Holoprosencephaly 4

Summary

Holoprosencephaly 4 (MONDO:0007734) is a disease caused by TGIF1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: TGIF1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 91

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	holoprosencephaly 4
Mondo ID	MONDO:0007734
MeSH	C564180
OMIM	142946
DOID	DOID:0110880
NCIT	C75475
UMLS	C1840528
MedGen	374488
GARD	0024573
Is cancer (heuristic)	no

Also known as: holoprosencephaly 4 · holoprosencephaly caused by mutation in TGIF1 · holoprosencephaly type 4 · HPE4 · TGIF1 holoprosencephaly

Data availability: 91 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › holoprosencephaly › holoprosencephaly 4

Related subtypes (16): holoprosencephaly 3, holoprosencephaly 2, holoprosencephaly 1, holoprosencephaly 6, holoprosencephaly 8, holoprosencephaly 7, chromosome 1q41-q42 deletion syndrome, holoprosencephaly 11, microform holoprosencephaly, lobar holoprosencephaly, alobar holoprosencephaly, holoprosencephaly 13, X-linked, holoprosencephaly 14, holoprosencephaly 12 with or without pancreatic agenesis, semilobar holoprosencephaly, holoprosencephaly 10

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

91 retrieved; paginated sample, class counts are floors:

36 uncertain significance, 20 likely benign, 11 benign, 10 benign/likely benign, 6 pathogenic, 5 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
643155	NC_000018.10:g.(?3447720)(3457960_?)del	LOC130062108	Pathogenic	criteria provided, single submitter
1452047	NC_000018.9:g.(?2847807)(3582246_?)del	MYOM1	Pathogenic	criteria provided, single submitter
2671956	NM_003244.4(TGIF1):c.257del (p.Phe86fs)	TGIF1	Pathogenic	criteria provided, single submitter
372529	NM_003244.4(TGIF1):c.269G>A (p.Arg90His)	TGIF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
533431	NM_003244.4(TGIF1):c.268C>T (p.Arg90Cys)	TGIF1	Pathogenic	criteria provided, single submitter
6980	NM_003244.4(TGIF1):c.188C>G (p.Pro63Arg)	TGIF1	Pathogenic	no assertion criteria provided
6983	NM_003244.4(TGIF1):c.16+1651C>G	TGIF1	Pathogenic	no assertion criteria provided
2582647	NM_003244.4(TGIF1):c.214del (p.Ser72fs)	TGIF1	Likely pathogenic	criteria provided, single submitter
3024102	NM_003244.4(TGIF1):c.16+1805del	TGIF1	Likely pathogenic	no assertion criteria provided
252791	NM_003244.4(TGIF1):c.16+1564G>A	TGIF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2648528	NM_003244.4(TGIF1):c.16+1720_16+1721del	TGIF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
326710	NM_003244.4(TGIF1):c.723G>A (p.Pro241=)	TGIF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
6979	NM_003244.4(TGIF1):c.83C>G (p.Ser28Cys)	TGIF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
992745	NM_003244.4(TGIF1):c.16+1499T>C	TGIF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1311889	NM_003244.4(TGIF1):c.338G>A (p.Arg113His)	TGIF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1342651	NM_003244.4(TGIF1):c.16+1829G>A	TGIF1	Uncertain significance	criteria provided, single submitter
1356112	NM_003244.4(TGIF1):c.376G>A (p.Val126Met)	TGIF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1372531	NM_003244.4(TGIF1):c.289A>G (p.Met97Val)	TGIF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1381331	NM_003244.4(TGIF1):c.572C>T (p.Ser191Leu)	TGIF1	Uncertain significance	criteria provided, single submitter
1397444	NM_003244.4(TGIF1):c.460A>G (p.Arg154Gly)	TGIF1	Uncertain significance	criteria provided, single submitter
1399122	NM_003244.4(TGIF1):c.609A>G (p.Ile203Met)	TGIF1	Uncertain significance	criteria provided, single submitter
1402348	NM_003244.4(TGIF1):c.488C>G (p.Pro163Arg)	TGIF1	Uncertain significance	criteria provided, single submitter
1482593	NM_003244.4(TGIF1):c.496G>A (p.Val166Ile)	TGIF1	Uncertain significance	criteria provided, single submitter
1720957	NM_003244.4(TGIF1):c.734A>G (p.Gln245Arg)	TGIF1	Uncertain significance	criteria provided, single submitter
1804888	NM_003244.4(TGIF1):c.16+1578C>A	TGIF1	Uncertain significance	criteria provided, single submitter
1922279	NM_003244.4(TGIF1):c.396C>G (p.Phe132Leu)	TGIF1	Uncertain significance	criteria provided, single submitter
1943486	NM_003244.4(TGIF1):c.778C>T (p.Arg260Trp)	TGIF1	Uncertain significance	criteria provided, single submitter
2125626	NM_003244.4(TGIF1):c.380T>C (p.Met127Thr)	TGIF1	Uncertain significance	criteria provided, single submitter
2152994	NM_003244.4(TGIF1):c.526A>G (p.Thr176Ala)	TGIF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2158745	NM_003244.4(TGIF1):c.416C>A (p.Thr139Asn)	TGIF1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
TGIF1	Definitive	Autosomal dominant	holoprosencephaly 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TGIF1	Orphanet:220386	Semilobar holoprosencephaly
TGIF1	Orphanet:280195	Septopreoptic holoprosencephaly
TGIF1	Orphanet:280200	Microform holoprosencephaly
TGIF1	Orphanet:93924	Lobar holoprosencephaly
TGIF1	Orphanet:93925	Alobar holoprosencephaly
TGIF1	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TGIF1	HGNC:11776	ENSG00000177426	Q15583	Homeobox protein TGIF1	gencc,clinvar
MYOM1	HGNC:7613	ENSG00000101605	P52179	Myomesin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TGIF1	Homeobox protein TGIF1	Binds to a retinoid X receptor (RXR) responsive element from the cellular retinol-binding protein II promoter (CRBPII-RXRE).
MYOM1	Myomesin-1	Major component of the vertebrate myofibrillar M band.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Antibody/Immunoglobulin	1	14.6×	0.135
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TGIF1	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
MYOM1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom

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
gall bladder	1
stromal cell of endometrium	1
ventricular zone	1
gluteal muscle	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TGIF1	267	ubiquitous	marker	stromal cell of endometrium, gall bladder, ventricular zone
MYOM1	215	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis, gluteal muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TGIF1	1,482
MYOM1	1,082

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYOM1	P52179	9
TGIF1	Q15583	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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 activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	368.4×	0.010	TGIF1
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	368.4×	0.010	TGIF1
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	308.6×	0.010	TGIF1
Signaling by TGF-beta Receptor Complex	1	200.3×	0.011	TGIF1
Signaling by TGFB family members	1	115.3×	0.016	TGIF1
RNA Polymerase II Transcription	1	22.5×	0.067	TGIF1
Gene expression (Transcription)	1	17.8×	0.072	TGIF1
Generic Transcription Pathway	1	15.1×	0.074	TGIF1
Signal Transduction	1	10.2×	0.098	TGIF1

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
positive regulation of amacrine cell differentiation	1	2106.5×	0.005	TGIF1
extraocular skeletal muscle development	1	1404.3×	0.005	MYOM1
regulation of gastrulation	1	1404.3×	0.005	TGIF1
amacrine cell differentiation	1	766.0×	0.005	TGIF1
negative regulation of retinoic acid receptor signaling pathway	1	766.0×	0.005	TGIF1
obsolete protein kinase A signaling	1	702.2×	0.005	MYOM1
nodal signaling pathway	1	561.7×	0.005	TGIF1
dorsal/ventral pattern formation	1	210.7×	0.010	TGIF1
fibroblast proliferation	1	195.9×	0.010	TGIF1
sarcomere organization	1	191.5×	0.010	MYOM1
positive regulation of protein secretion	1	172.0×	0.010	MYOM1
cellular response to growth factor stimulus	1	159.0×	0.010	TGIF1
positive regulation of fibroblast proliferation	1	147.8×	0.010	TGIF1
determination of left/right symmetry	1	127.7×	0.011	TGIF1
neural tube closure	1	93.6×	0.014	TGIF1
response to xenobiotic stimulus	1	34.5×	0.034	TGIF1
negative regulation of gene expression	1	34.5×	0.034	TGIF1
negative regulation of cell population proliferation	1	21.1×	0.052	TGIF1
positive regulation of gene expression	1	19.4×	0.054	MYOM1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.110	TGIF1

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
TGIF1	0	0
MYOM1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	MYOM1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TGIF1

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)
TGIF1	0	—
MYOM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.