Holoprosencephaly 5

Summary

Holoprosencephaly 5 (MONDO:0012322) is a disease caused by ZIC2 (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: ZIC2 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 407

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	holoprosencephaly 5
Mondo ID	MONDO:0012322
MeSH	C566464
OMIM	609637
DOID	DOID:0110878
NCIT	C75460
UMLS	C1864827
MedGen	355304
GARD	0024860
Is cancer (heuristic)	no

Also known as: holoprosencephaly 5 · holoprosencephaly caused by mutation in ZIC2 · holoprosencephaly type 5 · HPE5 · ZIC2 holoprosencephaly

Data availability: 407 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › holoprosencephaly › microform holoprosencephaly › holoprosencephaly 5

Related subtypes (2): solitary median maxillary central incisor syndrome, holoprosencephaly 9

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

407 retrieved; paginated sample, class counts are floors:

186 uncertain significance, 155 likely benign, 32 pathogenic, 12 likely pathogenic, 10 conflicting classifications of pathogenicity, 9 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
65488	1 bp del G 7		Pathogenic	no assertion criteria provided
2579261	GRCh38/hg38 13q32.2-34(chr13:98343655-110990677)x1	ABHD13	Pathogenic	criteria provided, single submitter
2425688	NC_000013.10:g.(?99336978)(102379160_?)del	CLYBL	Pathogenic	criteria provided, single submitter
830571	NC_000013.11:g.(?99385979)(99986648_?)del	CLYBL	Pathogenic	criteria provided, single submitter
1074668	NC_000013.10:g.(?92002837)(103343314_?)del	ITGBL1	Pathogenic	criteria provided, single submitter
468365	NM_007129.5(ZIC2):c.1377_1406dup (p.Ala461_Ala470dup)	LOC110008580	Pathogenic	criteria provided, multiple submitters, no conflicts
6639	NM_007129.5(ZIC2):c.1366GCN[45] (p.Ala456[15])	LOC110008580	Pathogenic	no assertion criteria provided
1073377	NM_007129.5(ZIC2):c.973C>T (p.Arg325Cys)	ZIC2	Pathogenic	criteria provided, single submitter
1435952	NM_007129.5(ZIC2):c.1156del (p.Val386fs)	ZIC2	Pathogenic	criteria provided, single submitter
1994794	NM_007129.5(ZIC2):c.1199_1207del (p.Lys400_Tyr402del)	ZIC2	Pathogenic	criteria provided, single submitter
2023461	NM_007129.5(ZIC2):c.911G>A (p.Trp304Ter)	ZIC2	Pathogenic	criteria provided, single submitter
2034810	NM_007129.5(ZIC2):c.722del (p.Gly241fs)	ZIC2	Pathogenic	criteria provided, single submitter
2431203	NM_007129.5(ZIC2):c.651del (p.Met217fs)	ZIC2	Pathogenic	criteria provided, single submitter
2760100	NM_007129.5(ZIC2):c.773G>A (p.Cys258Tyr)	ZIC2	Pathogenic	criteria provided, single submitter
30298	NM_007129.5(ZIC2):c.397_403del (p.Gly133fs)	ZIC2	Pathogenic	no assertion criteria provided
3657484	NM_007129.5(ZIC2):c.452C>A (p.Ser151Ter)	ZIC2	Pathogenic	criteria provided, single submitter
397654	NM_007129.5(ZIC2):c.1097_1098del (p.Glu366fs)	ZIC2	Pathogenic	criteria provided, single submitter
397655	NM_007129.5(ZIC2):c.793C>T (p.Gln265Ter)	ZIC2	Pathogenic	criteria provided, single submitter
397656	NM_007129.5(ZIC2):c.1095_1096del (p.Cys365_Glu366delinsTer)	ZIC2	Pathogenic	criteria provided, multiple submitters, no conflicts
397658	NM_007129.3:c.1148_1464del	ZIC2	Pathogenic	criteria provided, single submitter
437335	NM_007129.5(ZIC2):c.1085_1131del (p.Pro362fs)	ZIC2	Pathogenic	criteria provided, single submitter
468364	NM_007129.5(ZIC2):c.1076-2A>T	ZIC2	Pathogenic	criteria provided, single submitter
545578	NM_007129.5(ZIC2):c.321del (p.Tyr108fs)	ZIC2	Pathogenic	criteria provided, single submitter
65487	NM_007129.5(ZIC2):c.936del (p.Lys312fs)	ZIC2	Pathogenic	no assertion criteria provided
65492	NM_007129.5(ZIC2):c.1091_1092del (p.Gln364fs)	ZIC2	Pathogenic	no assertion criteria provided
659143	NM_007129.5(ZIC2):c.1215del (p.Ser406fs)	ZIC2	Pathogenic	criteria provided, single submitter
6637	NM_007129.4(ZIC2):c.177_178ins56	ZIC2	Pathogenic	no assertion criteria provided
6638	NM_007129.5(ZIC2):c.1318dup (p.Leu440fs)	ZIC2	Pathogenic	no assertion criteria provided
6640	NM_007129.5(ZIC2):c.1042_1048del (p.Glu348fs)	ZIC2	Pathogenic	no assertion criteria provided
6641	NM_007129.5(ZIC2):c.857_858del (p.His286fs)	ZIC2	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · 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
ZIC2	Definitive	Autosomal dominant	holoprosencephaly 5	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZIC2	Orphanet:220386	Semilobar holoprosencephaly
ZIC2	Orphanet:280195	Septopreoptic holoprosencephaly
ZIC2	Orphanet:280200	Microform holoprosencephaly
ZIC2	Orphanet:93924	Lobar holoprosencephaly
ZIC2	Orphanet:93925	Alobar holoprosencephaly
ZIC2	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ZIC2	HGNC:12873	ENSG00000043355	O95409	Zinc finger protein ZIC 2	gencc,clinvar
BIVM	HGNC:16034	ENSG00000134897	Q86UB2	Basic immunoglobulin-like variable motif-containing protein	clinvar
CLYBL	HGNC:18355	ENSG00000125246	Q8N0X4	Citramalyl-CoA lyase, mitochondrial	clinvar
ABHD13	HGNC:20293	ENSG00000139826	Q7L211	Protein ABHD13	clinvar
ITGBL1	HGNC:6164	ENSG00000198542	O95965	Integrin beta-like protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZIC2	Zinc finger protein ZIC 2	Acts as a transcriptional activator or repressor.
CLYBL	Citramalyl-CoA lyase, mitochondrial	Mitochondrial enzyme required to detoxify vitamin B12-poisoning metabolites.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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	5.5×	0.503
Transcription factor	1	1.6×	0.608
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZIC2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Znf_ZIC
BIVM	Other/Unknown	no
CLYBL	Kinase	yes	4.1.3.6	Aldolase/citrate-lyase_domain, Citrate_lyase_beta/mcl1/mcl2, Pyrv/PenolPyrv_kinase-like_dom
ABHD13	Other/Unknown	no		AB_hydrolase_1, AB_hydrolase_fold
ITGBL1	Other/Unknown	no		EGF, EGF_extracell, Integrin_bsu

