KBG syndrome

Summary

KBG syndrome (MONDO:0007846) is a disease caused by ANKRD11 (GenCC Definitive), with 10 cohort genes and 3 clinical trials. Top therapeutic interventions include methylphenidate hydrochloride.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ANKRD11 (GenCC Definitive)
• Cohort genes: 10
• ClinVar variants: 2,279
• Phenotypes (HPO): 40
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		164	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000400	Macrotia	Frequent (30-79%)
HP:0000426	Prominent nasal bridge	Frequent (30-79%)
HP:0000430	Underdeveloped nasal alae	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000465	Webbed neck	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000506	Telecanthus	Frequent (30-79%)
HP:0000574	Thick eyebrow	Frequent (30-79%)
HP:0000637	Long palpebral fissure	Frequent (30-79%)
HP:0000664	Synophrys	Frequent (30-79%)
HP:0000677	Oligodontia	Frequent (30-79%)
HP:0000891	Cervical ribs	Frequent (30-79%)
HP:0000954	Single transverse palmar crease	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001566	Widely-spaced maxillary central incisors	Frequent (30-79%)
HP:0001572	Macrodontia	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000219	Thin upper lip vermilion	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000325	Triangular face	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0002942	Thoracic kyphosis	Frequent (30-79%)
HP:0002948	Vertebral fusion	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0008513	Bilateral conductive hearing impairment	Frequent (30-79%)
HP:0010720	Abnormal hair pattern	Frequent (30-79%)
HP:0011842	Abnormality of skeletal morphology	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012725	Cutaneous syndactyly	Frequent (30-79%)
HP:0040019	Finger clinodactyly	Frequent (30-79%)
HP:0000311	Round face	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0002353	EEG abnormality	Occasional (5-29%)
HP:0004474	Persistent open anterior fontanelle	Occasional (5-29%)
HP:0045017	Congenital malformation of the left heart	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	KBG syndrome
Mondo ID	MONDO:0007846
MeSH	C537015
OMIM	148050
Orphanet	2332
DOID	DOID:14780
ICD-11	465550090
SNOMED CT	711156009
UMLS	C0220687
MedGen	66317
GARD	0000082
NORD	1322
Is cancer (heuristic)	no

Also known as: KBG syndrome · KBGS · macrodontia, mental retardation, characteristic facies, short stature, and skeletal anomalies · short stature, characteristic facies, macrodontia, intellectual disability, and skeletal anomalies · short stature, characteristic facies, macrodontia, mental retardation, and skeletal anomalies · short stature-facial and skeletal anomalies-intellectual disability-macrodontia syndrome

Data availability: 2,279 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › KBG syndrome

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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

600 retrieved; paginated sample, class counts are floors:

