Microcephaly

Summary

Microcephaly (MONDO:0001149) is a disease (an umbrella term covering 10 Mondo subtypes) caused by LMNB1 (GenCC Strong), with 70 cohort genes and 17 clinical trials. The dominant Reactome pathway is Anchoring of the basal body to the plasma membrane (14 cohort genes).

At a glance

• Causal gene: LMNB1 (GenCC Strong)
• Umbrella term: 10 Mondo subtypes
• Cohort genes: 70
• ClinVar variants: 537
• Clinical trials: 17

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly
Mondo ID	MONDO:0001149
MeSH	D008831
DOID	DOID:10907
ICD-10-CM	Q02
ICD-11	179350437
NCIT	C85874
SNOMED CT	1829003
UMLS	C4551563
MedGen	1644158
Is cancer (heuristic)	no

Also known as: microcephalus · microcephaly · microcephaly (disease) · microencephaly

Data availability: 537 ClinVar variants · 9 GenCC gene-disease records · 1 HPO phenotype · 3 cell lines.

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › microcephaly

Related subtypes (189): precocious puberty, complex cortical dysplasia with other brain malformations, imperforate anus, demyelinating disease, hypospadias, bone development disease, primary basilar invagination, familial bicuspid aortic valve, camptodactyly of fingers, isolated congenital digital clubbing, aorta coarctation, gingival fibromatosis-progressive deafness syndrome, Eng-Strom syndrome, Morgagni-Stewart-Morel syndrome, familial partial lipodystrophy, Dunnigan type, megalodactyly, odontomatosis-aortae esophagus stenosis syndrome, otodental syndrome, oculodental syndrome, Rutherfurd type, spina bifida, steatocystoma multiplex-natal teeth syndrome, distal symphalangism, thumb deformity-alopecia-pigmentation anomaly syndrome, double uterus-hemivagina-renal agenesis syndrome, amelogenesis imperfecta type 1G, Bloom syndrome, cardiac valvular defect, developmental, isolated cerebellar hypoplasia/agenesis, cleft palate-stapes fixation-oligodontia syndrome, Jalili syndrome, craniodiaphyseal dysplasia, craniofacial dyssynostosis, deafness-oligodontia syndrome, duodenal atresia, Fowler syndrome, multiple intestinal atresia, natal teeth-intestinal pseudoobstruction-patent ductus syndrome, atresia of small intestine, mulibrey nanism, oculocerebral hypopigmentation syndrome, Cross type, familial osteodysplasia, Anderson type, pancreatic agenesis, postaxial polydactyly-dental and vertebral anomalies syndrome, familial primary pulmonary hypoplasia, renal tubular dysgenesis of genetic origin, Rothmund-Thomson syndrome, familial isolated congenital asplenia, subaortic stenosis, membranous, non-eruption of teeth-maxillary hypoplasia-genu valgum syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, CK syndrome, Ogden syndrome, Nance-Horan syndrome, colonic atresia, Aicardi syndrome, torticollis-keloids-cryptorchidism-renal dysplasia syndrome, 46,XY complete gonadal dysgenesis, loose anagen syndrome, lung agenesis-heart defect-thumb anomalies syndrome, Chudley-McCullough syndrome, macrocephaly-autism syndrome, DNA ligase IV deficiency, horizontal gaze palsy with progressive scoliosis, cataract - congenital heart disease - neural tube defect syndrome, autosomal recessive frontotemporal pachygyria, craniofacial dysplasia - osteopenia syndrome, porencephaly-microcephaly-bilateral congenital cataract syndrome, congenital short bowel syndrome, familial median cleft of the upper and lower lips, progeroid features-hepatocellular carcinoma predisposition syndrome, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, aneurysm of sinus of Valsalva, blepharoptosis-cleft palate-ectrodactyly-dental anomalies syndrome, medullary sponge kidney, isolated congenital syngnathia, cleft lip and alveolus, diprosopus, T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency, high anorectal malformation, intermediate anorectal malformation, low anorectal malformation, microcephaly-polymicrogyria-corpus callosum agenesis syndrome, cordiform uterus, septate uterus, bicornuate uterus, uterine hypoplasia, agenesis and aplasia of uterine body, uterine cervical aplasia and agenesis, longitudinal vaginal septum, transverse vaginal septum, axial mesodermal dysplasia spectrum, multicystic dysplastic kidney, diabetic embryopathy, congenital microgastria, isolated cleft lip, cleft lip/palate, hereditary gingival fibromatosis, congenital bronchobiliary fistula, congenital hydrocephalus, maternal hyperthermia induced birth defects, diphallia, epibulbar lipodermoid-preauricular appendage-polythelia syndrome, bronchogenic cyst, duplication of urethra, hypohidrotic ectodermal dysplasia, Lowe-Kohn-Cohen syndrome, biliary atresia with splenic malformation syndrome, congenital pulmonary airway malformation, familial intestinal malrotation-facial anomalies syndrome, megalencephaly, cephalocele, cerebral cortical dysplasia, L1 syndrome, familial omphalocele syndrome with facial dysmorphism, penoscrotal transposition, pericardial and diaphragmatic defect, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, congenital deformities of limbs, familial isolated clinodactyly of fingers, congenital shoulder dislocation, congenital elbow dislocation, congenital knee dislocation, congenital patella dislocation, macrodactyly of fingers, macrodactyly of toes, upper limb hypertrophy, lower limb hypertrophy, duplication of the pituitary gland, diencephalic-mesencephalic junction dysplasia, steroid dehydrogenase deficiency-dental anomalies syndrome, congenital achiasma, tracheal agenesis, renal agenesis, hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome, isolated splenogonadal fusion, Joubert syndrome, congenital generalized hypercontractile muscle stiffness syndrome, congenital bilateral absence of vas deferens, congenital portosystemic shunt, lissencephaly spectrum disorders, Berardinelli-Seip congenital lipodystrophy, congenital primary megaureter, craniorachischisis, vaginal atresia, bronchopulmonary dysplasia, dentinogenesis imperfecta-short stature-hearing loss-intellectual disability syndrome, aniridia, atypical Werner syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, anterior segment dysgenesis, congenital esophageal diverticulum, renal hypoplasia, renal dysplasia, overgrowth syndrome, developmental defect during embryogenesis, acalvaria, congenital aortic valve insufficiency, congenital anomaly of superior vena cava, congenital anomaly of hepatic vein, posterior hypospadias, isolated micropenis, isolated partial vaginal agenesis, anorectal malformation, pulmonary agenesis, congenital tricuspid malformation, Noonan syndrome and Noonan-related syndrome, coronary sinus stenosis, coronary sinus atresia, cartilage development disorder, syndactyly, polydactyly, brachydactyly, neurocristopathy, congenital absence of septum pellucidum, branchial arch disease, congenital anomaly of cardiovascular system, atelencephaly, aprosencephaly, aortic valve stenosis, hereditary lethal multiple congenital anomalies/dysmorphic syndrome, congenital agenesis of the scrotum, keratinization disease, lactation disease, COACH syndrome, constitutional delay of growth and puberty, isolated congenital femoral bifurcation, congenital peritoneal encapsulation, isolated short stature, congenital high airway obstruction syndrome

