Hypertrophic pyloric stenosis

Summary

Hypertrophic pyloric stenosis (MONDO:0001560) is a disease with 4 cohort genes (22 GWAS associations across 3 studies) and 5 clinical trials.

At a glance

• Cohort genes: 4
• GWAS associations: 22
• Clinical trials: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertrophic pyloric stenosis
Mondo ID	MONDO:0001560
EFO	EFO:0004707
MeSH	D046248
DOID	DOID:12638
ICD-10-CM	Q40.0
NCIT	C98952
SNOMED CT	48644003
Is cancer (heuristic)	no

Also known as: congenital constriction of the pylorus · congenital hypertrophic pyloric stenosis · congenital Hypertrophy of the pylorus · congenital pyloric stenosis · congenital stricture of the pylorus · IHPS · infantile constriction of the pylorus · infantile hypertrophic pyloric stenosis · infantile Hypertrophy of the pylorus · infantile pyloric stenosis · infantile stricture of the pylorus · pyloric stenosis, infantile

Data availability: 22 GWAS associations (3 studies).

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › stomach disorder › pyloric stenosis › hypertrophic pyloric stenosis

Subtypes (2): acquired hypertrophic pyloric stenosis, inherited hypertrophic pyloric stenosis

Genetics & variants

GWAS landscape

22 GWAS associations across 3 studies. Top hits map to 7 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs6556059	1e-31	BNIP1 - RPL7AP33	T	1.48
rs11712066	3e-27	LINC02917	A	1.56
rs29784	8e-18	BNIP1 - RPL7AP33	T	1.36
rs573872	2e-15	LINC02006	G	1.32
rs6736913	3e-15	EML4	A	2.32
rs1933683	9e-11	MIR4291 - BARX1	G	1.34
rs12721025	2e-10	APOC3 - APOA1	A	1.59
rs7644486	5e-08	SLMAP	C	1.19
rs11216185	1e-07	SIK3	G	1.57
rs12870105	2e-07	LINC00355 - LGMNP1	G	1.37
rs1208285	6e-07	TARID, LINC01312	C	1.25

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST006705	Fadista J	2018	1,395	4,438	Genome-wide meta-analysis identifies BARX1 and EML4-MTA3 as new loci associated with infantile hypertrophic pyloric stenosis.
GCST002145	Feenstra B	2013	1,001	2,371	Plasma lipids, genetic variants near APOA1, and the risk of infantile hypertrophic pyloric stenosis.
GCST001399	Feenstra B	2012	1,001	2,401	Common variants near MBNL1 and NKX2-5 are associated with infantile hypertrophic pyloric stenosis.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	0
Tier 3: regulatory	1
Tier 4: intronic/intergenic	9