194 uncertain significance, 164 likely benign, 74 pathogenic, 71 conflicting classifications of pathogenicity, 36 benign/likely benign, 28 benign, 26 likely pathogenic, 6 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1341552	NC_000016.9:g.88365786_89584412del1218627	ACSF3	Pathogenic	criteria provided, single submitter
1012411	NM_013275.6(ANKRD11):c.3768_3769del (p.His1256fs)	ANKRD11	Pathogenic	criteria provided, multiple submitters, no conflicts
1027800	NM_013275.6(ANKRD11):c.3651C>A (p.Tyr1217Ter)	ANKRD11	Pathogenic	criteria provided, single submitter
1029215	NM_013275.6(ANKRD11):c.5145C>G (p.Tyr1715Ter)	ANKRD11	Pathogenic	criteria provided, multiple submitters, no conflicts
1031765	NM_013275.6(ANKRD11):c.2793dup (p.Gly932fs)	ANKRD11	Pathogenic	criteria provided, single submitter
1031769	NM_013275.6(ANKRD11):c.5550C>G (p.Tyr1850Ter)	ANKRD11	Pathogenic	criteria provided, multiple submitters, no conflicts
1031770	NM_013275.6(ANKRD11):c.5651C>G (p.Ser1884Ter)	ANKRD11	Pathogenic	criteria provided, multiple submitters, no conflicts
1031774	NM_013275.6(ANKRD11):c.7519C>T (p.Gln2507Ter)	ANKRD11	Pathogenic	criteria provided, multiple submitters, no conflicts
1064442	NM_013275.6(ANKRD11):c.5117del (p.Pro1706fs)	ANKRD11	Pathogenic	criteria provided, single submitter
1065425	NM_013275.6(ANKRD11):c.3843dup (p.Glu1282Ter)	ANKRD11	Pathogenic	criteria provided, single submitter
1065426	NM_013275.6(ANKRD11):c.4396_4397del (p.Arg1466fs)	ANKRD11	Pathogenic	criteria provided, multiple submitters, no conflicts
1068793	NM_013275.6(ANKRD11):c.5117dup (p.Thr1707fs)	ANKRD11	Pathogenic	criteria provided, single submitter
1073378	NM_013275.6(ANKRD11):c.7062dup (p.Ser2355fs)	ANKRD11	Pathogenic	criteria provided, multiple submitters, no conflicts
1164005	NM_013275.6(ANKRD11):c.5647_5651del (p.Phe1883fs)	ANKRD11	Pathogenic	no assertion criteria provided
1172606	NM_013275.6(ANKRD11):c.5494_5495del (p.Arg1832fs)	ANKRD11	Pathogenic	criteria provided, single submitter
1184461	NM_013275.6(ANKRD11):c.3127del (p.Leu1043fs)	ANKRD11	Pathogenic	no assertion criteria provided
1184462	NM_013275.6(ANKRD11):c.980_993del (p.Leu327fs)	ANKRD11	Pathogenic	no assertion criteria provided
1210092	NM_013275.6(ANKRD11):c.7806+1G>T	ANKRD11	Pathogenic	criteria provided, single submitter
1212718	NM_013275.6(ANKRD11):c.2054_2055del (p.Lys685fs)	ANKRD11	Pathogenic	criteria provided, multiple submitters, no conflicts
1215859	NM_013275.6(ANKRD11):c.7192C>T (p.Gln2398Ter)	ANKRD11	Pathogenic	criteria provided, multiple submitters, no conflicts
1251930	NM_013275.6(ANKRD11):c.4055_4058del (p.His1352fs)	ANKRD11	Pathogenic	criteria provided, single submitter
1254536	NM_013275.6(ANKRD11):c.5227C>T (p.Gln1743Ter)	ANKRD11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299327	NM_013275.6(ANKRD11):c.1742_1743del (p.Ser580_Ser581insTer)	ANKRD11	Pathogenic	criteria provided, single submitter
1320081	NM_013275.6(ANKRD11):c.397+1G>A	ANKRD11	Pathogenic	criteria provided, single submitter
1320207	NM_013275.6(ANKRD11):c.226+1G>A	ANKRD11	Pathogenic	criteria provided, single submitter
1323154	NM_013275.6(ANKRD11):c.2288_2289del (p.Glu763fs)	ANKRD11	Pathogenic	criteria provided, single submitter
1333832	NM_013275.6(ANKRD11):c.7144C>T (p.Gln2382Ter)	ANKRD11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341536	NM_013275.6(ANKRD11):c.1232C>A (p.Ser411Ter)	ANKRD11	Pathogenic	criteria provided, single submitter
1341537	NM_013275.6(ANKRD11):c.2523G>A (p.Trp841Ter)	ANKRD11	Pathogenic	criteria provided, multiple submitters, no conflicts
1341539	NM_013275.6(ANKRD11):c.3319_3322del (p.Lys1107fs)	ANKRD11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 32 · 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
ANKRD11	Definitive	Autosomal dominant	KBG syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANKRD11	Orphanet:2332	KBG syndrome
ANKRD11	Orphanet:261250	16q24.3 microdeletion syndrome
TBX1	Orphanet:1727	22q11.2 duplication syndrome
TBX1	Orphanet:3303	Tetralogy of Fallot
TBX1	Orphanet:567	22q11.2 deletion syndrome
TBX1	Orphanet:665044	Common arterial trunk with aortic dominance
TBX1	Orphanet:665058	Common arterial trunk with pulmonary dominance and interrupted aortic arch
TBX1	Orphanet:685017	Combined immunodeficiency due to TBX1 deficiency
KAT6B	Orphanet:3047	Blepharophimosis-intellectual disability syndrome, SBBYS type
KAT6B	Orphanet:85201	Genitopatellar syndrome
COL2A1	Orphanet:137678	Spondyloepiphyseal dysplasia with metatarsal shortening
COL2A1	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL2A1	Orphanet:1856	Spondyloperipheral dysplasia-short ulna syndrome
COL2A1	Orphanet:209867	Autosomal dominant rhegmatogenous retinal detachment
COL2A1	Orphanet:2380	Legg-Calvé-Perthes disease
COL2A1	Orphanet:459051	Spondyloepiphyseal dysplasia, Stanescu type
COL2A1	Orphanet:485	Kniest dysplasia
COL2A1	Orphanet:85166	Platyspondylic dysplasia, Torrance type
COL2A1	Orphanet:85198	Dysspondyloenchondromatosis
COL2A1	Orphanet:86820	Familial avascular necrosis of femoral head
COL2A1	Orphanet:90653	Stickler syndrome type 1
COL2A1	Orphanet:93279	Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis
COL2A1	Orphanet:93296	Achondrogenesis type 2
COL2A1	Orphanet:93297	Hypochondrogenesis
COL2A1	Orphanet:93315	Spondylometaphyseal dysplasia, ‘corner fracture’ type
COL2A1	Orphanet:93316	Spondylometaphyseal dysplasia, Schmidt type
COL2A1	Orphanet:93346	Spondyloepimetaphyseal dysplasia congenita, Strudwick type
COL2A1	Orphanet:94068	Spondyloepiphyseal dysplasia congenita
SETD5	Orphanet:435638	3p25.3 microdeletion syndrome
SETD5	Orphanet:528084	Non-specific syndromic intellectual disability
ACSF3	Orphanet:289504	Combined malonic and methylmalonic acidemia
MVD	Orphanet:79152	Disseminated superficial actinic porokeratosis

