heterotaxy, visceral, 1, X-linked

Summary

heterotaxy, visceral, 1, X-linked (MONDO:0010607) is a disease caused by ZIC3 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: ZIC3 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 122

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	heterotaxy, visceral, 1, X-linked
Mondo ID	MONDO:0010607
MeSH	C538116
OMIM	306955
DOID	DOID:0051016
UMLS	C1844020
MedGen	336609
GARD	0008591
Is cancer (heuristic)	no

Also known as: congenital heart defects, nonsyndromic, 1, X-linked, X-linked recessive · heterotaxy, visceral, 1, X-linked · heterotaxy, visceral, 1, X-linked, X-linked recessive · heterotaxy, visceral, X-linked · HTX1 · visceral heterotaxy caused by mutation in ZIC3 · X-linked visceral heterotaxy 1 · ZIC3 visceral heterotaxy

Data availability: 122 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › visceral heterotaxy › heterotaxy, visceral, 1, X-linked

Related subtypes (18): right atrial isomerism, situs inversus, laterality defects, autosomal dominant, heterotaxy, visceral, 2, autosomal, heterotaxy, visceral, 3, autosomal, heterotaxy, visceral, 4, autosomal, heterotaxy, visceral, 6, autosomal, heterotaxy, visceral, 7, autosomal, heterotaxy, visceral, 8, autosomal, dextrocardia, levocardia, heterotaxy, visceral, 9, autosomal, with male infertility, heterotaxy, visceral, 10, autosomal, with male infertility, heterotaxy, visceral, 11, autosomal, with male infertility, heterotaxy, visceral, 5, autosomal, heterotaxy, visceral, 12, autosomal, heterotaxy, visceral, 13, autosomal, heterotaxy, visceral, 14, autosomal

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

122 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 29 pathogenic, 20 likely benign, 10 benign, 10 conflicting classifications of pathogenicity, 7 benign/likely benign, 6 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1458589	NC_000023.10:g.(?135067662)(136652229_?)del	ADGRG4	Pathogenic	criteria provided, single submitter
545551	NC_000023.10:g.36649710_136649711del100000002insG	FAM156A	Pathogenic	no assertion criteria provided
1074222	NM_003413.4(ZIC3):c.1103del (p.Arg368fs)	ZIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075476	NM_003413.4(ZIC3):c.860_864del (p.Val287fs)	ZIC3	Pathogenic	criteria provided, single submitter
11433	NM_003413.4(ZIC3):c.968C>T (p.Thr323Met)	ZIC3	Pathogenic	criteria provided, multiple submitters, no conflicts
11434	NM_003413.4(ZIC3):c.804C>A (p.Cys268Ter)	ZIC3	Pathogenic	no assertion criteria provided
11436	NM_003413.4(ZIC3):c.745C>T (p.Gln249Ter)	ZIC3	Pathogenic	no assertion criteria provided
11437	NM_003413.4(ZIC3):c.758G>C (p.Cys253Ser)	ZIC3	Pathogenic	no assertion criteria provided
11438	NM_003413.4(ZIC3):c.1213A>G (p.Lys405Glu)	ZIC3	Pathogenic	no assertion criteria provided
11440	NM_003413.4(ZIC3):c.972_973insTT (p.Glu325fs)	ZIC3	Pathogenic	no assertion criteria provided
11441	NM_003413.4(ZIC3):c.763T>G (p.Trp255Gly)	ZIC3	Pathogenic	no assertion criteria provided
1416124	NM_003413.4(ZIC3):c.810del (p.Thr271fs)	ZIC3	Pathogenic	criteria provided, single submitter
1707614	NM_003413.4(ZIC3):c.599del (p.Arg200fs)	ZIC3	Pathogenic	criteria provided, single submitter
2118034	NM_003413.4(ZIC3):c.976A>T (p.Lys326Ter)	ZIC3	Pathogenic	criteria provided, single submitter
2118751	NM_003413.4(ZIC3):c.727_740del (p.Met243fs)	ZIC3	Pathogenic	criteria provided, single submitter
216089	NM_003413.3(ZIC3):c.(?-1)(*1_?)del	ZIC3	Pathogenic	criteria provided, single submitter
2737377	NM_003413.4(ZIC3):c.463G>T (p.Glu155Ter)	ZIC3	Pathogenic	criteria provided, single submitter
2814022	NM_003413.4(ZIC3):c.109_112del (p.Leu37fs)	ZIC3	Pathogenic	criteria provided, single submitter
3233415	NM_001330661.1(ZIC3):c.1224+3286A>G	ZIC3	Pathogenic	criteria provided, single submitter
3725958	NM_003413.4(ZIC3):c.764G>A (p.Trp255Ter)	ZIC3	Pathogenic	criteria provided, single submitter
464967	NM_003413.4(ZIC3):c.476_479del (p.Tyr159fs)	ZIC3	Pathogenic	criteria provided, single submitter
4714750	NM_003413.4(ZIC3):c.208C>T (p.Gln70Ter)	ZIC3	Pathogenic	criteria provided, single submitter
545552	NM_003413.4(ZIC3):c.755C>A (p.Ser252Ter)	ZIC3	Pathogenic	criteria provided, single submitter
545553	NM_003413.4(ZIC3):c.757T>A (p.Cys253Ser)	ZIC3	Pathogenic	no assertion criteria provided
545554	NM_003413.4(ZIC3):c.128C>A (p.Ser43Ter)	ZIC3	Pathogenic	no assertion criteria provided
545555	NM_003413.4(ZIC3):c.593_609del (p.Pro198fs)	ZIC3	Pathogenic	no assertion criteria provided
570392	NM_003413.4(ZIC3):c.535dup (p.Val179fs)	ZIC3	Pathogenic	criteria provided, single submitter
645837	NM_003413.4(ZIC3):c.571del (p.Glu191fs)	ZIC3	Pathogenic	criteria provided, single submitter
853140	NM_003413.4(ZIC3):c.128C>G (p.Ser43Ter)	ZIC3	Pathogenic	criteria provided, single submitter
951637	NM_003413.4(ZIC3):c.508_514del (p.Ala170fs)	ZIC3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
ZIC3	Definitive	X-linked	congenital heart disease with heterotaxy syndrome	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZIC3	Orphanet:157769	Situs ambiguus
ZIC3	Orphanet:216718	Isolated congenitally uncorrected transposition of the great arteries