MAF distribution

Bucket	Variants
common (>=0.05)	10
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	5
intron_variant	3
stop_gained	1
regulatory_region_variant	1
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs6556059	5	173218763	T>A,C	0.351	intergenic_variant	BNIP1 - RPL7AP33	1e-31	Tier 4: intronic/intergenic
rs11712066	3	152112520	A>C,G,T	0.24	intergenic_variant	LINC02917	3e-27	Tier 4: intronic/intergenic
rs29784	5	173168305	C>A,G,T	0.45	intergenic_variant	BNIP1 - RPL7AP33	8e-18	Tier 4: intronic/intergenic
rs573872	3	153754374	T>G	0.217	intron_variant	LINC02006	2e-15	Tier 4: intronic/intergenic
rs6736913	2	42282878	A>C,G,T	0.017	stop_gained	EML4	3e-15	Tier 1: coding
rs1933683	9	93950489	C>G	0.104	regulatory_region_variant	MIR4291 - BARX1	9e-11	Tier 3: regulatory
rs12721025	11	116835331	G>A,C	0.057	intergenic_variant	APOC3 - APOA1	2e-10	Tier 4: intronic/intergenic
rs7644486	3	57884236	T>A,C	0.277	intron_variant	SLMAP	5e-08	Tier 4: intronic/intergenic
rs11216185	11	116912258	T>G	0.05	intron_variant	SIK3	1e-07	Tier 4: intronic/intergenic
rs12870105	13	64542179	A>G	0.125	intergenic_variant	LINC00355 - LGMNP1	2e-07	Tier 4: intronic/intergenic
rs1208285	6	133837662	T>A,C,G	0.39	non_coding_transcript_exon_variant	TARID, LINC01312	6e-07	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NKX2-5	Orphanet:101351	Familial isolated congenital asplenia
NKX2-5	Orphanet:1479	Atrial septal defect-atrioventricular conduction defects syndrome
NKX2-5	Orphanet:1627	Deletion 5q35 syndrome
NKX2-5	Orphanet:2248	Hypoplastic left heart syndrome
NKX2-5	Orphanet:3303	Tetralogy of Fallot
NKX2-5	Orphanet:334	Hereditary atrial fibrillation
NKX2-5	Orphanet:402075	Familial bicuspid aortic valve
NKX2-5	Orphanet:871	Hereditary progressive cardiac conduction defect
NKX2-5	Orphanet:95712	Thyroid ectopia
NKX2-5	Orphanet:95713	Athyreosis
NKX2-5	Orphanet:99103	Atrial septal defect, ostium secundum type
APOA1	Orphanet:425	Apolipoprotein A-I deficiency
APOA1	Orphanet:93560	AApoAI amyloidosis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BNIP1	HGNC:1082	ENSG00000113734	Q12981	Vesicle transport protein SEC20	gwas
NKX2-5	HGNC:2488	ENSG00000183072	P52952	Homeobox protein Nkx-2.5	gwas
APOA1	HGNC:600	ENSG00000118137	P02647	Apolipoprotein A-I	gwas
MBNL1	HGNC:6923	ENSG00000152601	Q9NR56	Muscleblind-like protein 1	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BNIP1	Vesicle transport protein SEC20	As part of a SNARE complex may be involved in endoplasmic reticulum membranes fusion and be required for the maintenance of endoplasmic reticulum organization.
NKX2-5	Homeobox protein Nkx-2.5	Transcription factor required for the development of the heart and the spleen.
APOA1	Apolipoprotein A-I	Participates in the reverse transport of cholesterol from tissues to the liver for excretion by promoting cholesterol efflux from tissues and by acting as a cofactor for the lecithin cholesterol acyltransferase (LCAT).
MBNL1	Muscleblind-like protein 1	Mediates pre-mRNA alternative splicing regulation.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 2 · 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	4.1×	0.149
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BNIP1	Other/Unknown	no		Sec20, Sec20_C
NKX2-5	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
APOA1	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
MBNL1	Transcription factor	no		Znf_CCCH, Znf-CCCH_Muscleblind-like

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
oocyte	1
secondary oocyte	1
apex of heart	1
cardiac atrium	1
right atrium auricular region	1
jejunal mucosa	1
liver	1
right lobe of liver	1
blood vessel layer	1
calcaneal tendon	1
superficial temporal artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BNIP1	226	ubiquitous	marker	secondary oocyte, oocyte, diaphragm
NKX2-5	98	broad	yes	apex of heart, right atrium auricular region, cardiac atrium
APOA1	170	broad	marker	jejunal mucosa, right lobe of liver, liver
MBNL1	303	ubiquitous	marker	calcaneal tendon, blood vessel layer, superficial temporal artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOA1	3,608
MBNL1	2,642
NKX2-5	2,355
BNIP1	1,672

