Congenital hypothalamic hamartoma syndrome

Summary

Congenital hypothalamic hamartoma syndrome (MONDO:0009436) is a disease caused by SMO (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: SMO (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 39

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital hypothalamic hamartoma syndrome
Mondo ID	MONDO:0009436
MeSH	C537158
OMIM	241800
Orphanet	2113
ICD-11	2057991470
NCIT	C4385
SNOMED CT	237714006
UMLS	C5435677
MedGen	1724922
GARD	0002934
Is cancer (heuristic)	no

Also known as: congenital hypothalamic hamartoma syndrome · hamartoma of hypothalamus · hamartoma of the hypothalamus · hypothalamic hamartoma · hypothalamic hamartomas · Pallister-Hall-like syndrome

Data availability: 39 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Pallister-Hall syndrome › congenital hypothalamic hamartoma syndrome

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

39 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 7 pathogenic, 4 benign, 3 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1804042	NM_144643.4(SCLT1):c.1043del (p.Ser348fs)	SCLT1	Pathogenic	criteria provided, single submitter
975032	NM_005631.5(SMO):c.2291_2292del (p.Gln764fs)	SMO	Pathogenic	no assertion criteria provided
975033	NM_005631.5(SMO):c.781C>T (p.Arg261Cys)	SMO	Pathogenic	no assertion criteria provided
975034	NM_005631.5(SMO):c.1339G>T (p.Glu447Ter)	SMO	Pathogenic	no assertion criteria provided
975035	NM_005631.5(SMO):c.1727G>A (p.Arg576Gln)	SMO	Pathogenic	no assertion criteria provided
975036	NM_005631.5(SMO):c.1726C>T (p.Arg576Trp)	SMO	Pathogenic	criteria provided, single submitter
975037	NM_005631.5(SMO):c.1285A>T (p.Ile429Phe)	SMO	Pathogenic	no assertion criteria provided
1804041	NM_144643.4(SCLT1):c.2060dup (p.Asn687fs)	SCLT1	Likely pathogenic	criteria provided, single submitter
982409	NM_005631.5(SMO):c.754T>C (p.Phe252Leu)	SMO	Likely pathogenic	criteria provided, single submitter
982410	NM_005631.5(SMO):c.1198C>T (p.Arg400Cys)	SMO	Likely pathogenic	criteria provided, single submitter
265180	NM_000168.6(GLI3):c.241G>A (p.Glu81Lys)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265182	NM_000168.6(GLI3):c.3118G>A (p.Glu1040Lys)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135262	NM_005631.5(SMO):c.2314C>T (p.Arg772Cys)	SMO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
435332	NM_000168.6(GLI3):c.3284A>G (p.Asp1095Gly)	GLI3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2672141	NM_005631.5(SMO):c.173C>T (p.Pro58Leu)	LOC129999303	Uncertain significance	criteria provided, single submitter
1333308	NM_005631.5(SMO):c.1792G>A (p.Gly598Arg)	SMO	Uncertain significance	criteria provided, single submitter
135265	NM_005631.5(SMO):c.517C>T (p.Arg173Cys)	SMO	Uncertain significance	criteria provided, single submitter
135576	NM_005631.5(SMO):c.2057C>T (p.Ala686Val)	SMO	Uncertain significance	criteria provided, single submitter
2436204	NM_005631.5(SMO):c.1798G>A (p.Val600Met)	SMO	Uncertain significance	criteria provided, single submitter
2443394	NM_005631.5(SMO):c.2126G>A (p.Arg709Gln)	SMO	Uncertain significance	criteria provided, multiple submitters, no conflicts
2499846	NM_005631.5(SMO):c.385G>A (p.Val129Ile)	SMO	Uncertain significance	criteria provided, multiple submitters, no conflicts
2579485	NM_005631.5(SMO):c.591G>A (p.Leu197=)	SMO	Uncertain significance	criteria provided, multiple submitters, no conflicts
2672174	NM_005631.5(SMO):c.1358-3C>T	SMO	Uncertain significance	criteria provided, single submitter
3237387	NM_005631.5(SMO):c.979G>A (p.Ala327Thr)	SMO	Uncertain significance	criteria provided, single submitter
3237435	NM_005631.5(SMO):c.244G>C (p.Val82Leu)	SMO	Uncertain significance	criteria provided, multiple submitters, no conflicts
3600448	NM_005631.5(SMO):c.413G>A (p.Arg138Gln)	SMO	Uncertain significance	criteria provided, single submitter
3600465	NM_005631.5(SMO):c.2029A>G (p.Lys677Glu)	SMO	Uncertain significance	criteria provided, single submitter
3600496	NM_005631.5(SMO):c.2062C>T (p.Pro688Ser)	SMO	Uncertain significance	criteria provided, single submitter
3892521	NM_005631.5(SMO):c.869G>A (p.Arg290His)	SMO	Uncertain significance	criteria provided, single submitter
3958877	NM_005631.5(SMO):c.1534C>T (p.Arg512Cys)	SMO	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 11 · 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
SMO	Strong	Autosomal recessive	congenital hypothalamic hamartoma syndrome	9
SMOX	Strong	Autosomal recessive	congenital hypothalamic hamartoma syndrome	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMO	Orphanet:1553	Curry-Jones syndrome
SMO	Orphanet:2495	Meningioma
SMO	Orphanet:388	Hirschsprung disease
SCLT1	Orphanet:110	Bardet-Biedl syndrome
GLI3	Orphanet:36	Acrocallosal syndrome
GLI3	Orphanet:380	Greig cephalopolysyndactyly syndrome
GLI3	Orphanet:672	Pallister-Hall syndrome
GLI3	Orphanet:93322	Isolated tibial hemimelia
GLI3	Orphanet:93334	Postaxial polydactyly type A
GLI3	Orphanet:93335	Postaxial polydactyly type B
GLI3	Orphanet:93338	Polysyndactyly