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
tibialis anterior	1
kidney epithelium	1
liver	1
right lobe of liver	1
calcaneal tendon	1
leukocyte	1
monocyte	1
frontal pole	1
middle frontal gyrus	1
paraflocculus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZIC2	139	broad	marker	cerebellar cortex, cerebellar hemisphere, cerebellum
BIVM	257	tissue_specific	marker	left ventricle myocardium, tibialis anterior, cardiac muscle of right atrium
CLYBL	234	ubiquitous	marker	kidney epithelium, right lobe of liver, liver
ABHD13	214	ubiquitous	marker	monocyte, leukocyte, calcaneal tendon
ITGBL1	243	broad	marker	frontal pole, paraflocculus, middle frontal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLYBL	2,156
BIVM	2,003
ZIC2	1,738
ITGBL1	1,086
ABHD13	551

Structural data

PDB: 1 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLYBL	Q8N0X4	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABHD13	Q7L211	92.06
ITGBL1	O95965	84.28
BIVM	Q86UB2	66.50
ZIC2	O95409	51.36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 5 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
RUNX2 regulates genes involved in cell migration	1	713.8×	0.006	ITGBL1
Formation of the anterior neural plate	1	519.1×	0.006	ZIC2
Transcriptional regulation by RUNX2	1	126.9×	0.016	ITGBL1
RNA Polymerase II Transcription	1	11.3×	0.128	ITGBL1
Gene expression (Transcription)	1	8.9×	0.128	ITGBL1
Generic Transcription Pathway	1	7.5×	0.128	ITGBL1

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
regulation of cobalamin metabolic process	1	5617.3×	0.002	CLYBL
positive regulation of cobalamin metabolic process	1	5617.3×	0.002	CLYBL
protein homotrimerization	1	330.4×	0.017	CLYBL
cell adhesion mediated by integrin	1	224.7×	0.017	ITGBL1
obsolete positive regulation of DNA-binding transcription factor activity	1	200.6×	0.017	ZIC2
cell-matrix adhesion	1	54.5×	0.045	ITGBL1
integrin-mediated signaling pathway	1	53.5×	0.045	ITGBL1
central nervous system development	1	38.5×	0.055	ZIC2
cell-cell adhesion	1	33.8×	0.055	ITGBL1
brain development	1	26.5×	0.058	ZIC2
visual perception	1	26.5×	0.058	ZIC2
cell migration	1	20.5×	0.068	ITGBL1
cell adhesion	1	12.5×	0.102	ITGBL1
negative regulation of DNA-templated transcription	1	10.5×	0.110	ZIC2
cell differentiation	1	9.7×	0.110	ZIC2
positive regulation of DNA-templated transcription	1	9.3×	0.110	ZIC2
regulation of transcription by RNA polymerase II	1	3.9×	0.236	ZIC2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 0 of 5 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
ZIC2	0	0
BIVM	0	0
CLYBL	0	0
ABHD13	0	0
ITGBL1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CLYBL	4.1.3.6	citrate (pro-3S)-lyase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	CLYBL
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	ZIC2, BIVM, ABHD13, ITGBL1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZIC2	0	—
BIVM	0	—
CLYBL	0	—
ABHD13	0	—
ITGBL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.