Birk-Barel syndrome

Summary

Birk-Barel syndrome (MONDO:0012856) is a disease caused by KCNK9 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KCNK9 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 18
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0000194	Open mouth	Frequent (30-79%)
HP:0000268	Dolichocephaly	Frequent (30-79%)
HP:0000289	Broad philtrum	Frequent (30-79%)
HP:0000322	Short philtrum	Frequent (30-79%)
HP:0000338	Hypomimic face	Frequent (30-79%)
HP:0000341	Narrow forehead	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000411	Protruding ear	Frequent (30-79%)
HP:0000446	Narrow nasal bridge	Frequent (30-79%)
HP:0000455	Broad nasal tip	Frequent (30-79%)
HP:0000752	Hyperactivity	Frequent (30-79%)
HP:0000960	Sacral dimple	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001319	Neonatal hypotonia	Frequent (30-79%)
HP:0001618	Dysphonia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002553	Highly arched eyebrow	Frequent (30-79%)
HP:0002705	High, narrow palate	Frequent (30-79%)
HP:0010804	Tented upper lip vermilion	Frequent (30-79%)
HP:0011081	Incisor macrodontia	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012471	Thick vermilion border	Frequent (30-79%)
HP:0030197	Fatigable weakness of skeletal muscles	Frequent (30-79%)
HP:0030200	Fatiguable weakness of proximal limb muscles	Frequent (30-79%)
HP:0040288	Nasogastric tube feeding	Frequent (30-79%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001308	Tongue fasciculations	Occasional (5-29%)
HP:0005060	Limited elbow flexion/extension	Occasional (5-29%)
HP:0005879	Congenital finger flexion contractures	Occasional (5-29%)
HP:0007002	Motor axonal neuropathy	Occasional (5-29%)
HP:0007269	Spinal muscular atrophy	Occasional (5-29%)
HP:0008366	Foot joint contracture	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Birk-Barel syndrome
Mondo ID	MONDO:0012856
MeSH	C567357
OMIM	612292
Orphanet	166108
DOID	DOID:0050675
SNOMED CT	764861005
UMLS	C2676770
MedGen	393583
GARD	0010358
NORD	1896
Is cancer (heuristic)	no

Also known as: Birk Barel intellectual disability dysmorphism syndrome · Birk Barel mental retardation dysmorphism syndrome · BIRK-Barel intellectual disability dysmorphism syndrome · BIRK-Barel mental retardation dysmorphism syndrome · Birk-Barel syndrome · intellectual disability-hypotonia-facial dysmorphism syndrome · KCNK9 Imprinting Syndrome · mental retardation with hypotonia and Facial Dysmorphism

Data availability: 18 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Birk-Barel syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid 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

18 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 4 likely pathogenic, 2 pathogenic, 2 conflicting classifications of pathogenicity, 1 not provided, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
397636	NM_001282534.2(KCNK9):c.706G>C (p.Gly236Arg)	KCNK9	Pathogenic	no assertion criteria provided
4741	NM_001282534.2(KCNK9):c.706G>A (p.Gly236Arg)	KCNK9	Pathogenic	criteria provided, multiple submitters, no conflicts
585073	NM_001366145.2(TRPM3):c.3004G>A (p.Val1002Met)	TRPM3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3256793	NM_001282534.2(KCNK9):c.477G>A (p.Met159Ile)	KCNK9	Likely pathogenic	no assertion criteria provided
372887	NM_001282534.2(KCNK9):c.392G>A (p.Arg131His)	KCNK9	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293529	NM_001282534.2(KCNK9):c.716T>C (p.Leu239Pro)	KCNK9	Likely pathogenic	criteria provided, single submitter
982629	NM_001282534.2(KCNK9):c.710C>A (p.Ala237Asp)	KCNK9	Likely pathogenic	criteria provided, single submitter
452563	NM_001282534.2(KCNK9):c.25C>G (p.Leu9Val)	KCNK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
983124	NM_001282534.2(KCNK9):c.391C>T (p.Arg131Cys)	KCNK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033821	NM_001282534.2(KCNK9):c.467T>C (p.Met156Thr)	KCNK9	Uncertain significance	criteria provided, single submitter
1304328	NM_001282534.2(KCNK9):c.932C>A (p.Ser311Ter)	KCNK9	Uncertain significance	criteria provided, multiple submitters, no conflicts
2921202	NM_001282534.2(KCNK9):c.973C>A (p.His325Asn)	KCNK9	Uncertain significance	criteria provided, single submitter
3376668	NM_001282534.2(KCNK9):c.1055G>T (p.Ser352Ile)	KCNK9	Uncertain significance	criteria provided, single submitter
3595286	NM_001282534.2(KCNK9):c.1109G>A (p.Arg370His)	KCNK9	Uncertain significance	criteria provided, single submitter
3777194	NM_001282534.2(KCNK9):c.846_854dup (p.Pro284_Arg285insSerArgPro)	KCNK9	Uncertain significance	criteria provided, single submitter
634574	NM_001282534.2(KCNK9):c.223G>A (p.Gly75Ser)	KCNK9	Uncertain significance	criteria provided, single submitter
989376	NM_001282534.2(KCNK9):c.599T>C (p.Ile200Thr)	KCNK9	Uncertain significance	criteria provided, multiple submitters, no conflicts
2672078	NM_001282534.2(KCNK9):c.373T>C (p.Phe125Leu)	KCNK9	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
KCNK9	Strong	Autosomal dominant	Birk-Barel syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNK9	Orphanet:166108	Birk-Barel syndrome
TRPM3	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNK9	HGNC:6283	ENSG00000169427	Q9NPC2	Potassium channel subfamily K member 9	gencc,clinvar
TRPM3	HGNC:17992	ENSG00000083067	Q9HCF6	Transient receptor potential cation channel subfamily M member 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNK9	Potassium channel subfamily K member 9	K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization.
TRPM3	Transient receptor potential cation channel subfamily M member 3	Constitutively active, non-selective divalent cation-conducting channel that is permeable to Ca(2+), Mn(2+), and Mg(2+), with a high permeability for Ca(2+).

