Multiple intestinal atresia

Summary

Multiple intestinal atresia (MONDO:0009465) is a disease caused by TTC7A (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: TTC7A (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 991
• Phenotypes (HPO): 3

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	4.05	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

3 HPO clinical features (Orphanet curated; top 3 by frequency):

HPO ID	Term	Frequency
HP:0100867	Duodenal stenosis	Very frequent (80-99%)
HP:0002589	Gastrointestinal atresia	Very frequent (80-99%)
HP:0001561	Polyhydramnios	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple intestinal atresia
Mondo ID	MONDO:0009465
MeSH	C562441
Orphanet	2300
SNOMED CT	95472001
UMLS	C0220744
MedGen	65090
GARD	0003013
MedDRA	10028210
Is cancer (heuristic)	no

Also known as: intestinal atresia multiple · isolated multiple intestinal atresia · multiple intestinal atresia

Data availability: 991 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › intestinal disorder › intestinal atresia › multiple intestinal atresia

Related subtypes (1): duodenal atresia

Subtypes (1): gastrointestinal defect and immunodeficiency syndrome

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

600 retrieved; paginated sample, class counts are floors:

308 likely benign, 234 uncertain significance, 21 pathogenic, 14 benign, 8 pathogenic/likely pathogenic, 7 conflicting classifications of pathogenicity, 7 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069120	NM_020458.4(TTC7A):c.565del (p.Arg188_Leu189insTer)	LOC126806211	Pathogenic	criteria provided, single submitter
1073084	NC_000002.11:g.(?47168661)(47238594_?)del	MCFD2	Pathogenic	criteria provided, single submitter
2426554	NC_000002.11:g.(?47132602)(47206066_?)del	MCFD2	Pathogenic	criteria provided, single submitter
2819608	NM_020458.4(TTC7A):c.176del (p.Pro59fs)	MCFD2	Pathogenic	criteria provided, single submitter
1068689	NM_020458.4(TTC7A):c.1621C>T (p.Gln541Ter)	TTC7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071145	NM_020458.4(TTC7A):c.192del (p.Phe64fs)	TTC7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073085	NC_000002.11:g.(?47177482)(47301062_?)del	TTC7A	Pathogenic	criteria provided, single submitter
1320635	NM_020458.4(TTC7A):c.2018-1G>C	TTC7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1409221	NM_020458.4(TTC7A):c.2146C>T (p.Gln716Ter)	TTC7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1433649	NM_020458.4(TTC7A):c.1355dup (p.Met453fs)	TTC7A	Pathogenic	criteria provided, single submitter
1437718	NM_020458.4(TTC7A):c.1322_1323del (p.Val441fs)	TTC7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451842	NM_020458.4(TTC7A):c.1783G>T (p.Glu595Ter)	TTC7A	Pathogenic	criteria provided, single submitter
1456875	NM_020458.4(TTC7A):c.1213C>T (p.Arg405Ter)	TTC7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460133	NM_020458.4(TTC7A):c.1784_1787del (p.Glu595fs)	TTC7A	Pathogenic	criteria provided, single submitter
1704590	NM_020458.4(TTC7A):c.1630del (p.Leu544fs)	TTC7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190390	NM_020458.4(TTC7A):c.315_318del (p.Asn104_Tyr105insTer)	TTC7A	Pathogenic	criteria provided, multiple submitters, no conflicts
190391	NM_020458.4(TTC7A):c.844-1G>T	TTC7A	Pathogenic	criteria provided, single submitter
190392	NM_020458.4(TTC7A):c.1204-2A>G	TTC7A	Pathogenic	criteria provided, single submitter
190393	NM_020458.4(TTC7A):c.1576C>T (p.Gln526Ter)	TTC7A	Pathogenic	criteria provided, multiple submitters, no conflicts
190395	NM_020458.4(TTC7A):c.211G>A (p.Glu71Lys)	TTC7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2001826	NM_020458.4(TTC7A):c.226C>T (p.Gln76Ter)	TTC7A	Pathogenic	criteria provided, single submitter
2022174	NM_020458.4(TTC7A):c.2109del (p.Met704fs)	TTC7A	Pathogenic	criteria provided, single submitter
2033508	NM_020458.4(TTC7A):c.2264del (p.Ala755fs)	TTC7A	Pathogenic	criteria provided, single submitter
2034849	NM_020458.4(TTC7A):c.2272A>T (p.Lys758Ter)	TTC7A	Pathogenic	criteria provided, single submitter
2049714	NM_020458.4(TTC7A):c.1281_1282insTT (p.Gly428fs)	TTC7A	Pathogenic	criteria provided, single submitter
2049998	NM_020458.4(TTC7A):c.1528C>T (p.Gln510Ter)	TTC7A	Pathogenic	criteria provided, single submitter
2426555	NC_000002.11:g.(?47202092)(47206066_?)del	TTC7A	Pathogenic	criteria provided, single submitter
2707939	NM_020458.4(TTC7A):c.1450G>T (p.Glu484Ter)	TTC7A	Pathogenic	criteria provided, single submitter
2814056	NM_020458.4(TTC7A):c.499G>T (p.Glu167Ter)	TTC7A	Pathogenic	criteria provided, single submitter
1066268	NM_020458.4(TTC7A):c.1919+1G>C	TTC7A	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
TTC7A	Strong	Autosomal recessive	multiple intestinal atresia	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TTC7A	Orphanet:436252	Combined immunodeficiency-multiple intestinal atresia
CALM2	Orphanet:101016	Romano-Ward syndrome
CALM2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
MCFD2	Orphanet:35909	Combined deficiency of factor V and factor VIII

