Holoprosencephaly 2

Summary

Holoprosencephaly 2 (MONDO:0007999) is a disease caused by SIX3 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: SIX3 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 159

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	holoprosencephaly 2
Mondo ID	MONDO:0007999
MeSH	C563579
OMIM	157170
DOID	DOID:0110872
NCIT	C74995
UMLS	C1834877
MedGen	322517
GARD	0024593
Is cancer (heuristic)	no

Also known as: holoprosencephaly 2 · holoprosencephaly caused by mutation in SIX3 · holoprosencephaly type 2 · HPE2 · SIX3 holoprosencephaly

Data availability: 159 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › holoprosencephaly › holoprosencephaly 2

Related subtypes (16): holoprosencephaly 3, holoprosencephaly 4, 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

159 retrieved; paginated sample, class counts are floors:

65 uncertain significance, 46 likely benign, 14 pathogenic, 12 conflicting classifications of pathogenicity, 10 benign/likely benign, 6 benign, 5 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
441532	NM_005413.3(SIX3):c.[206G>A;406_407dup]		Pathogenic	no assertion criteria provided
3247230	NC_000002.11:g.(?44001278)(45236249_?)del	ABCG5	Pathogenic	criteria provided, single submitter
1299645	NM_005413.4(SIX3):c.402_416del (p.Arg135_Ala139del)	SIX3	Pathogenic	criteria provided, single submitter
1995795	NM_005413.4(SIX3):c.425del (p.Thr142fs)	SIX3	Pathogenic	criteria provided, single submitter
2729808	NM_005413.4(SIX3):c.20del (p.Leu7fs)	SIX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734182	NM_005413.4(SIX3):c.275T>G (p.Val92Gly)	SIX3	Pathogenic	criteria provided, single submitter
30380	NM_005413.4(SIX3):c.385G>T (p.Glu129Ter)	SIX3	Pathogenic	no assertion criteria provided
449840	NM_005413.4(SIX3):c.406_407del (p.Ala136fs)	SIX3	Pathogenic	criteria provided, multiple submitters, no conflicts
545576	NM_005413.4(SIX3):c.441_451del (p.Leu148fs)	SIX3	Pathogenic	criteria provided, single submitter
579427	NM_005413.4(SIX3):c.507G>A (p.Trp169Ter)	SIX3	Pathogenic	criteria provided, single submitter
6093	NM_005413.4(SIX3):c.676C>G (p.Leu226Val)	SIX3	Pathogenic	no assertion criteria provided
6095	NM_005413.4(SIX3):c.749T>C (p.Val250Ala)	SIX3	Pathogenic	criteria provided, single submitter
6096	NM_005413.4(SIX3):c.556_557dup (p.Pro187fs)	SIX3	Pathogenic	no assertion criteria provided
6099	NM_005413.4(SIX3):c.339G>T (p.Trp113Cys)	SIX3	Pathogenic	criteria provided, single submitter
65501	NM_005413.4(SIX3):c.696_705del (p.Asn232fs)	SIX3	Pathogenic	no assertion criteria provided
1299646	NM_022455.5(NSD1):c.6542C>T (p.Ser2181Phe)	NSD1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3359075	NM_005413.4(SIX3):c.401C>A (p.Ala134Glu)	SIX3	Likely pathogenic	criteria provided, single submitter
3381887	NM_005413.4(SIX3):c.671G>A (p.Trp224Ter)	SIX3	Likely pathogenic	criteria provided, single submitter
6094	NM_005413.4(SIX3):c.770G>C (p.Arg257Pro)	SIX3	Likely pathogenic	criteria provided, single submitter
