	10.2×	0.098	ASCL1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
noradrenergic neuron development	2	3370.4×	6e-06	ASCL1, PHOX2B
sympathetic ganglion development	2	1872.4×	9e-06	ASCL1, PHOX2B
motor neuron migration	2	1685.2×	9e-06	ASCL1, PHOX2B
sympathetic nervous system development	2	936.2×	2e-05	ASCL1, PHOX2B
negative regulation of neuron differentiation	2	271.8×	2e-04	ASCL1, PHOX2B
neuron development	2	255.3×	2e-04	ASCL1, PHOX2B
positive regulation of neuron differentiation	2	198.3×	3e-04	ASCL1, PHOX2B
noradrenergic neuron fate commitment	1	8426.0×	6e-04	ASCL1
neuroblast fate determination	1	8426.0×	6e-04	ASCL1
medullary reticular formation development	1	8426.0×	6e-04	PHOX2B
parasympathetic nervous system development	1	8426.0×	6e-04	PHOX2B
efferent axon development in a lateral line nerve	1	8426.0×	6e-04	PHOX2B
regulation of timing of subpallium neuron differentiation	1	8426.0×	6e-04	ASCL1
lung neuroendocrine cell differentiation	1	8426.0×	6e-04	ASCL1
carotid body glomus cell differentiation	1	8426.0×	6e-04	ASCL1
retrotrapezoid nucleus neuron differentiation	1	8426.0×	6e-04	PHOX2B
cellular response to magnetism	1	8426.0×	6e-04	ASCL1
regulation of gene expression	2	83.4×	6e-04	ASCL1, PHOX2B
vestibular nucleus development	1	4213.0×	8e-04	ASCL1
musculoskeletal movement, spinal reflex action	1	4213.0×	8e-04	ASCL1
subpallium neuron fate commitment	1	4213.0×	8e-04	ASCL1
adrenal chromaffin cell differentiation	1	4213.0×	8e-04	ASCL1
cellular response to carbon dioxide	1	4213.0×	8e-04	PHOX2B
spinal cord oligodendrocyte cell fate specification	1	2808.7×	9e-04	ASCL1
cell differentiation in hindbrain	1	2808.7×	9e-04	PHOX2B
cerebral cortex GABAergic interneuron differentiation	1	2808.7×	9e-04	ASCL1
hindbrain tangential cell migration	1	2808.7×	9e-04	PHOX2B
autonomic nervous system development	1	2808.7×	9e-04	PHOX2B
olfactory pit development	1	2808.7×	9e-04	ASCL1
ventral spinal cord interneuron fate commitment	1	2808.7×	9e-04	ASCL1

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
ASCL1	0	0
PHOX2B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	ASCL1, PHOX2B

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)
ASCL1	0	—
PHOX2B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 13.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	11
PHASE2/PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01243697	PHASE2/PHASE3	COMPLETED	Assessment of Desogestrel in Ondine Syndrome
NCT01500473	PHASE2	TERMINATED	Therapeutic Effect of Desogestrel on Ventilatory Control in Patients With Congenital Central Hypoventilation Syndrome
NCT03088020	Not specified	RECRUITING	International Congenital Central Hypoventilation Syndrome (CCHS) Registry and CCHS SHARE
NCT03568669	Not specified	RECRUITING	Neurocognition in Congenital Central Hypoventilation Syndrome (CCHS)
NCT06337149	Not specified	RECRUITING	Relationship Between Breathing and Attention in Children With Ondine Syndrome
NCT06554275	Not specified	RECRUITING	CCHS Secure Health-hub Advancing Research Efforts (CCHS SHARE)
NCT06997146	Not specified	NOT_YET_RECRUITING	Identifying Biomarkers & Dysregulated Biological Pathways in Blood and Urine of Congenital Central Hypoventilation Syndrome (CCHS) Patients
NCT07081464	Not specified	NOT_YET_RECRUITING	Locus Coeruleus and CCHS (Congenital Central Hypoventilation Syndrome)
NCT01225679	Not specified	COMPLETED	Late-onset Congenital Central Hypoventilation Syndrome and the Mutation of Phox2B Gene
NCT02315339	Not specified	TERMINATED	European Home Mechanical Ventilation Registry
NCT03053011	Not specified	COMPLETED	Evaluation of the Awakening Capability by a Vibrating Bracelet (BRASSARD)
NCT03095729	Not specified	COMPLETED	Cognitive Consequences of an Activation of the Cortical Drive to Breath (VENTIPSY)
NCT04447196	Not specified	UNKNOWN	Prevalence of Rest Dyspnea and Impact of Non Invasive Ventilation on Breathing Sensations in CCHS Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DESOGESTREL	4	2
MEDRONATE DISODIUM	-1	1