Congenital laryngomalacia

Summary

Congenital laryngomalacia (MONDO:0007878) is a disease with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 3
• Phenotypes (HPO): 4

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-5 / 10 000	40	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

4 HPO clinical features (Orphanet curated; top 4 by frequency):

HPO ID	Term	Frequency
HP:0001601	Laryngomalacia	Very frequent (80-99%)
HP:0001608	Abnormality of the voice	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0100335	Non-midline cleft of the upper lip	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital laryngomalacia
Mondo ID	MONDO:0007878
MeSH	D055092
OMIM	150280
Orphanet	2373
DOID	DOID:0080833
ICD-10-CM	Q31.5
ICD-11	64182721
NCIT	C98971
SNOMED CT	253737007
UMLS	C0264303
MedGen	120500
GARD	0006865
MedDRA	10060786
Is cancer (heuristic)	no

Also known as: congenital laryngeal stridor · laryngomalacia congenital

Data availability: 3 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › upper respiratory tract disorder › laryngeal disorder › congenital laryngomalacia

Related subtypes (19): spasmodic dystonia, laryngostenosis, laryngitis, laryngeal abductor paralysis, larynx atresia, congenital laryngeal web, H syndrome, primary laryngeal lymphangioma, congenital laryngeal palsy, congenital subglottic stenosis, congenital laryngeal cyst, laryngocele, laryngeal diphtheria, laryngeal granuloma, laryngeal neoplasm, polyp of vocal cord, voice disorders, acquired laryngomalacia, idiopathic subglottic stenosis

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

3 retrieved; paginated sample, class counts are floors:

3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
813009	NM_001110792.2(MECP2):c.148_152del (p.Glu50fs)	MECP2	Likely pathogenic	no assertion criteria provided
627622	NM_001365902.3(NFIX):c.440G>A (p.Gly147Glu)	NFIX	Likely pathogenic	criteria provided, single submitter
2570654	NM_020922.5(WNK3):c.4000dup (p.Arg1334fs)	WNK3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MECP2	Orphanet:1762	Proximal Xq28 duplication syndrome
MECP2	Orphanet:209370	MECP2-related severe neonatal encephalopathy
MECP2	Orphanet:3077	X-linked intellectual disability-psychosis-macroorchidism syndrome
MECP2	Orphanet:3095	Atypical Rett syndrome
MECP2	Orphanet:536	Systemic lupus erythematosus
MECP2	Orphanet:777	X-linked non-syndromic intellectual disability
MECP2	Orphanet:778	Rett syndrome
NFIX	Orphanet:420179	Malan overgrowth syndrome
NFIX	Orphanet:447980	19p13.3 microduplication syndrome
NFIX	Orphanet:561	Marshall-Smith syndrome

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
WNK3	HGNC:14543	ENSG00000196632	Q9BYP7	Serine/threonine-protein kinase WNK3	clinvar
MECP2	HGNC:6990	ENSG00000169057	P51608	Methyl-CpG-binding protein 2	clinvar
NFIX	HGNC:7788	ENSG00000008441	Q14938	Nuclear factor 1 X-type	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WNK3	Serine/threonine-protein kinase WNK3	Serine/threonine-protein kinase component of the WNK3-SPAK/OSR1 kinase cascade, which plays an important role in the regulation of electrolyte homeostasis and regulatory volume increase in response to hyperosmotic stress.
MECP2	Methyl-CpG-binding protein 2	Chromosomal protein that binds to methylated DNA.
NFIX	Nuclear factor 1 X-type	Recognizes and binds the palindromic sequence 5’-TTGGCNNNNNGCCAA-3’ present in viral and cellular promoters and in the origin of replication of adenovirus type 2.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WNK3	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
MECP2	Other/Unknown	no		Methyl_CpG_DNA-bd, DNA-bd_dom_sf, Me_CpG-bd_MeCP2
NFIX	Other/Unknown	no		CTF/NFI, MAD_homology1_Dwarfin-type, CTF/NFI_DNA-bd_N

