Pituitary hormone deficiency, combined, 6

Summary

Pituitary hormone deficiency, combined, 6 (MONDO:0013518) is a disease caused by OTX2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: OTX2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 35

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pituitary hormone deficiency, combined, 6
Mondo ID	MONDO:0013518
OMIM	613986
DOID	DOID:0061022
UMLS	C3151440
MedGen	462790
GARD	0016520
Is cancer (heuristic)	no

Also known as: combined pituitary hormone deficiencies, genetic form caused by mutation in OTX2 · CPHD6 · OTX2 combined pituitary hormone deficiencies, genetic form · pituitary hormone deficiency, combined, 6 · pituitary hormone deficiency, combined, type 6

Data availability: 35 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › combined pituitary hormone deficiencies, genetic form › pituitary hormone deficiency, combined, 6

Related subtypes (8): isolated congenital growth hormone deficiency, septooptic dysplasia, congenital isolated adrenocorticotropic hormone deficiency, non-acquired combined pituitary hormone deficiency with spine abnormalities, short stature-pituitary and cerebellar defects-small sella turcica syndrome, panhypopituitarism, pituitary hormone deficiency, combined, 1, pituitary hormone deficiency, combined or isolated, 8

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

35 retrieved; paginated sample, class counts are floors:

22 uncertain significance, 5 conflicting classifications of pathogenicity, 4 benign/likely benign, 2 benign, 1 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3382712	NM_021728.4(OTX2):c.706_725del (p.Thr236fs)	OTX2	Likely pathogenic	criteria provided, single submitter
288894	NM_021728.4(OTX2):c.641C>A (p.Thr214Asn)	OTX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313420	NM_021728.4(OTX2):c.273+11T>C	OTX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313421	NM_021728.4(OTX2):c.270G>T (p.Val90=)	OTX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
803030	NM_021728.4(OTX2):c.425C>G (p.Pro142Arg)	OTX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
881938	NM_021728.4(OTX2):c.444G>A (p.Pro148=)	OTX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029266	NM_021728.4(OTX2):c.730G>A (p.Ala244Thr)	OTX2	Uncertain significance	criteria provided, single submitter
1417039	NM_021728.4(OTX2):c.380G>A (p.Arg127Gln)	OTX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
30023	NM_021728.4(OTX2):c.698A>G (p.Asn233Ser)	OTX2	Uncertain significance	criteria provided, single submitter
313408	NM_021728.4(OTX2):c.*933C>T	OTX2	Uncertain significance	criteria provided, single submitter
313410	NM_021728.4(OTX2):c.*764G>A	OTX2	Uncertain significance	criteria provided, single submitter
313411	NM_021728.4(OTX2):c.*648C>G	OTX2	Uncertain significance	criteria provided, single submitter
313412	NM_021728.4(OTX2):c.*647A>G	OTX2	Uncertain significance	criteria provided, single submitter
313416	NM_021728.4(OTX2):c.*219G>A	OTX2	Uncertain significance	criteria provided, single submitter
313418	NM_021728.4(OTX2):c.380G>T (p.Arg127Leu)	OTX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
313419	NM_021728.4(OTX2):c.380G>C (p.Arg127Pro)	OTX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
313424	NM_021728.4(OTX2):c.-119-65G>T	OTX2	Uncertain significance	criteria provided, single submitter
3576630	NM_021728.4(OTX2):c.439G>A (p.Val147Ile)	OTX2	Uncertain significance	criteria provided, single submitter
880601	NM_021728.4(OTX2):c.96G>T (p.Pro32=)	OTX2	Uncertain significance	criteria provided, single submitter
881431	NM_021728.4(OTX2):c.*1018T>C	OTX2	Uncertain significance	criteria provided, single submitter
881432	NM_021728.4(OTX2):c.*993G>C	OTX2	Uncertain significance	criteria provided, single submitter
881494	NM_021728.4(OTX2):c.713A>T (p.His238Leu)	OTX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
881870	NM_021728.4(OTX2):c.*667A>C	OTX2	Uncertain significance	criteria provided, single submitter
881937	NM_021728.4(OTX2):c.464C>G (p.Ala155Gly)	OTX2	Uncertain significance	criteria provided, single submitter
883039	NM_021728.4(OTX2):c.*648C>A	OTX2	Uncertain significance	criteria provided, single submitter
883040	NM_021728.4(OTX2):c.*543A>G	OTX2	Uncertain significance	criteria provided, single submitter
883118	NM_021728.4(OTX2):c.406A>G (p.Ser136Gly)	OTX2	Uncertain significance	criteria provided, single submitter
883822	NM_021728.4(OTX2):c.*147G>T	OTX2	Uncertain significance	criteria provided, single submitter
288866	NM_021728.4(OTX2):c.*10G>A	OTX2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
313407	NM_021728.4(OTX2):c.*966A>G	OTX2	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 7 · 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
OTX2	Strong	Autosomal dominant	pituitary hormone deficiency, combined, 6	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
OTX2	Orphanet:178364	Syndromic microphthalmia type 5
OTX2	Orphanet:3157	Septo-optic dysplasia spectrum
OTX2	Orphanet:35612	Nanophthalmos
OTX2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
OTX2	Orphanet:98938	Colobomatous microphthalmia
OTX2	Orphanet:990	Agnathia-holoprosencephaly-situs inversus syndrome
OTX2	Orphanet:99001	Butterfly-shaped pigment dystrophy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
OTX2	HGNC:8522	ENSG00000165588	P32243	Homeobox protein OTX2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OTX2	Homeobox protein OTX2	Transcription factor probably involved in the development of the brain and the sense organs.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OTX2	Transcription factor	no		HD, Otx2_TF, Otx_TF

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
pigmented layer of retina	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OTX2	62	broad	marker	secondary oocyte, oocyte, pigmented layer of retina

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OTX2	2,368

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OTX2	P32243	60.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 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
Formation of the posterior neural plate	1	1142.0×	1e-03	OTX2
Formation of the anterior neural plate	1	1038.2×	1e-03	OTX2

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
regulation of fibroblast growth factor receptor signaling pathway	1	2407.4×	0.003	OTX2
positive regulation of gastrulation	1	2407.4×	0.003	OTX2
primitive streak formation	1	1404.3×	0.003	OTX2
positive regulation of embryonic development	1	1123.5×	0.003	OTX2
regulation of smoothened signaling pathway	1	624.1×	0.003	OTX2
dopaminergic neuron differentiation	1	624.1×	0.003	OTX2
midbrain development	1	601.9×	0.003	OTX2
forebrain development	1	351.1×	0.005	OTX2
protein-containing complex assembly	1	113.9×	0.013	OTX2
axon guidance	1	90.6×	0.014	OTX2
positive regulation of DNA-templated transcription	1	27.9×	0.042	OTX2
positive regulation of transcription by RNA polymerase II	1	14.9×	0.073	OTX2
regulation of transcription by RNA polymerase II	1	11.7×	0.086	OTX2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
OTX2	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	1	OTX2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
OTX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.