Subtypes (10): microcephalic osteodysplastic primordial dwarfism, microcephaly and chorioretinopathy, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Amish lethal microcephaly, microcephaly, seizures, and developmental delay, isolated congenital microcephaly, isolated microcephaly, microcephaly with intellectual disability, microcephaly with lissencephaly and/or hydranencephaly, microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia

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

537 retrieved; paginated sample, class counts are floors:

220 uncertain significance, 126 pathogenic, 68 conflicting classifications of pathogenicity, 58 likely pathogenic, 34 pathogenic/likely pathogenic, 19 likely benign, 7 benign/likely benign, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
267798	46;XY;t(9;16)(p24;q22)dn		Pathogenic	criteria provided, single submitter
267802	46;XY;t(11;19)(p11.2;p13.3)dn		Pathogenic	criteria provided, single submitter
267821	46;XX;t(3;12)(q13.2;q14)dn		Pathogenic	criteria provided, single submitter
267854	46;XX;inv(2)(p23q31)dn		Pathogenic	criteria provided, single submitter
267874	46;XX;inv(2)(p23q31.3)		Pathogenic	criteria provided, single submitter
267882	46;XX;inv(7)(q11.23q36.3)dn		Pathogenic	criteria provided, single submitter
267883	46;X;inv(X)(p11.4q24)dn		Pathogenic	criteria provided, single submitter
268035	46;XX;t(19;21)(q13.3;q22.3)dn		Pathogenic	criteria provided, single submitter
268039	46;XY;t(3;18)(q13.31;q22.1)dn		Pathogenic	criteria provided, single submitter
997077	GRCh37/hg19 Xp22.33(chrX:61091-787353)		Pathogenic	criteria provided, single submitter
1330165	GRCh37/hg19 3q23-25.32(chr3:142729607-157921084)x3	AADAC	Pathogenic	criteria provided, single submitter
1047873	GRCh37/hg19 7q31.2-31.33(chr7:116297277-126370694)	AASS	Pathogenic	criteria provided, single submitter
813717	GRCh37/hg19 16p13.3-11.2(chr16:5805001-34230001)	ABAT	Pathogenic	no assertion criteria provided
983212	NM_005157.6(ABL1):c.1517T>C (p.Val506Ala)	ABL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
813525	NM_001614.5(ACTG1):c.628C>T (p.Arg210Cys)	ACTG1	Pathogenic	criteria provided, multiple submitters, no conflicts
2579268	GRCh38/hg38 8p23.1-12(chr8:12721809-30183737)x1	ADAM28	Pathogenic	criteria provided, single submitter
974790	GRCh37/hg19 6q16.3-22.1(chr6:101296547-117004249)x3	AFG1L	Pathogenic	no assertion criteria provided
66086	NM_001099922.3(ALG13):c.320A>G (p.Asn107Ser)	ALG13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523258	GRCh37/hg19 17p11.2(chr17:16936603-18184130)	ALKBH5	Pathogenic	criteria provided, single submitter
183357	NM_004722.4(AP4M1):c.952C>T (p.Arg318Ter)	AP4M1	Pathogenic	criteria provided, multiple submitters, no conflicts
1697211	NM_001659.3(ARF3):c.200A>T (p.Asp67Val)	ARF3	Pathogenic	criteria provided, single submitter
1697212	NM_001659.3(ARF3):c.277G>A (p.Asp93Asn)	ARF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1697213	NM_001659.3(ARF3):c.379A>G (p.Lys127Glu)	ARF3	Pathogenic	criteria provided, single submitter
210291	NM_001374828.1(ARID1B):c.4479G>A (p.Pro1493=)	ARID1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
813718	GRCh37/hg19 6q25.3(chr6:157075546-157443054)	ARID1B	Pathogenic	no assertion criteria provided
180227	NC_000006.11:g.(116681080_116735056)_(119687719_119775014)del	ASF1A	Pathogenic	no assertion criteria provided
1172591	NM_018136.5(ASPM):c.727C>T (p.Arg243Ter)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
