Temple-Baraitser syndrome

Summary

Temple-Baraitser syndrome (MONDO:0012735) is a disease caused by KCNH1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KCNH1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 31
• Phenotypes (HPO): 48

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

48 HPO clinical features (Orphanet curated; top 48 by frequency):

HPO ID	Term	Frequency
HP:0000154	Wide mouth	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000400	Macrotia	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000445	Wide nose	Frequent (30-79%)
HP:0000527	Long eyelashes	Frequent (30-79%)
HP:0000574	Thick eyebrow	Frequent (30-79%)
HP:0000684	Delayed eruption of teeth	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0001488	Bilateral ptosis	Frequent (30-79%)
HP:0001847	Long hallux	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002058	Myopathic facies	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0010624	Aplastic/hypoplastic toenail	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0011304	Broad thumb	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0012443	Abnormality of brain morphology	Frequent (30-79%)
HP:0012471	Thick vermilion border	Frequent (30-79%)
HP:0010803	Everted upper lip vermilion	Occasional (5-29%)
HP:0010804	Tented upper lip vermilion	Occasional (5-29%)
HP:0012553	Hypoplastic thumbnail	Occasional (5-29%)
HP:0012555	Absent nail of hallux	Occasional (5-29%)
HP:0000194	Open mouth	Occasional (5-29%)
HP:0000212	Gingival overgrowth	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000232	Everted lower lip vermilion	Occasional (5-29%)
HP:0000272	Malar flattening	Occasional (5-29%)
HP:0000293	Full cheeks	Occasional (5-29%)
HP:0000294	Low anterior hairline	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0001802	Absent toenail	Occasional (5-29%)
HP:0001804	Hypoplastic fingernail	Occasional (5-29%)
HP:0006016	Delayed phalangeal epiphyseal ossification	Occasional (5-29%)
HP:0009648	Triangular shaped distal phalanx of the thumb	Occasional (5-29%)
HP:0009660	Short phalanx of the thumb	Occasional (5-29%)
HP:0009882	Short distal phalanx of finger	Occasional (5-29%)
HP:0009890	High anterior hairline	Occasional (5-29%)
HP:0009928	Thick nasal alae	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Temple-Baraitser syndrome
Mondo ID	MONDO:0012735
MeSH	C567516
OMIM	611816
Orphanet	420561
UMLS	C2678486
MedGen	395636
GARD	0009441
Is cancer (heuristic)	no

Also known as: mental retardation, severe, and absent nails of hallux and pollex · severe intellectual disability and absent nails of hallux and pollex · severe intellectual disability-aplasia/hypoplasia of thumb and hallux syndrome · severe mental retardation and absent nails of hallux and pollex · Temple-Baraitser syndrome · TMBTS

Data availability: 31 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › KCNH1 associated disorder › Temple-Baraitser syndrome