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ANKRD11	HGNC:21316	ENSG00000167522	Q6UB99	Ankyrin repeat domain-containing protein 11	gencc,clinvar
TBX1	HGNC:11592	ENSG00000184058	O43435	T-box transcription factor TBX1	clinvar
TTF2	HGNC:12398	ENSG00000116830	Q9UNY4	Transcription termination factor 2	clinvar
KAT6B	HGNC:17582	ENSG00000156650	Q8WYB5	Histone acetyltransferase KAT6B	clinvar
CDK10	HGNC:1770	ENSG00000185324	Q15131	Cyclin-dependent kinase 10	clinvar
COL2A1	HGNC:2200	ENSG00000139219	P02458	Collagen alpha-1(II) chain	clinvar
SETD5	HGNC:25566	ENSG00000168137	Q9C0A6	Histone-lysine N-methyltransferase SETD5	clinvar
ZNF778	HGNC:26479	ENSG00000170100	Q96MU6	Zinc finger protein 778	clinvar
ACSF3	HGNC:27288	ENSG00000176715	Q4G176	Malonate–CoA ligase ACSF3, mitochondrial	clinvar
MVD	HGNC:7529	ENSG00000167508	P53602	Diphosphomevalonate decarboxylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANKRD11	Ankyrin repeat domain-containing protein 11	Chromatin regulator which modulates histone acetylation and gene expression in neural precursor cells.
TBX1	T-box transcription factor TBX1	Transcription factor that plays a key role in cardiovascular development by promoting pharyngeal arch segmentation during embryonic development.
TTF2	Transcription termination factor 2	DsDNA-dependent ATPase which acts as a transcription termination factor by coupling ATP hydrolysis with removal of RNA polymerase II from the DNA template.
KAT6B	Histone acetyltransferase KAT6B	Histone acetyltransferase which may be involved in both positive and negative regulation of transcription.
CDK10	Cyclin-dependent kinase 10	Cyclin-dependent kinase that phosphorylates the transcription factor ETS2 (in vitro) and positively controls its proteasomal degradation (in cells).
COL2A1	Collagen alpha-1(II) chain	Type II collagen is specific for cartilaginous tissues.
SETD5	Histone-lysine N-methyltransferase SETD5	Chromatin regulator required for brain development: acts as a regulator of RNA elongation rate, thereby regulating neural stem cell (NSC) proliferation and synaptic transmission.
ZNF778	Zinc finger protein 778	May be involved in transcriptional regulation.
ACSF3	Malonate–CoA ligase ACSF3, mitochondrial	Catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate, but not acetate, into their respective CoA thioester.
MVD	Diphosphomevalonate decarboxylase	Catalyzes the ATP dependent decarboxylation of (R)-5-diphosphomevalonate to form isopentenyl diphosphate (IPP).