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
TTC7A	HGNC:19750	ENSG00000068724	Q9ULT0	Tetratricopeptide repeat protein 7A	gencc,clinvar
CALM2	HGNC:1445	ENSG00000143933	P0DP24	Calmodulin-2	clinvar
MCFD2	HGNC:18451	ENSG00000180398	Q8NI22	Multiple coagulation factor deficiency protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TTC7A	Tetratricopeptide repeat protein 7A	Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane.
CALM2	Calmodulin-2	Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding.
MCFD2	Multiple coagulation factor deficiency protein 2	The MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TTC7A	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC7_N
CALM2	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
MCFD2	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS

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
left testis	1
right testis	1
sperm	1
Brodmann (1909) area 23	1
middle temporal gyrus	1
orbitofrontal cortex	1
adrenal tissue	1
parotid gland	1
seminal vesicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TTC7A	236	ubiquitous	marker	sperm, right testis, left testis
CALM2	310	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, orbitofrontal cortex
MCFD2	295	ubiquitous	marker	parotid gland, seminal vesicle, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCFD2	881
TTC7A	779
CALM2	3

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CALM2	P0DP24	21
MCFD2	Q8NI22	17

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TTC7A	Q9ULT0	84.59

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
CASP4 inflammasome assembly	1	634.4×	0.013	CALM2
Enterobacterial factors antagonize host defense	1	407.9×	0.013	CALM2
Cargo concentration in the ER	1	167.9×	0.022	MCFD2
COPII-mediated vesicle transport	1	81.6×	0.033	MCFD2
ER to Golgi Anterograde Transport	1	66.4×	0.033	MCFD2
Transport to the Golgi and subsequent modification	1	51.4×	0.035	MCFD2
Asparagine N-linked glycosylation	1	30.1×	0.052	MCFD2
Membrane Trafficking	1	18.5×	0.069	MCFD2
Vesicle-mediated transport	1	17.4×	0.069	MCFD2
Post-translational protein modification	1	9.6×	0.112	MCFD2
Metabolism of proteins	1	6.2×	0.155	MCFD2

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
negative regulation of ryanodine-sensitive calcium-release channel activity	1	2808.7×	0.007	CALM2
negative regulation of calcium ion export across plasma membrane	1	1404.3×	0.007	CALM2
presynaptic endocytosis	1	1123.5×	0.007	CALM2
regulation of cell communication by electrical coupling involved in cardiac conduction	1	624.1×	0.009	CALM2
calcineurin-mediated signaling	1	510.7×	0.009	CALM2
detection of calcium ion	1	374.5×	0.009	CALM2
regulation of calcium-mediated signaling	1	374.5×	0.009	CALM2
regulation of cardiac muscle contraction	1	295.6×	0.010	CALM2
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	224.7×	0.011	CALM2
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	224.7×	0.011	CALM2
phosphatidylinositol phosphate biosynthetic process	1	160.5×	0.013	TTC7A
regulation of heart rate	1	156.0×	0.013	CALM2
regulation of cytokinesis	1	140.4×	0.013	CALM2
substantia nigra development	1	122.1×	0.014	CALM2
response to calcium ion	1	106.0×	0.014	CALM2
G2/M transition of mitotic cell cycle	1	104.0×	0.014	CALM2
long-term synaptic potentiation	1	93.6×	0.015	CALM2
hemopoiesis	1	89.2×	0.015	TTC7A
intracellular iron ion homeostasis	1	81.4×	0.015	TTC7A
protein localization to plasma membrane	1	36.2×	0.033	TTC7A
vesicle-mediated transport	1	32.1×	0.035	MCFD2
gene expression	1	26.6×	0.040	MCFD2
protein transport	1	14.6×	0.070	MCFD2
G protein-coupled receptor signaling pathway	1	12.1×	0.081	CALM2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TTC7A	0	0
CALM2	0	0
MCFD2	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
CALM2	1	Binding:1

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

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	3	TTC7A, CALM2, MCFD2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TTC7A	0	—
CALM2	1	—
MCFD2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.