Clark-Baraitser syndrome

Summary

Clark-Baraitser syndrome (MONDO:0030914) is a disease caused by TRIP12 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TRIP12 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 135

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Clark-Baraitser syndrome
Mondo ID	MONDO:0030914
MeSH	C536208
OMIM	300602, 617752
Orphanet	600731
DOID	DOID:0080234
UMLS	C2931130
MedGen	443983
GARD	0009994
Is cancer (heuristic)	no

Also known as: autosomal dominant mental retardation 49 · Clark-Baraitser syndrome · intellectual disability, autosomal dominant 49 · intellectual disability, tall stature, obesity, macrocephaly and typical facial features · mental retardation, autosomal dominant 49 · mental retardation, tall stature, obesity, macrocephaly and typical facial features · MRD49

Data availability: 135 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › autosomal dominant non-syndromic intellectual disability › Clark-Baraitser syndrome

Related subtypes (25): intellectual disability, autosomal dominant 22, neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language, intellectual disability, autosomal dominant 33, intellectual disability, autosomal dominant 34, intellectual disability, autosomal dominant 41, intellectual disability, autosomal dominant 43, intellectual disability, autosomal dominant 58, intellectual disability, autosomal dominant 45, intellectual disability, autosomal dominant 46, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 50, intellectual disability, autosomal dominant 51, intellectual disability, autosomal dominant 52, intellectual disability, autosomal dominant 53, intellectual disability, autosomal dominant 54, intellectual disability, autosomal dominant 55, with seizures, intellectual disability, autosomal dominant 56, intellectual developmental disorder 61, intellectual developmental disorder 59, intellectual developmental disorder 60 with seizures, intellectual developmental disorder 62, intellectual developmental disorder, autosomal dominant 63, with macrocephaly, Coffin-Siris syndrome 6, intellectual disability, autosomal dominant 57, intellectual developmental disorder, autosomal dominant 73

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

135 retrieved; paginated sample, class counts are floors:

62 uncertain significance, 32 pathogenic, 17 likely pathogenic, 11 conflicting classifications of pathogenicity, 5 benign, 4 pathogenic/likely pathogenic, 2 likely benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028708	NM_001348323.3(TRIP12):c.5459dup (p.Ala1821fs)	TRIP12	Pathogenic	criteria provided, single submitter
1098288	NM_001348323.3(TRIP12):c.4904G>A (p.Arg1635Gln)	TRIP12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1164053	NM_001348323.3(TRIP12):c.2378_2379insT (p.Val794fs)	TRIP12	Pathogenic	no assertion criteria provided
1285508	NM_001348323.3(TRIP12):c.4726del (p.Ser1576fs)	TRIP12	Pathogenic	criteria provided, single submitter
1326281	NM_001348323.3(TRIP12):c.2776G>T (p.Gly926Ter)	TRIP12	Pathogenic	no assertion criteria provided
1703055	NM_001348323.3(TRIP12):c.3816+2T>A	TRIP12	Pathogenic	criteria provided, single submitter
1709568	NM_001348323.3(TRIP12):c.4216-2A>G	TRIP12	Pathogenic	criteria provided, single submitter
1992332	NM_001348323.3(TRIP12):c.5452_5453delinsAAACAAATTGTAAATTGTACCA (p.Pro1818fs)	TRIP12	Pathogenic	criteria provided, single submitter
2438549	NM_001348323.3(TRIP12):c.5675del (p.Asn1892fs)	TRIP12	Pathogenic	criteria provided, single submitter
2446125	NM_001348323.3(TRIP12):c.3787C>T (p.Arg1263Ter)	TRIP12	Pathogenic	criteria provided, single submitter
2498135	NM_001348323.3(TRIP12):c.2065C>T (p.Gln689Ter)	TRIP12	Pathogenic	criteria provided, multiple submitters, no conflicts
2578429	NM_001348323.3(TRIP12):c.3869del (p.Leu1290fs)	TRIP12	Pathogenic	criteria provided, single submitter
2579158	NM_001348323.3(TRIP12):c.1012C>T (p.Gln338Ter)	TRIP12	Pathogenic	criteria provided, multiple submitters, no conflicts
2584503	NM_001348323.3(TRIP12):c.4317del (p.Gln1440fs)	TRIP12	Pathogenic	criteria provided, single submitter
2627078	NM_001348323.3(TRIP12):c.1787_1800del (p.Met596fs)	TRIP12	Pathogenic	no assertion criteria provided
3063732	NM_001348323.3(TRIP12):c.638_639del (p.Arg213fs)	TRIP12	Pathogenic	criteria provided, single submitter
3254927	NM_001348323.3(TRIP12):c.2624del (p.Pro875fs)	TRIP12	Pathogenic	criteria provided, single submitter
3256549	NM_001348323.3(TRIP12):c.3551del (p.Asn1184fs)	TRIP12	Pathogenic	criteria provided, single submitter
3382573	NM_001348323.3(TRIP12):c.5538_5566del (p.Glu1846fs)	TRIP12	Pathogenic	criteria provided, single submitter
4082281	NM_001348323.3(TRIP12):c.1969del (p.Gln657fs)	TRIP12	Pathogenic	criteria provided, single submitter
446136	NM_001348323.3(TRIP12):c.586_587del (p.Ser196fs)	TRIP12	Pathogenic	criteria provided, multiple submitters, no conflicts
446137	NM_001348323.3(TRIP12):c.3482+1G>A	TRIP12	Pathogenic	no assertion criteria provided
446138	NM_001348323.3(TRIP12):c.5009G>A (p.Arg1670Gln)	TRIP12	Pathogenic	no assertion criteria provided
446139	NM_001348323.3(TRIP12):c.3671_3672del (p.Val1223_Ser1224insTer)	TRIP12	Pathogenic	criteria provided, single submitter
446140	NM_001348323.3(TRIP12):c.3204dup (p.Gly1069fs)	TRIP12	Pathogenic	criteria provided, single submitter
446141	NM_001348323.3(TRIP12):c.3968+1G>A	TRIP12	Pathogenic	no assertion criteria provided
4819459	NM_001348323.3(TRIP12):c.1080del (p.Ser361fs)	TRIP12	Pathogenic	criteria provided, single submitter
489242	NM_001348323.3(TRIP12):c.1651C>T (p.Arg551Ter)	TRIP12	Pathogenic	criteria provided, multiple submitters, no conflicts
619982	NM_001348323.3(TRIP12):c.4318C>T (p.Gln1440Ter)	TRIP12	Pathogenic	criteria provided, single submitter
801907	NM_001348323.3(TRIP12):c.3166C>T (p.Gln1056Ter)	TRIP12	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
TRIP12	Definitive	Autosomal dominant	Clark-Baraitser syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRIP12	Orphanet:528084	Non-specific syndromic intellectual disability

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
TRIP12	HGNC:12306	ENSG00000153827	Q14669	E3 ubiquitin-protein ligase TRIP12	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRIP12	E3 ubiquitin-protein ligase TRIP12	E3 ubiquitin-protein ligase involved in ubiquitin fusion degradation (UFD) pathway and regulation of DNA repair.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRIP12	Enzyme (other)	yes	2.3.2.26	HECT_dom, WWE_dom, ARM-like

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
calcaneal tendon	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRIP12	302	ubiquitous	marker	calcaneal tendon, male germ cell, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRIP12	4,193

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRIP12	Q14669	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.027	TRIP12

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
heterochromatin boundary formation	1	8426.0×	9e-04	TRIP12
DNA repair-dependent chromatin remodeling	1	674.1×	0.006	TRIP12
regulation of embryonic development	1	330.4×	0.008	TRIP12
protein polyubiquitination	1	115.4×	0.017	TRIP12
ubiquitin-dependent protein catabolic process	1	74.2×	0.019	TRIP12
DNA repair	1	63.8×	0.019	TRIP12
DNA damage response	1	53.5×	0.019	TRIP12
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.019	TRIP12

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
TRIP12	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TRIP12	2.3.2.26	HECT-type E3 ubiquitin transferase

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	TRIP12
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)
TRIP12	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.