Diaphragmatic hernia 3

Summary

Diaphragmatic hernia 3 (MONDO:0012431) is a disease caused by ZFPM2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ZFPM2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diaphragmatic hernia 3
Mondo ID	MONDO:0012431
MeSH	C565710
OMIM	610187
UMLS	C1857781
MedGen	347546
GARD	0015474
Is cancer (heuristic)	no

Also known as: congenital diaphragmatic hernia caused by mutation in ZFPM2 · diaphragmatic hernia 3 · diaphragmatic hernia type 3 · DIH3 · ZFPM2 congenital diaphragmatic hernia

Data availability: 24 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › diaphragm disorder › congenital diaphragmatic hernia › diaphragmatic hernia 3

Related subtypes (4): diaphragmatic hernia 1, diaphragmatic hernia 2, hernia, anterior diaphragmatic, diaphragmatic hernia 4, with cardiovascular defects

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

24 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 4 conflicting classifications of pathogenicity, 3 benign/likely benign, 3 pathogenic, 2 likely pathogenic, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
6131	NM_012082.4(ZFPM2):c.2527A>G (p.Thr843Ala)	LOC126860469	Pathogenic	no assertion criteria provided
1706571	NM_012082.4(ZFPM2):c.349C>T (p.Arg117Ter)	ZFPM2	Pathogenic	criteria provided, single submitter
6129	NM_012082.4(ZFPM2):c.334C>T (p.Arg112Ter)	ZFPM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
987903	NM_012082.4(ZFPM2):c.757_761dup (p.Cys255fs)	ZFPM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
987904	NM_012082.4(ZFPM2):c.1396_1399dup (p.Tyr467fs)	ZFPM2-AS1	Pathogenic	criteria provided, single submitter
3235947	GRCh38/hg38 8q23.1(chr8:105628485-105634938)	ZFPM2	Likely pathogenic	criteria provided, single submitter
4280046	NM_012082.4(ZFPM2):c.964+1G>C	ZFPM2	Likely pathogenic	criteria provided, single submitter
2917419	NM_012082.4(ZFPM2):c.1463T>C (p.Ile488Thr)	ZFPM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
39518	NM_012082.4(ZFPM2):c.1632G>A (p.Met544Ile)	ZFPM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
6130	NM_012082.4(ZFPM2):c.2107A>C (p.Met703Leu)	ZFPM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
633465	NM_012082.4(ZFPM2):c.130G>A (p.Glu44Lys)	ZFPM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2441879	NM_012082.4(ZFPM2):c.2164G>C (p.Ala722Pro)	LOC126860469	Uncertain significance	criteria provided, single submitter
3780810	NM_012082.4(ZFPM2):c.2875A>T (p.Arg959Ter)	LOC126860469	Uncertain significance	criteria provided, single submitter
544220	NM_012082.4(ZFPM2):c.3086A>T (p.Lys1029Ile)	LOC126860469	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892914	NM_012082.4(ZFPM2):c.235G>C (p.Asp79His)	ZFPM2	Uncertain significance	criteria provided, single submitter
3892915	NM_012082.4(ZFPM2):c.350G>A (p.Arg117Gln)	ZFPM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892916	NM_012082.4(ZFPM2):c.931C>G (p.Arg311Gly)	ZFPM2	Uncertain significance	criteria provided, single submitter
4056342	NM_012082.4(ZFPM2):c.1720C>T (p.Arg574Ter)	ZFPM2	Uncertain significance	criteria provided, single submitter
633466	NM_012082.4(ZFPM2):c.1168A>C (p.Lys390Gln)	ZFPM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
982981	NM_012082.4(ZFPM2):c.3335G>A (p.Ser1112Asn)	ZFPM2-AS1	Uncertain significance	criteria provided, single submitter
1574529	NM_012082.4(ZFPM2):c.2963A>C (p.Lys988Thr)	LOC126860469	Likely benign	criteria provided, multiple submitters, no conflicts
1558608	NM_012082.4(ZFPM2):c.40+12C>G	ZFPM2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
6127	NM_012082.4(ZFPM2):c.1969A>G (p.Ser657Gly)	ZFPM2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
6128	NM_012082.4(ZFPM2):c.89A>G (p.Glu30Gly)	ZFPM2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
ZFPM2	Strong	Autosomal dominant	diaphragmatic hernia 3	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZFPM2	Orphanet:2140	Congenital diaphragmatic hernia
ZFPM2	Orphanet:251510	46,XY partial gonadal dysgenesis
ZFPM2	Orphanet:3303	Tetralogy of Fallot

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
ZFPM2	HGNC:16700	ENSG00000169946	Q8WW38	Zinc finger protein ZFPM2	gencc,clinvar
ZFPM2-AS1	HGNC:50698	ENSG00000251003		ZFPM2 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZFPM2	Zinc finger protein ZFPM2	Transcription regulator that plays a central role in heart morphogenesis and development of coronary vessels from epicardium, by regulating genes that are essential during cardiogenesis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZFPM2	Transcription factor	no		Znf_C2H2_type, Znf_CCHC_FOG, Znf_C2H2_sf
ZFPM2-AS1	Other/Unknown	no

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
biceps brachii	1
germinal epithelium of ovary	1
skeletal muscle tissue of biceps brachii	1
endometrium	1
male germ line stem cell (sensu Vertebrata) in testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZFPM2	239	ubiquitous	marker	skeletal muscle tissue of biceps brachii, germinal epithelium of ovary, biceps brachii
ZFPM2-AS1	129	broad	marker	right uterine tube, endometrium, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZFPM2	1,437
ZFPM2-AS1	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZFPM2	Q8WW38	51.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Transcriptional regulation of testis differentiation	1	713.8×	0.003	ZFPM2
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.015	ZFPM2

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
right ventricular cardiac muscle tissue morphogenesis	1	8426.0×	0.002	ZFPM2
negative regulation of female gonad development	1	4213.0×	0.002	ZFPM2
gonadal mesoderm development	1	1685.2×	0.003	ZFPM2
positive regulation of male gonad development	1	1685.2×	0.003	ZFPM2
outflow tract septum morphogenesis	1	648.1×	0.005	ZFPM2
positive regulation of cardiac muscle cell proliferation	1	624.1×	0.005	ZFPM2
embryonic organ development	1	481.5×	0.005	ZFPM2
ventricular septum morphogenesis	1	432.1×	0.005	ZFPM2
negative regulation of fat cell differentiation	1	312.1×	0.006	ZFPM2
vasculogenesis	1	255.3×	0.007	ZFPM2
lung development	1	198.3×	0.008	ZFPM2
fat cell differentiation	1	181.2×	0.008	ZFPM2
heart development	1	78.8×	0.018	ZFPM2
in utero embryonic development	1	72.0×	0.018	ZFPM2
negative regulation of DNA-templated transcription	1	31.6×	0.038	ZFPM2
cell differentiation	1	29.1×	0.039	ZFPM2
negative regulation of transcription by RNA polymerase II	1	17.7×	0.060	ZFPM2
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	ZFPM2

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
ZFPM2	0	0
ZFPM2-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	ZFPM2, ZFPM2-AS1

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)
ZFPM2	0	—
ZFPM2-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.