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)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
cauda epididymis	1
corpus epididymis	1
Brodmann (1909) area 10	1
paraflocculus	1
sural nerve	1
cortical plate	1
ganglionic eminence	1
nipple	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WNK3	181	broad	marker	corpus epididymis, buccal mucosa cell, cauda epididymis
MECP2	277	ubiquitous	marker	paraflocculus, Brodmann (1909) area 10, sural nerve
NFIX	267	ubiquitous	marker	cortical plate, nipple, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MECP2	5,688
NFIX	2,162
WNK3	1,097

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WNK3	Q9BYP7	9
MECP2	P51608	9
NFIX	Q14938	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Loss of MECP2 binding ability to 5hmC-DNA	1	3806.7×	0.004	MECP2
MECP2 regulates transcription of genes involved in GABA signaling	1	1268.9×	0.004	MECP2
Loss of phosphorylation of MECP2 at T308	1	951.7×	0.004	MECP2
Loss of MECP2 binding ability to 5mC-DNA	1	951.7×	0.004	MECP2
MECP2 regulates transcription factors	1	761.3×	0.004	MECP2
Loss of MECP2 binding ability to the NCoR/SMRT complex	1	543.8×	0.004	MECP2
MECP2 regulates transcription of neuronal ligands	1	475.8×	0.004	MECP2
MECP2 regulates neuronal receptors and channels	1	200.3×	0.009	MECP2
RNA Polymerase III Transcription Termination	1	165.5×	0.009	NFIX
Regulation of MECP2 expression and activity	1	122.8×	0.011	MECP2
Nuclear events stimulated by ALK signaling in cancer	1	108.8×	0.011	MECP2
Transcriptional Regulation by MECP2	1	105.7×	0.011	MECP2
RNA Polymerase III Abortive And Retractive Initiation	1	92.8×	0.012	NFIX
Stimuli-sensing channels	1	45.3×	0.022	WNK3

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
catecholamine secretion	1	5617.3×	0.005	MECP2
trans-synaptic signaling by BDNF	1	5617.3×	0.005	MECP2
cardiolipin metabolic process	1	2808.7×	0.005	MECP2
positive regulation of sodium ion transmembrane transporter activity	1	2808.7×	0.005	WNK3
nervous system process involved in regulation of systemic arterial blood pressure	1	1872.4×	0.005	MECP2
biogenic amine metabolic process	1	1872.4×	0.005	MECP2
response to other organism	1	1872.4×	0.005	MECP2
proprioception	1	1404.3×	0.006	MECP2
negative regulation of pancreatic juice secretion	1	1123.5×	0.007	WNK3
glucocorticoid metabolic process	1	936.2×	0.007	MECP2
inositol metabolic process	1	802.5×	0.007	MECP2
monoatomic ion homeostasis	1	802.5×	0.007	WNK3
positive regulation of microtubule nucleation	1	702.2×	0.007	MECP2
regulation of calcium ion import	1	702.2×	0.007	WNK3
regulation of monoatomic cation transmembrane transport	1	702.2×	0.007	WNK3
positive regulation of peptidyl-threonine phosphorylation	1	624.1×	0.007	WNK3
negative regulation of smooth muscle cell differentiation	1	624.1×	0.007	MECP2
osmosensory signaling pathway	1	510.7×	0.008	WNK3
regulation of respiratory gaseous exchange by nervous system process	1	432.1×	0.008	MECP2
L-glutamine metabolic process	1	432.1×	0.008	MECP2
cellular hyperosmotic response	1	401.2×	0.008	WNK3
startle response	1	374.5×	0.008	MECP2
membraneless organelle assembly	1	374.5×	0.008	WNK3
negative regulation of gene expression via chromosomal CpG island methylation	1	351.1×	0.008	MECP2
renal sodium ion absorption	1	330.4×	0.008	WNK3
genomic imprinting	1	330.4×	0.008	MECP2
glial cell proliferation	1	295.6×	0.008	MECP2
positive regulation of sodium ion transport	1	280.9×	0.008	WNK3
ventricular system development	1	280.9×	0.008	MECP2
neuron maturation	1	267.5×	0.008	MECP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
WNK3	1	2
MECP2	0	0
NFIX	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADAVOSERTIB	2	WNK3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
WNK3	142	Binding:142
MECP2	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
WNK3	142

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

1 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)
ADAVOSERTIB	2	WNK3

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	1	WNK3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MECP2, NFIX

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)
MECP2	1	—
NFIX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.