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
SMO	HGNC:11119	ENSG00000128602	Q99835	Protein smoothened	gencc,clinvar
SMOX	HGNC:15862	ENSG00000088826	Q9NWM0	Spermine oxidase	gencc,clinvar
SCLT1	HGNC:26406	ENSG00000151466	Q96NL6	Sodium channel and clathrin linker 1	clinvar
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMO	Protein smoothened	G protein-coupled receptor which associates with the patched protein (PTCH) to transduce hedgehog protein signaling.
SMOX	Spermine oxidase	Flavoenzyme which catalyzes the oxidation of spermine to spermidine.
SCLT1	Sodium channel and clathrin linker 1	Adapter protein that links SCN10A to clathrin.
GLI3	Transcriptional activator GLI3	Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · 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
GPCR	1	6.0×	0.538
Enzyme (other)	1	3.0×	0.538
Transcription factor	1	2.1×	0.538
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMO	GPCR	yes		Frizzled/Smoothened_7TM, Frizzled/SFRP, GPCR_2-like_7TM
SMOX	Enzyme (other)	yes	1.5.3.16	Amino_oxidase, FAD/NAD-bd_sf, Flavin_monoamine_oxidase
SCLT1	Other/Unknown	no		SCLT1
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

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
ventricular zone	2
left ovary	1
right ovary	1
C1 segment of cervical spinal cord	1
amygdala	1
lower esophagus mucosa	1
buccal mucosa cell	1
leukocyte	1
monocyte	1
olfactory bulb	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMO	225	ubiquitous	marker	ventricular zone, left ovary, right ovary
SMOX	258	ubiquitous	marker	amygdala, lower esophagus mucosa, C1 segment of cervical spinal cord
SCLT1	217	ubiquitous	marker	buccal mucosa cell, monocyte, leukocyte
GLI3	263	ubiquitous	marker	ventricular zone, olfactory bulb, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMO	2,882
GLI3	2,825
SCLT1	1,478
SMOX	717

Intra-cohort edges

A	B	Sources
GLI3	SMO	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMO	Q99835	15
SMOX	Q9NWM0	2
GLI3	P10071	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SCLT1	Q96NL6	82.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Hedgehog ‘off’ state	2	89.2×	0.002	SMO, GLI3
Hedgehog ‘on’ state	2	79.3×	0.002	SMO, GLI3
Cilium Assembly	2	54.4×	0.003	SMO, SCLT1
PAOs oxidise polyamines to amines	1	951.7×	0.004	SMOX
Interconversion of polyamines	1	713.8×	0.004	SMOX
Organelle biogenesis and maintenance	2	33.0×	0.004	SMO, SCLT1
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	407.9×	0.006	GLI3
Activation of SMO	1	158.6×	0.014	SMO
BBSome-mediated cargo-targeting to cilium	1	124.1×	0.016	SMO
RUNX2 regulates osteoblast differentiation	1	114.2×	0.016	GLI3
Cargo trafficking to the periciliary membrane	1	62.1×	0.026	SMO
GLI3 is processed to GLI3R by the proteasome	1	56.0×	0.027	GLI3
Class B/2 (Secretin family receptors)	1	47.6×	0.028	SMO
Signaling by Hedgehog	1	46.0×	0.028	SMO
Anchoring of the basal body to the plasma membrane	1	28.3×	0.042	SCLT1
GPCR ligand binding	1	16.0×	0.069	SMO
Signaling by GPCR	1	10.0×	0.102	SMO
Signal Transduction	1	2.5×	0.339	SMO

