Megacystis-microcolon-intestinal hypoperistalsis syndrome 1

Summary

Megacystis-microcolon-intestinal hypoperistalsis syndrome 1 (MONDO:0100354) is a disease caused by MYLK (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MYLK (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 158
• Phenotypes (HPO): 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		230	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000021	Megacystis	Very frequent (80-99%)
HP:0002017	Nausea and vomiting	Very frequent (80-99%)
HP:0003270	Abdominal distention	Very frequent (80-99%)
HP:0004388	Microcolon	Very frequent (80-99%)
HP:0100771	Hypoperistalsis	Very frequent (80-99%)
HP:0000003	Multicystic kidney dysplasia	Frequent (30-79%)
HP:0000072	Hydroureter	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0002566	Intestinal malrotation	Frequent (30-79%)
HP:0011024	Abnormality of the gastrointestinal tract	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0001522	Death in infancy	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0001539	Omphalocele	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)
HP:0100544	Neoplasm of the heart	Occasional (5-29%)
HP:0100806	Sepsis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	megacystis-microcolon-intestinal hypoperistalsis syndrome 1
Mondo ID	MONDO:0100354
MeSH	C536138
OMIM	249210
Orphanet	2241
DOID	DOID:0060610
NCIT	C98982
SNOMED CT	253781004
UMLS	C5542316
MedGen	1778116
GARD	0015195
Is cancer (heuristic)	no

Also known as: Berdon syndrome · megacystis microcolon intestinal hypoperistalsis syndrome · megacystis, microcolon, hypoperistalsis syndrome · megacystis, microcolon, intestinal hypoperistalsis syndrome · megacystis-microcolon-intestinal hypoperistalsis syndrome · megacystis-microcolon-intestinal hypoperistalsis syndrome, MMIH · megacystis-microcolon-intestinal hypoperistalsis-hydronephrosis syndrome · MMIH syndrome · MMIHS

Data availability: 158 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › megacystis-microcolon-intestinal hypoperistalsis syndrome › megacystis-microcolon-intestinal hypoperistalsis syndrome 1

Related subtypes (4): megacystis-microcolon-intestinal hypoperistalsis syndrome 2, megacystis-microcolon-intestinal hypoperistalsis syndrome 3, megacystis-microcolon-intestinal hypoperistalsis syndrome 4, megacystis-microcolon-intestinal hypoperistalsis syndrome 5

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

158 retrieved; paginated sample, class counts are floors:

102 uncertain significance, 27 conflicting classifications of pathogenicity, 16 likely benign, 9 benign/likely benign, 3 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
427851	NM_053025.4(MYLK):c.3985+5G>T	MYLK	Pathogenic	criteria provided, single submitter
1318562	NM_053025.4(MYLK):c.376A>G (p.Ser126Gly)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
155819	NM_053025.4(MYLK):c.2596G>A (p.Gly866Ser)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225287	NM_053025.4(MYLK):c.4292C>T (p.Pro1431Leu)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
264267	NM_053025.4(MYLK):c.1075C>A (p.Pro359Thr)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
264351	NM_053025.4(MYLK):c.2474C>T (p.Pro825Leu)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342880	NM_053025.4(MYLK):c.3898G>A (p.Ala1300Thr)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342881	NM_053025.4(MYLK):c.3610C>T (p.Arg1204Trp)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342884	NM_053025.4(MYLK):c.2936C>T (p.Pro979Leu)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
409711	NM_053025.4(MYLK):c.3121G>A (p.Ala1041Thr)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
471702	NM_053025.4(MYLK):c.1474G>A (p.Ala492Thr)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
493371	NM_053025.4(MYLK):c.344G>A (p.Arg115His)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
504425	NM_053025.4(MYLK):c.2462+5G>A	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
519971	NM_053025.4(MYLK):c.3076G>A (p.Val1026Met)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
519975	NM_053025.4(MYLK):c.2149G>A (p.Asp717Asn)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
520021	NM_053025.4(MYLK):c.1375G>A (p.Gly459Ser)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
539076	NM_053025.4(MYLK):c.1254C>G (p.Ser418Arg)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
539078	NM_053025.4(MYLK):c.1612C>T (p.Arg538Trp)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
539092	NM_053025.4(MYLK):c.3901C>T (p.Arg1301Cys)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
571663	NM_053025.4(MYLK):c.3832-8G>C	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625982	NM_053025.4(MYLK):c.2627G>A (p.Arg876His)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
644920	NM_053025.4(MYLK):c.848C>T (p.Ser283Leu)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
652142	NM_053025.4(MYLK):c.3577A>C (p.Ser1193Arg)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
661651	NM_053025.4(MYLK):c.2403C>T (p.Gly801=)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
810714	NM_053025.4(MYLK):c.535C>T (p.Arg179Ter)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
915657	NM_053025.4(MYLK):c.250G>A (p.Gly84Ser)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
952930	NM_053025.4(MYLK):c.4406G>A (p.Arg1469Lys)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222741	NM_053025.4(MYLK):c.5447G>A (p.Arg1816His)	MYLK-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1320709	NM_053025.4(MYLK):c.5092A>C (p.Asn1698His)	LOC126806791	Uncertain significance	criteria provided, multiple submitters, no conflicts
1368072	NM_053025.4(MYLK):c.5015A>G (p.Asn1672Ser)	LOC126806791	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
MYLK	Strong	Autosomal recessive	megacystis-microcolon-intestinal hypoperistalsis syndrome 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYLK	Orphanet:2241	Megacystis-microcolon-intestinal hypoperistalsis syndrome
MYLK	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYLK	HGNC:7590	ENSG00000065534	Q15746	Myosin light chain kinase, smooth muscle	gencc,clinvar
MYLK-AS1	HGNC:42440	ENSG00000239523		MYLK antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYLK	Myosin light chain kinase, smooth muscle	Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYLK	Kinase	yes	2.7.11.18	Prot_kinase_dom, Ig_sub2, Ig_sub
MYLK-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
cauda epididymis	1
saphenous vein	1
seminal vesicle	1
esophagogastric junction muscularis propria	1
lower esophagus	1
lower esophagus muscularis layer	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYLK	289	ubiquitous	marker	cauda epididymis, saphenous vein, seminal vesicle
MYLK-AS1	168	ubiquitous	yes	esophagogastric junction muscularis propria, lower esophagus muscularis layer, lower esophagus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYLK	2,763
MYLK-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYLK	Q15746	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
RHO GTPases activate PAKs	1	543.8×	0.013	MYLK
Smooth Muscle Contraction	1	265.6×	0.013	MYLK
Muscle contraction	1	77.2×	0.026	MYLK
RHO GTPase Effectors	1	68.0×	0.026	MYLK
Signaling by Rho GTPases	1	34.2×	0.035	MYLK
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.035	MYLK
Signal Transduction	1	10.2×	0.098	MYLK