21582	NM_018136.5(ASPM):c.3796G>T (p.Glu1266Ter)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
402179	NM_018136.5(ASPM):c.1729_1730del (p.Ser577fs)	ASPM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
643176	NM_018136.5(ASPM):c.9324del (p.Leu3109fs)	ASPM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 139 · 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
LMNB1	Definitive	Autosomal dominant	microcephaly 26, primary, autosomal dominant	10
TTI1	Strong	Autosomal recessive	neurodevelopmental disorder with microcephaly and movement abnormalities	3
SPDL1	Limited	Autosomal recessive	microcephaly
TEDC1	Limited	Autosomal recessive	microcephaly	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LMNB1	Orphanet:2514	Autosomal dominant primary microcephaly
LMNB1	Orphanet:99027	Adult-onset autosomal dominant leukodystrophy
BCS1L	Orphanet:123	Björnstad syndrome
BCS1L	Orphanet:1460	Isolated complex III deficiency
BCS1L	Orphanet:254902	Renal tubulopathy-encephalopathy-liver failure syndrome
BCS1L	Orphanet:53693	GRACILE syndrome
RREB1	Orphanet:567	22q11.2 deletion syndrome
SALL1	Orphanet:857	Townes-Brocks syndrome
SBF1	Orphanet:363981	Charcot-Marie-Tooth disease type 4B3
BLM	Orphanet:125	Bloom syndrome
SCN1A	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SCN1A	Orphanet:2382	Lennox-Gastaut syndrome
SCN1A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN1A	Orphanet:33069	Dravet syndrome
SCN1A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN1A	Orphanet:569	Familial or sporadic hemiplegic migraine
SCN4A	Orphanet:681	Hypokalemic periodic paralysis
SCN4A	Orphanet:682	Hyperkalemic periodic paralysis
SCN4A	Orphanet:684	Paramyotonia congenita of Von Eulenburg
SCN4A	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
SCN4A	Orphanet:99734	Myotonia fluctuans
SCN4A	Orphanet:99735	Myotonia permanens
SCN4A	Orphanet:99736	Acetazolamide-responsive myotonia
SDHD	Orphanet:100093	Carcinoid syndrome
SDHD	Orphanet:201	Cowden syndrome
SDHD	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
SDHD	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHD	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHD	Orphanet:97286	Carney-Stratakis syndrome
SEC24C	Orphanet:567	22q11.2 deletion syndrome
SEM1	Orphanet:2440	Isolated split hand-split foot malformation
SIM1	Orphanet:171829	6q16 microdeletion syndrome
SIM1	Orphanet:369873	Obesity due to SIM1 deficiency
SIM1	Orphanet:398079	SIM1-related Prader-Willi-like syndrome
SLC1A4	Orphanet:447997	Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome
SLC2A1	Orphanet:168577	Hereditary cryohydrocytosis with reduced stomatin
SLC2A1	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SLC2A1	Orphanet:2131	Alternating hemiplegia of childhood
SLC2A1	Orphanet:53583	Paroxysmal dystonic choreathetosis with episodic ataxia and spasticity
SLC2A1	Orphanet:71277	Classic glucose transporter type 1 deficiency syndrome
SLC2A1	Orphanet:86911	Epilepsy with myoclonic absences
SLC2A1	Orphanet:98811	Paroxysmal exertion-induced dyskinesia
SLC9A6	Orphanet:85278	Christianson syndrome
SMARCA2	Orphanet:3051	Nicolaides-Baraitser syndrome
SMARCA2	Orphanet:637013	SMARCA2-related blepharophimosis-intellectual disability syndrome
SMARCA4	Orphanet:1465	Coffin-Siris syndrome
SMARCA4	Orphanet:231108	Rhabdoid tumor predisposition syndrome
SMARCA4	Orphanet:370396	Small cell carcinoma of the ovary
SMARCA4	Orphanet:466962	SMARCA4-deficient sarcoma of thorax