Related subtypes (1): Zimmermann-Laband syndrome 1

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

31 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 5 pathogenic, 4 conflicting classifications of pathogenicity, 3 benign/likely benign, 3 pathogenic/likely pathogenic, 2 benign, 1 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1493344	NM_172362.3(KCNH1):c.1069C>T (p.Arg357Trp)	KCNH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162520	NM_172362.3(KCNH1):c.1480A>G (p.Ile494Val)	KCNH1	Pathogenic	criteria provided, multiple submitters, no conflicts
162521	NM_172362.3(KCNH1):c.1546C>T (p.Leu516Phe)	KCNH1	Pathogenic	no assertion criteria provided
162522	NM_172362.3(KCNH1):c.1508A>G (p.Gln503Arg)	KCNH1	Pathogenic	no assertion criteria provided
162523	NM_172362.3(KCNH1):c.651G>C (p.Lys217Asn)	KCNH1	Pathogenic	no assertion criteria provided
183418	NM_172362.3(KCNH1):c.1486G>A (p.Gly496Arg)	KCNH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279981	NM_172362.3(KCNH1):c.1070G>A (p.Arg357Gln)	KCNH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449572	NM_172362.3(KCNH1):c.1465C>T (p.Leu489Phe)	KCNH1	Pathogenic	criteria provided, multiple submitters, no conflicts
4530651	NM_172362.3(KCNH1):c.1070G>T (p.Arg357Leu)	KCNH1	Likely pathogenic	no assertion criteria provided
1213775	NM_172362.3(KCNH1):c.2054C>T (p.Thr685Met)	KCNH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1216384	NM_172362.3(KCNH1):c.2482G>A (p.Gly828Arg)	KCNH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1418174	NM_172362.3(KCNH1):c.2392G>A (p.Val798Ile)	KCNH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1600068	NM_172362.3(KCNH1):c.2162T>C (p.Met721Thr)	KCNH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029267	NM_172362.3(KCNH1):c.2206C>G (p.Pro736Ala)	KCNH1	Uncertain significance	criteria provided, single submitter
1285479	NM_172362.3(KCNH1):c.1493T>C (p.Val498Ala)	KCNH1	Uncertain significance	criteria provided, single submitter
1306379	NM_172362.3(KCNH1):c.2788A>G (p.Arg930Gly)	KCNH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1307585	NM_172362.3(KCNH1):c.1022G>A (p.Arg341Lys)	KCNH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1339058	NM_172362.3(KCNH1):c.1180G>A (p.Ala394Thr)	KCNH1	Uncertain significance	criteria provided, single submitter
1426249	NM_172362.3(KCNH1):c.2930A>G (p.Gln977Arg)	KCNH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1691262	NM_172362.3(KCNH1):c.338T>C (p.Ile113Thr)	KCNH1	Uncertain significance	criteria provided, single submitter
1699286	NM_172362.3(KCNH1):c.2735A>C (p.His912Pro)	KCNH1	Uncertain significance	criteria provided, single submitter
3234026	NM_172362.3(KCNH1):c.1201G>C (p.Gly401Arg)	KCNH1	Uncertain significance	criteria provided, single submitter
3891442	NM_172362.3(KCNH1):c.2198C>T (p.Pro733Leu)	KCNH1	Uncertain significance	criteria provided, single submitter
587447	NM_172362.3(KCNH1):c.1034G>C (p.Gly345Ala)	KCNH1	Uncertain significance	criteria provided, single submitter
689343	NM_172362.3(KCNH1):c.2265G>C (p.Glu755Asp)	KCNH1	Uncertain significance	criteria provided, single submitter
1174747	NM_172362.3(KCNH1):c.80-19dup	KCNH1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1206068	NM_172362.3(KCNH1):c.80-6del	KCNH1	Benign	criteria provided, multiple submitters, no conflicts
1243506	NM_172362.3(KCNH1):c.2136T>C (p.Asp712=)	KCNH1	Benign	criteria provided, multiple submitters, no conflicts
1919735	NM_172362.3(KCNH1):c.2829A>C (p.Lys943Asn)	KCNH1	Likely benign	criteria provided, single submitter
707476	NM_172362.3(KCNH1):c.2448G>A (p.Ala816=)	KCNH1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
KCNH1	Strong	Autosomal dominant	Temple-Baraitser syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNH1	Orphanet:3473	Zimmermann-Laband syndrome
KCNH1	Orphanet:420561	Temple-Baraitser syndrome

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
KCNH1	HGNC:6250	ENSG00000143473	O95259	Voltage-gated delayed rectifier potassium channel KCNH1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNH1	Voltage-gated delayed rectifier potassium channel KCNH1	Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel that mediates outward-rectifying potassium currents which, on depolarization, reaches a steady-state level and do not inactivate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNH1	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C

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
Brodmann (1909) area 9	1
male germ line stem cell (sensu Vertebrata) in testis	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNH1	154	broad	marker	Brodmann (1909) area 9, prefrontal cortex, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNH1	1,109

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNH1	O95259	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Voltage gated Potassium channels	1	243.0×	0.011	KCNH1
Potassium Channels	1	134.3×	0.011	KCNH1
Neuronal System	1	44.3×	0.023	KCNH1

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
myoblast fusion	1	601.9×	0.008	KCNH1
regulation of membrane potential	1	230.8×	0.008	KCNH1
cellular response to calcium ion	1	200.6×	0.008	KCNH1
potassium ion transport	1	191.5×	0.008	KCNH1
potassium ion transmembrane transport	1	135.9×	0.009	KCNH1
regulation of cell population proliferation	1	115.4×	0.009	KCNH1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNH1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNH1	24	Binding:23, Toxicity:1

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	1	KCNH1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
KCNH1	24	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.