989366	NM_005413.4(SIX3):c.581G>C (p.Arg194Pro)	SIX3	Likely pathogenic	criteria provided, single submitter
1378258	NM_005413.4(SIX3):c.111_128dup (p.Gly42_Gly47dup)	SIX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193312	NM_005413.4(SIX3):c.187GGC[8] (p.Gly69dup)	SIX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2071436	NM_005413.4(SIX3):c.86T>C (p.Leu29Pro)	SIX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2083599	NM_005413.4(SIX3):c.124_141del (p.Gly42_Gly47del)	SIX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2604087	NM_005413.4(SIX3):c.61G>T (p.Asp21Tyr)	SIX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2808118	NM_005413.4(SIX3):c.515C>G (p.Ala172Gly)	SIX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
284060	NM_005413.4(SIX3):c.369G>A (p.Glu123=)	SIX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285308	NM_005413.4(SIX3):c.947C>T (p.Thr316Ile)	SIX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
445995	NM_005413.4(SIX3):c.824T>C (p.Ile275Thr)	SIX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
498484	NM_005413.4(SIX3):c.786C>A (p.Arg262=)	SIX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 14 · 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
SIX3	Definitive	Autosomal dominant	holoprosencephaly 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SIX3	Orphanet:220386	Semilobar holoprosencephaly
SIX3	Orphanet:280195	Septopreoptic holoprosencephaly
SIX3	Orphanet:280200	Microform holoprosencephaly
SIX3	Orphanet:485275	Acquired schizencephaly
SIX3	Orphanet:93924	Lobar holoprosencephaly
SIX3	Orphanet:93925	Alobar holoprosencephaly
SIX3	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
SIX2	Orphanet:488437	SIX2-related frontonasal dysplasia
ABCG5	Orphanet:2882	Sitosterolemia
ABCG5	Orphanet:391665	Homozygous familial hypercholesterolemia
NSD1	Orphanet:1627	Deletion 5q35 syndrome
NSD1	Orphanet:228415	5q35 microduplication syndrome
NSD1	Orphanet:3447	Weaver syndrome
NSD1	Orphanet:821	Sotos syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SIX3	HGNC:10889	ENSG00000138083	O95343	Homeobox protein SIX3	gencc,clinvar
SIX2	HGNC:10888	ENSG00000170577	Q9NPC8	Homeobox protein SIX2	clinvar
ABCG5	HGNC:13886	ENSG00000138075	Q9H222	ATP-binding cassette sub-family G member 5	clinvar
NSD1	HGNC:14234	ENSG00000165671	Q96L73	Histone-lysine N-methyltransferase, H3 lysine-36 specific	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SIX3	Homeobox protein SIX3	Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes.
SIX2	Homeobox protein SIX2	Transcription factor that plays an important role in the development of several organs, including kidney, skull and stomach.
ABCG5	ATP-binding cassette sub-family G member 5	ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane.
NSD1	Histone-lysine N-methyltransferase, H3 lysine-36 specific	Histone methyltransferase that dimethylates Lys-36 of histone H3 (H3K36me2).