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tonic smooth muscle contraction	1	16852.0×	6e-04	MYLK
aorta smooth muscle tissue morphogenesis	1	4213.0×	0.001	MYLK
bleb assembly	1	1532.0×	0.002	MYLK
cellular hypotonic response	1	1404.3×	0.002	MYLK
regulation of synaptic vesicle endocytosis	1	887.0×	0.002	MYLK
smooth muscle contraction	1	802.5×	0.002	MYLK
positive regulation of calcium ion transport	1	581.1×	0.002	MYLK
positive regulation of wound healing	1	526.6×	0.002	MYLK
protein phosphorylation	1	68.0×	0.016	MYLK
positive regulation of cell migration	1	61.7×	0.016	MYLK

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MYLK	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYLK	28	4
MYLK-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	MYLK
AFATINIB	4	MYLK
FEDRATINIB	4	MYLK
RUXOLITINIB	4	MYLK
NIFEDIPINE	4	MYLK
BOSUTINIB	4	MYLK
GILTERITINIB	4	MYLK
TOVORAFENIB	4	MYLK
NINTEDANIB	4	MYLK
SUNITINIB	4	MYLK
DASATINIB	4	MYLK
QUIZARTINIB	4	MYLK
MIDOSTAURIN	4	MYLK
FASUDIL	3	MYLK
DOVITINIB	3	MYLK
LESTAURTINIB	3	MYLK
RUBOXISTAURIN	3	MYLK
VX-702	2	MYLK
SU-014813	2	MYLK
REBASTINIB	2	MYLK
TANZISERTIB	2	MYLK
CEP-32496	2	MYLK
BAFETINIB	2	MYLK
PEXMETINIB	2	MYLK
R-406	2	MYLK
BI-2536	2	MYLK
KW-2449	1	MYLK
IMD-0354	1	MYLK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MYLK	303	Binding:303

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MYLK	2.7.11.18	myosin-light-chain kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MYLK	303

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

28 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)
PONATINIB	4	MYLK
AFATINIB	4	MYLK
FEDRATINIB	4	MYLK
RUXOLITINIB	4	MYLK
NIFEDIPINE	4	MYLK
BOSUTINIB	4	MYLK
GILTERITINIB	4	MYLK
TOVORAFENIB	4	MYLK
NINTEDANIB	4	MYLK
SUNITINIB	4	MYLK
DASATINIB	4	MYLK
QUIZARTINIB	4	MYLK
MIDOSTAURIN	4	MYLK
FASUDIL	3	MYLK
DOVITINIB	3	MYLK
LESTAURTINIB	3	MYLK
RUBOXISTAURIN	3	MYLK
VX-702	2	MYLK
SU-014813	2	MYLK
REBASTINIB	2	MYLK
TANZISERTIB	2	MYLK
CEP-32496	2	MYLK
BAFETINIB	2	MYLK
PEXMETINIB	2	MYLK
R-406	2	MYLK
BI-2536	2	MYLK
KW-2449	1	MYLK
IMD-0354	1	MYLK

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MYLK
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	1	MYLK-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MYLK-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.