Protein-family classification

Druggable: 2 · 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	2	111.5×	8e-05

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNK9	Ion channel	yes		2pore_dom_K_chnl_TASK, 2pore_dom_K_chnl, KCNK9
TRPM3	Ion channel	yes		Ion_trans_dom, TRPM_tetra, TRPM_tetra_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
dorsal motor nucleus of vagus nerve	1
medial globus pallidus	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNK9	137	tissue_specific	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
TRPM3	193	broad	marker	pigmented layer of retina, dorsal motor nucleus of vagus nerve, medial globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNK9	1,496
TRPM3	1,184

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNK9	Q9NPC2	22
TRPM3	Q9HCF6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TWIK-releated acid-sensitive K+ channel (TASK)	1	2855.0×	0.003	KCNK9
Tandem pore domain potassium channels	1	475.8×	0.008	KCNK9
Phase 4 - resting membrane potential	1	300.5×	0.009	KCNK9
TRP channels	1	203.9×	0.010	TRPM3
Potassium Channels	1	67.2×	0.024	KCNK9
Cardiac conduction	1	54.4×	0.024	KCNK9
Muscle contraction	1	38.6×	0.029	KCNK9
Neuronal System	1	22.1×	0.045	KCNK9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of aldosterone secretion	1	8426.0×	0.002	KCNK9
regulation of action potential firing rate	1	2808.7×	0.002	KCNK9
regulation of resting membrane potential	1	648.1×	0.006	KCNK9
monoatomic cation transport	1	383.0×	0.006	TRPM3
cellular response to acidic pH	1	366.4×	0.006	KCNK9
zinc ion transmembrane transport	1	351.1×	0.006	TRPM3
monoatomic cation transmembrane transport	1	312.1×	0.006	TRPM3
potassium ion import across plasma membrane	1	183.2×	0.009	KCNK9
protein homotetramerization	1	118.7×	0.012	TRPM3
calcium ion transmembrane transport	1	105.3×	0.012	TRPM3
potassium ion transport	1	95.8×	0.012	KCNK9
calcium ion transport	1	90.6×	0.012	TRPM3
visual perception	1	39.8×	0.025	KCNK9

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
KCNK9	MIBEFRADIL DIHYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNK9	4	4
TRPM3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIBEFRADIL DIHYDROCHLORIDE	4	KCNK9
LORATADINE	4	KCNK9
BAFREKALANT	2	KCNK9
CLOROTEPINE	2	KCNK9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNK9	33	Binding:31, Functional:2
TRPM3	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 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)
MIBEFRADIL DIHYDROCHLORIDE	4	KCNK9
LORATADINE	4	KCNK9
BAFREKALANT	2	KCNK9
CLOROTEPINE	2	KCNK9

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNK9
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TRPM3
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)
TRPM3	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.