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
ZIC3	HGNC:12874	ENSG00000156925	O60481	Zinc finger protein ZIC 3	gencc,clinvar
ADGRG4	HGNC:18992	ENSG00000156920	Q8IZF6	Adhesion G-protein coupled receptor G4	clinvar
FAM156A	HGNC:30114	ENSG00000268350	Q8NDB6	Protein FAM156A/FAM156B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZIC3	Zinc finger protein ZIC 3	Acts as a transcriptional activator.
ADGRG4	Adhesion G-protein coupled receptor G4	Orphan adhesion G-protein coupled receptor (aGPCR).

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · 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
GPCR	1	8.0×	0.360
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZIC3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Znf_ZIC
ADGRG4	GPCR	yes		GPS, GPCR_2_secretin-like, PTX_dom
FAM156A	Other/Unknown	no		Dppa3

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
cerebellar cortex	2
right hemisphere of cerebellum	2
cerebellar hemisphere	1
buccal mucosa cell	1
duodenum	1
jejunal mucosa	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZIC3	81	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ADGRG4	55	tissue_specific	marker	buccal mucosa cell, duodenum, jejunal mucosa
FAM156A	134	broad	marker	pituitary gland, right hemisphere of cerebellum, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZIC3	1,600
ADGRG4	768
FAM156A	205

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZIC3	O60481	2
ADGRG4	Q8IZF6	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FAM156A	Q8NDB6	68.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 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
POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation	1	878.5×	0.002	ZIC3
Transcriptional regulation of pluripotent stem cells	1	543.8×	0.002	ZIC3

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
central nervous system segmentation	1	8426.0×	0.003	ZIC3
neural plate development	1	4213.0×	0.003	ZIC3
determination of left/right asymmetry in nervous system	1	4213.0×	0.003	ZIC3
atrial cardiac muscle tissue development	1	2106.5×	0.003	ZIC3
determination of pancreatic left/right asymmetry	1	1685.2×	0.003	ZIC3
axial mesoderm development	1	1685.2×	0.003	ZIC3
germ-line stem cell population maintenance	1	1404.3×	0.003	ZIC3
determination of digestive tract left/right asymmetry	1	1404.3×	0.003	ZIC3
determination of liver left/right asymmetry	1	1404.3×	0.003	ZIC3
paraxial mesoderm development	1	842.6×	0.004	ZIC3
outer ear morphogenesis	1	766.0×	0.004	ZIC3
primitive streak formation	1	702.2×	0.004	ZIC3
left/right axis specification	1	601.9×	0.004	ZIC3
limb morphogenesis	1	526.6×	0.004	ZIC3
cranial skeletal system development	1	468.1×	0.005	ZIC3
face development	1	401.2×	0.005	ZIC3
olfactory bulb development	1	383.0×	0.005	ZIC3
embryonic pattern specification	1	271.8×	0.007	ZIC3
mRNA transcription by RNA polymerase II	1	165.2×	0.010	ZIC3
stem cell differentiation	1	150.5×	0.011	ZIC3
heart looping	1	133.8×	0.012	ZIC3
determination of left/right symmetry	1	127.7×	0.012	ZIC3
hippocampus development	1	115.4×	0.012	ZIC3
lung development	1	99.1×	0.014	ZIC3
smoothened signaling pathway	1	90.6×	0.015	ZIC3
skeletal system development	1	62.9×	0.020	ZIC3
central nervous system development	1	57.7×	0.021	ZIC3
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	56.5×	0.021	ADGRG4
neuron differentiation	1	50.1×	0.023	ZIC3
cell surface receptor signaling pathway	1	32.0×	0.034	ADGRG4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
ZIC3	0	0
ADGRG4	0	0
FAM156A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	ADGRG4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ZIC3, FAM156A

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)
ZIC3	0	—
ADGRG4	0	—
FAM156A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.