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APOA1	P02647	31
MBNL1	Q9NR56	6
NKX2-5	P52952	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BNIP1	Q12981	80.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 52. Enrichment computed across 4 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
Defective ABCA1 causes TGD	1	1903.3×	0.019	APOA1
HDL clearance	1	761.3×	0.019	APOA1
HDL assembly	1	475.8×	0.019	APOA1
Chylomicron assembly	1	380.7×	0.019	APOA1
Chylomicron remodeling	1	380.7×	0.019	APOA1
HDL remodeling	1	380.7×	0.019	APOA1
Scavenging by Class B Receptors	1	346.1×	0.019	APOA1
Scavenging of heme from plasma	1	292.8×	0.019	APOA1
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	253.8×	0.019	NKX2-5
Plasma lipoprotein assembly	1	237.9×	0.019	APOA1
Physiological factors	1	223.9×	0.019	NKX2-5
ABC transporters in lipid homeostasis	1	200.3×	0.019	APOA1
Scavenging by Class A Receptors	1	200.3×	0.019	APOA1
Vesicle-mediated transport	2	23.2×	0.019	BNIP1, APOA1
Binding and Uptake of Ligands by Scavenger Receptors	1	181.3×	0.019	APOA1
Plasma lipoprotein remodeling	1	158.6×	0.019	APOA1
Plasma lipoprotein clearance	1	158.6×	0.019	APOA1
ABC transporter disorders	1	146.4×	0.019	APOA1
Cardiogenesis	1	141.0×	0.019	NKX2-5
Metabolism of fat-soluble vitamins	1	126.9×	0.020	APOA1
Dengue virus activates/modulates innate and adaptive immune responses	1	112.0×	0.022	APOA1
Visual phototransduction	1	86.5×	0.027	APOA1
Retinoid metabolism and transport	1	82.8×	0.027	APOA1
Plasma lipoprotein assembly, remodeling, and clearance	1	76.1×	0.028	APOA1
Heme signaling	1	71.8×	0.028	APOA1
Maturation of DENV proteins	1	70.5×	0.028	APOA1
Response to elevated platelet cytosolic Ca2+	1	54.4×	0.035	APOA1
Regulation of lipid metabolism by PPARalpha	1	47.0×	0.038	APOA1
Disorders of transmembrane transporters	1	46.4×	0.038	APOA1
Golgi-to-ER retrograde transport	1	44.3×	0.039	BNIP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Purkinje myocyte differentiation	1	4213.0×	0.006	NKX2-5
septum secundum development	1	4213.0×	0.006	NKX2-5
apoptotic process in response to mitochondrial fragmentation	1	4213.0×	0.006	BNIP1
right ventricular cardiac muscle tissue morphogenesis	1	2106.5×	0.006	NKX2-5
atrioventricular node cell fate commitment	1	2106.5×	0.006	NKX2-5
cardiac ventricle formation	1	1404.3×	0.006	NKX2-5
apoptotic process involved in heart morphogenesis	1	1404.3×	0.006	NKX2-5
proepicardium development	1	1404.3×	0.006	NKX2-5
pulmonary myocardium development	1	1404.3×	0.006	NKX2-5
protein oxidation	1	1404.3×	0.006	APOA1
peptidyl-methionine modification	1	1404.3×	0.006	APOA1
ventricular cardiac myofibril assembly	1	1404.3×	0.006	NKX2-5
atrial cardiac muscle cell development	1	1404.3×	0.006	NKX2-5
bundle of His development	1	1053.2×	0.006	NKX2-5
atrial cardiac muscle tissue development	1	1053.2×	0.006	NKX2-5
regulation of intestinal cholesterol absorption	1	1053.2×	0.006	APOA1
positive regulation of cardioblast differentiation	1	1053.2×	0.006	NKX2-5
atrioventricular node cell development	1	1053.2×	0.006	NKX2-5
positive regulation of phospholipid efflux	1	1053.2×	0.006	APOA1
endoplasmic reticulum membrane fusion	1	842.6×	0.006	BNIP1
acylglycerol homeostasis	1	842.6×	0.006	APOA1
regulation of cardiac muscle cell proliferation	1	842.6×	0.006	NKX2-5
negative regulation of cell adhesion molecule production	1	842.6×	0.006	APOA1
cellular response to lipoprotein particle stimulus	1	842.6×	0.006	APOA1
negative regulation of cytokine production involved in immune response	1	702.2×	0.006	APOA1
atrioventricular node development	1	702.2×	0.006	NKX2-5
glucocorticoid metabolic process	1	702.2×	0.006	APOA1
negative regulation of very-low-density lipoprotein particle remodeling	1	702.2×	0.006	APOA1
lipoprotein biosynthetic process	1	702.2×	0.006	APOA1
vitamin transport	1	702.2×	0.006	APOA1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BNIP1	0	0
NKX2-5	0	0
APOA1	0	0
MBNL1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MBNL1	8	Binding:8
APOA1	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	BNIP1, NKX2-5, APOA1, MBNL1

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
BNIP1	0	—
NKX2-5	0	—
APOA1	2	—
MBNL1	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00195949	PHASE3	COMPLETED	Laparoscopic Versus Open Pyloromyotomy for Infants With Idiopathic Hypertrophic Pyloric Stenosis
NCT01159509	Not specified	UNKNOWN	The Effect of Hypertrophic Pyloric Stenosis (HPS) on Sodium Intake in Childhood
NCT03095144	Not specified	UNKNOWN	Spinal Anesthesia and General Anesthesia for Pyloromyotomy - Surgical Outcomes a Comparison Retrospective Study
NCT04148040	Not specified	UNKNOWN	Per-oral Pyloromyotomy for Treating Infantile Hypertrophic Pyloric Stenosis
NCT05068622	Not specified	UNKNOWN	Gastric Tube in Pyloric Stenosis