Protein-family classification

Druggable: 2 · Difficult: 5 · Unknown: 3 · Druggable fraction: 0.2

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
Kinase	2	5.5×	0.097
Transcription factor	4	3.3×	0.097
Scaffold/PPI	1	1.7×	0.599
Other/Unknown	3	0.5×	0.976

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANKRD11	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, ANKRD11
TBX1	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
TTF2	Transcription factor	no		SNF2_N, Helicase_C-like, DNA/RNA_helicase_DEAH_CS
KAT6B	Transcription factor	no	2.3.1.48	Znf_PHD, HAT_MYST-type, Histone_H1/H5_H15
CDK10	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
COL2A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
SETD5	Other/Unknown	no		SET_dom, SETD5_SET, SET_dom_sf
ZNF778	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
ACSF3	Other/Unknown	no		AMP-dep_synth/lig_dom, AMP-binding_CS, AMP-bd_C
MVD	Kinase	yes	4.1.1.33	Mev_decarb, Ribsml_uS5_D2-typ_fold_subgr, Ribosomal_Su5_D2-typ_SF

Expression context

Cohort genes with no expression data: 0.

8 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	5
adrenal tissue	2
colonic epithelium	2
stromal cell of endometrium	1
tendon of biceps brachii	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1
cortical plate	1
ventricular zone	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
right uterine tube	1
cartilage tissue	1
corpus epididymis	1
tibia	1
monocyte	1
mononuclear cell	1
granulocyte	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANKRD11	278	ubiquitous	marker	tendon of biceps brachii, sural nerve, stromal cell of endometrium
TBX1	220	broad	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg
TTF2	229	ubiquitous	marker	sural nerve, adrenal tissue, colonic epithelium
KAT6B	140	ubiquitous	yes	cortical plate, ventricular zone, sural nerve
CDK10	286	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, left lobe of thyroid gland
COL2A1	145	broad	marker	tibia, cartilage tissue, corpus epididymis
SETD5	284	ubiquitous	marker	adrenal tissue, colonic epithelium, sural nerve
ZNF778	193	ubiquitous	yes	sural nerve, monocyte, mononuclear cell
ACSF3	173	ubiquitous	marker	mucosa of transverse colon, granulocyte, right adrenal gland
MVD	189	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACSF3	2,854
TTF2	2,689
COL2A1	2,491
ANKRD11	2,384
KAT6B	2,214
SETD5	1,865
CDK10	1,293
TBX1	1,256
MVD	1,189
ZNF778	475