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
positive regulation of neuroblast proliferation	2	290.6×	0.002	SMO, GLI3
positive regulation of protein import into nucleus	2	210.7×	0.002	SMO, GLI3
neuroblast proliferation	2	183.2×	0.002	SMO, GLI3
ventral midline determination	1	4213.0×	0.002	SMO
lateral ganglionic eminence cell proliferation	1	4213.0×	0.002	GLI3
lambdoid suture morphogenesis	1	4213.0×	0.002	GLI3
sagittal suture morphogenesis	1	4213.0×	0.002	GLI3
mammary gland specification	1	4213.0×	0.002	GLI3
anterior semicircular canal development	1	4213.0×	0.002	GLI3
lateral semicircular canal development	1	4213.0×	0.002	GLI3
mesenchymal to epithelial transition involved in metanephric renal vesicle formation	1	4213.0×	0.002	SMO
regulation of heart morphogenesis	1	4213.0×	0.002	SMO
odontogenesis of dentin-containing tooth	2	150.5×	0.002	SMO, GLI3
smoothened signaling pathway	2	90.6×	0.002	SMO, GLI3
anterior/posterior pattern specification	2	90.6×	0.002	SMO, GLI3
protein import into nucleus	2	72.0×	0.002	SMO, GLI3
smoothened signaling pathway involved in ventral spinal cord interneuron specification	1	2106.5×	0.003	GLI3
smoothened signaling pathway involved in spinal cord motor neuron cell fate specification	1	2106.5×	0.003	GLI3
negative regulation of hair follicle development	1	2106.5×	0.003	SMO
larynx morphogenesis	1	2106.5×	0.003	GLI3
osteoblast differentiation	2	60.6×	0.003	SMO, GLI3
polyamine catabolic process	1	1404.3×	0.003	SMOX
nose morphogenesis	1	1404.3×	0.003	GLI3
spermine catabolic process	1	1404.3×	0.003	SMOX
negative regulation of alpha-beta T cell differentiation	1	1404.3×	0.003	GLI3
frontal suture morphogenesis	1	1404.3×	0.003	GLI3
cell differentiation involved in kidney development	1	1404.3×	0.003	GLI3
pancreas morphogenesis	1	1404.3×	0.003	SMO
hindgut morphogenesis	1	1053.2×	0.004	GLI3
regulation of cerebellar granule cell precursor proliferation	1	1053.2×	0.004	SMO

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
SMO	INFIGRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMO	11	4
SMOX	0	0
SCLT1	0	0
GLI3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INFIGRATINIB	4	SMO
SONIDEGIB	4	SMO
SONIDEGIB PHOSPHATE	4	SMO
VISMODEGIB	4	SMO
LINIFANIB	3	SMO
PATIDEGIB	3	SMO
FORETINIB	2	SMO
CEP-32496	2	SMO
TALADEGIB	2	SMO
TAK-441	1	SMO
LEQ506	1	SMO

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SMO	131	Binding:111, Functional:20
SMOX	18	Binding:15, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SMOX	1.5.3.16	spermine oxidase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SMO	131

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

11 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)
INFIGRATINIB	4	SMO
SONIDEGIB	4	SMO
SONIDEGIB PHOSPHATE	4	SMO
VISMODEGIB	4	SMO
LINIFANIB	3	SMO
PATIDEGIB	3	SMO
FORETINIB	2	SMO
CEP-32496	2	SMO
TALADEGIB	2	SMO
TAK-441	1	SMO
LEQ506	1	SMO

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SMO
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	SMOX
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SCLT1, GLI3

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)
GLI3	0	SMO
SMOX	18	—
SCLT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.