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 0 · Druggable fraction: 0.25

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	3	6.2×	0.013
Transporter	1	19.4×	0.050

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SIX3	Transcription factor	no		HD, Homeodomain-like_sf, SIX1_SD
SIX2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
ABCG5	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
NSD1	Transcription factor	no	2.1.1.357	PWWP_dom, SET_dom, Znf_PHD

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
nasal cavity epithelium	1
pigmented layer of retina	1
retina	1
gastrocnemius	1
olfactory segment of nasal mucosa	1
parotid gland	1
duodenum	1
jejunal mucosa	1
right lobe of liver	1
calcaneal tendon	1
colonic epithelium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SIX3	92	broad	marker	pigmented layer of retina, retina, nasal cavity epithelium
SIX2	156	broad	marker	olfactory segment of nasal mucosa, gastrocnemius, parotid gland
ABCG5	61	tissue_specific	marker	jejunal mucosa, right lobe of liver, duodenum
NSD1	235	ubiquitous	marker	sural nerve, colonic epithelium, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NSD1	2,979
ABCG5	1,996
SIX3	1,536
SIX2	1,355

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCG5	Q9H222	8
NSD1	Q96L73	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SIX2	Q9NPC8	75.99
SIX3	O95343	70.38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCG8 causes GBD4 and sitosterolemia	1	1903.3×	0.004	ABCG5
Defective ABCG5 causes sitosterolemia	1	1903.3×	0.004	ABCG5
Kidney development	1	271.9×	0.017	SIX2
ABC transporters in lipid homeostasis	1	200.3×	0.017	ABCG5
Formation of the ureteric bud	1	165.5×	0.017	SIX2
ABC transporter disorders	1	146.4×	0.017	ABCG5
NR1H2 and NR1H3-mediated signaling	1	131.3×	0.017	ABCG5
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	102.9×	0.019	ABCG5
PKMTs methylate histone lysines	1	53.6×	0.033	NSD1
Disorders of transmembrane transporters	1	46.4×	0.034	ABCG5
ABC-family protein mediated transport	1	40.5×	0.036	ABCG5
Signaling by Nuclear Receptors	1	34.0×	0.039	ABCG5
Transport of small molecules	1	8.4×	0.141	ABCG5
Developmental Biology	1	4.8×	0.221	SIX2
Disease	1	4.4×	0.226	ABCG5
Signal Transduction	1	3.4×	0.267	ABCG5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
proximal/distal axis specification	1	4213.0×	0.003	SIX3
regulation of peptidyl-serine phosphorylation	1	4213.0×	0.003	NSD1
nephron morphogenesis	1	4213.0×	0.003	SIX2
regulation of branching involved in ureteric bud morphogenesis	1	4213.0×	0.003	SIX2
regulation of RNA polymerase II regulatory region sequence-specific DNA binding	1	4213.0×	0.003	NSD1
optic vesicle morphogenesis	1	2106.5×	0.003	SIX3
negative regulation of intestinal phytosterol absorption	1	2106.5×	0.003	ABCG5
negative regulation of intestinal cholesterol absorption	1	2106.5×	0.003	ABCG5
mesenchymal stem cell maintenance involved in nephron morphogenesis	1	2106.5×	0.003	SIX2
mesenchymal cell differentiation involved in kidney development	1	2106.5×	0.003	SIX2
mesenchymal stem cell proliferation	1	2106.5×	0.003	SIX2
protein import into nucleus	2	72.0×	0.003	SIX3, SIX2
regulation of neural retina development	1	1404.3×	0.004	SIX3
condensed mesenchymal cell proliferation	1	1404.3×	0.004	SIX2
forebrain anterior/posterior pattern specification	1	1053.2×	0.004	SIX3
lens induction in camera-type eye	1	1053.2×	0.004	SIX3
neuroblast migration	1	842.6×	0.005	SIX3
regulation of neuroblast proliferation	1	842.6×	0.005	SIX3
lens fiber cell apoptotic process	1	842.6×	0.005	SIX3
sterol transport	1	702.2×	0.005	ABCG5
telencephalon regionalization	1	702.2×	0.005	SIX3
mesenchymal to epithelial transition involved in metanephros morphogenesis	1	526.6×	0.005	SIX2
mesodermal cell fate specification	1	526.6×	0.005	SIX2
neuroblast differentiation	1	526.6×	0.005	SIX3
forebrain dorsal/ventral pattern formation	1	526.6×	0.005	SIX3
circadian behavior	1	468.1×	0.005	SIX3
nephron development	1	468.1×	0.005	SIX2
regulation of cell cycle phase transition	1	468.1×	0.005	SIX3
positive regulation of chondrocyte proliferation	1	468.1×	0.005	SIX2
apoptotic process involved in development	1	421.3×	0.006	SIX3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NSD1	VENETOCLAX

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NSD1	7	4
SIX3	0	0
SIX2	0	0
ABCG5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VENETOCLAX	4	NSD1
PRIMAQUINE	4	NSD1
CHLOROQUINE PHOSPHATE	4	NSD1
SURAMIN	3	NSD1
SINEFUNGIN	2	NSD1
PF-03882845	1	NSD1
PLUMBAGIN	1	NSD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NSD1	90	Binding:90

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NSD1	2.1.1.357, 2.1.1.362	[histone H3]-lysine36 N-dimethyltransferase, [histone H4]-N-methyl-L-lysine20 N-methyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

7 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.

Compound	Max phase	Cohort target (bioactivity)
VENETOCLAX	4	NSD1
PRIMAQUINE	4	NSD1
CHLOROQUINE PHOSPHATE	4	NSD1
SURAMIN	3	NSD1
SINEFUNGIN	2	NSD1
PF-03882845	1	NSD1
PLUMBAGIN	1	NSD1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NSD1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ABCG5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SIX3, SIX2

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)
SIX3	0	—
SIX2	0	—
ABCG5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.