Intra-cohort edges

A	B	Sources
ANKRD11	SETD5	string_interaction
ANKRD11	ZNF778	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 6 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL2A1	P02458	11
KAT6B	Q8WYB5	3
TBX1	O43435	1
MVD	P53602	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACSF3	Q4G176	86.58
CDK10	Q15131	86.27
ZNF778	Q96MU6	63.83
TTF2	Q9UNY4	62.70
SETD5	Q9C0A6	47.10
ANKRD11	Q6UB99	39.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 36. Enrichment computed across 10 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of dolichyl-phosphate	1	271.9×	0.057	MVD
Cholesterol biosynthesis	1	190.3×	0.057	MVD
Lanosterol biosynthesis	1	126.9×	0.057	MVD
Fibronectin matrix formation	1	95.2×	0.057	COL2A1
Synthesis of very long-chain fatty acyl-CoAs	1	76.1×	0.057	ACSF3
Fatty acyl-CoA biosynthesis	1	73.2×	0.057	ACSF3
Cardiogenesis	1	70.5×	0.057	TBX1
MET activates PTK2 signaling	1	63.4×	0.057	COL2A1
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	52.9×	0.057	MVD
Synthesis of substrates in N-glycan biosythesis	1	48.8×	0.057	MVD
Activation of gene expression by SREBF (SREBP)	1	43.3×	0.057	MVD
Collagen chain trimerization	1	43.3×	0.057	COL2A1
Signaling by PDGF	1	42.3×	0.057	COL2A1
NCAM1 interactions	1	41.4×	0.057	COL2A1
Metabolism of lipids	2	10.5×	0.057	ACSF3, MVD
Developmental Lineage of Pancreatic Ductal Cells	1	38.1×	0.058	COL2A1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	34.6×	0.059	MVD
Assembly of collagen fibrils and other multimeric structures	1	33.4×	0.059	COL2A1
Collagen degradation	1	29.3×	0.062	COL2A1
Collagen biosynthesis and modifying enzymes	1	28.4×	0.062	COL2A1
Non-integrin membrane-ECM interactions	1	25.7×	0.064	COL2A1
ECM proteoglycans	1	25.0×	0.064	COL2A1
Metabolism of steroids	1	22.9×	0.065	MVD
Integrin cell surface interactions	1	22.4×	0.065	COL2A1
Fatty acid metabolism	1	21.9×	0.065	ACSF3
Regulation of endogenous retroelements by KRAB-ZFP proteins	1	17.8×	0.076	ZNF778
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	14.5×	0.089	COL2A1
Chromatin organization	1	13.6×	0.091	KAT6B
HATs acetylate histones	1	13.2×	0.091	KAT6B
Chromatin modifying enzymes	1	12.1×	0.096	KAT6B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
malonate catabolic process	1	1685.2×	0.011	ACSF3
regulation of animal organ morphogenesis	1	1685.2×	0.011	TBX1
face morphogenesis	2	99.1×	0.011	ANKRD11, TBX1
heart morphogenesis	2	74.9×	0.011	TBX1, COL2A1
inner ear morphogenesis	2	60.2×	0.011	TBX1, COL2A1
odontogenesis of dentin-containing tooth	2	60.2×	0.011	ANKRD11, TBX1
vagus nerve morphogenesis	1	842.6×	0.017	TBX1
positive regulation of tongue muscle cell differentiation	1	842.6×	0.017	TBX1
isopentenyl diphosphate biosynthetic process, mevalonate pathway	1	561.7×	0.018	MVD
traversing start control point of mitotic cell cycle	1	421.3×	0.018	CDK10
ear morphogenesis	1	421.3×	0.018	TBX1
negative regulation of transcription by RNA polymerase III	1	337.0×	0.018	SETD5
tongue morphogenesis	1	337.0×	0.018	TBX1
soft palate development	1	337.0×	0.018	TBX1
regulation of DNA-templated transcription elongation	1	280.9×	0.018	SETD5
muscle cell fate commitment	1	280.9×	0.018	TBX1
otic vesicle development	1	280.9×	0.018	COL2A1
anterior head development	1	280.9×	0.018	COL2A1
semicircular canal morphogenesis	1	240.7×	0.018	TBX1
regulation of developmental process	1	240.7×	0.018	KAT6B
parathyroid gland development	1	240.7×	0.018	TBX1
cartilage development involved in endochondral bone morphogenesis	1	240.7×	0.018	COL2A1
muscle tissue morphogenesis	1	240.7×	0.018	TBX1
regulation of cell cycle G2/M phase transition	1	240.7×	0.018	CDK10
negative regulation of mesenchymal cell apoptotic process	1	240.7×	0.018	TBX1
lymph vessel development	1	187.2×	0.018	TBX1
proteoglycan metabolic process	1	187.2×	0.018	COL2A1
muscle organ morphogenesis	1	187.2×	0.018	TBX1
coronary artery morphogenesis	1	187.2×	0.018	TBX1
isoprenoid biosynthetic process	1	168.5×	0.018	MVD

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 9

Druggability breadth: 5 of 10 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDK10	3	2
ANKRD11	0	0
TBX1	0	0
TTF2	0	0
KAT6B	0	0
COL2A1	0	0
SETD5	0	0
ZNF778	0	0
ACSF3	0	0
MVD	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	CDK10
AT-9283	2	CDK10
INDIRUBIN	2	CDK10

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
CDK10	59	Binding:59
KAT6B	22	Binding:20, Functional:2
MVD	3	Binding:3
COL2A1	2	Binding:2
ACSF3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KAT6B	2.3.1.48	histone acetyltransferase
CDK10	2.7.11.22	cyclin-dependent kinase
MVD	4.1.1.33	diphosphomevalonate decarboxylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
MOLIBRESIB	2	CDK10
AT-9283	2	CDK10
INDIRUBIN	2	CDK10

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	1	CDK10
C	Druggable family + PDB, no drug	1	MVD
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	8	ANKRD11, TBX1, TTF2, KAT6B, COL2A1, SETD5, ZNF778, ACSF3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ANKRD11	0	—
TBX1	0	—
TTF2	0	—
KAT6B	22	—
COL2A1	2	—
SETD5	0	—
ZNF778	0	—
ACSF3	1	—
MVD	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06465641	PHASE4	RECRUITING	Methylphenidate in KBG Syndrome: N-of-1 Series
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
METHYLPHENIDATE HYDROCHLORIDE	4	1