Cohort genes → proteins

70 cohort genes, 70 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	70

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LMNB1	HGNC:6637	ENSG00000113368	P20700	Lamin-B1	gencc,clinvar
TEDC1	HGNC:20127	ENSG00000185347	Q86SX3	Tubulin epsilon and delta complex protein 1	gencc
SPDL1	HGNC:26010	ENSG00000040275	Q96EA4	Protein Spindly	gencc
TTI1	HGNC:29029	ENSG00000101407	O43156	TELO2-interacting protein 1 homolog	gencc
BCS1L	HGNC:1020	ENSG00000074582	Q9Y276	Mitochondrial chaperone BCS1	clinvar
RREB1	HGNC:10449	ENSG00000124782	Q92766	Ras-responsive element-binding protein 1	clinvar
SALL1	HGNC:10524	ENSG00000103449	Q9NSC2	Sal-like protein 1	clinvar
SBF1	HGNC:10542	ENSG00000100241	O95248	Myotubularin-related protein 5	clinvar
BLM	HGNC:1058	ENSG00000197299	P54132	RecQ-like DNA helicase BLM	clinvar
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	clinvar
SCN4A	HGNC:10591	ENSG00000007314	P35499	Sodium channel protein type 4 subunit alpha	clinvar
SDHD	HGNC:10683	ENSG00000204370	O14521	Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial	clinvar
SEC24C	HGNC:10705	ENSG00000176986	P53992	Protein transport protein Sec24C	clinvar
SEM1	HGNC:10845	ENSG00000127922	P60896	26S proteasome complex subunit SEM1	clinvar
SIM1	HGNC:10882	ENSG00000112246	P81133	Single-minded homolog 1	clinvar
SLC1A4	HGNC:10942	ENSG00000115902	P43007	Neutral amino acid transporter A	clinvar
SLC2A1	HGNC:11005	ENSG00000117394	P11166	Solute carrier family 2, facilitated glucose transporter member 1	clinvar
SLC9A6	HGNC:11079	ENSG00000198689	Q92581	Sodium/hydrogen exchanger 6	clinvar
SMARCA2	HGNC:11098	ENSG00000080503	P51531	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	clinvar
SMARCA4	HGNC:11100	ENSG00000127616	P51532	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	clinvar
SMARCA5	HGNC:11101	ENSG00000153147	O60264	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5	clinvar
SMARCAL1	HGNC:11102	ENSG00000138375	Q9NZC9	SNF2 related chromatin remodeling annealing helicase 1	clinvar
ARID1A	HGNC:11110	ENSG00000117713	O14497	AT-rich interactive domain-containing protein 1A	clinvar
SMC1A	HGNC:11111	ENSG00000072501	Q14683	Structural maintenance of chromosomes protein 1A	clinvar
SMO	HGNC:11119	ENSG00000128602	Q99835	Protein smoothened	clinvar
SNAP25	HGNC:11132	ENSG00000132639	P60880	Synaptosomal-associated protein 25	clinvar
CAPN15	HGNC:11182	ENSG00000103326	O75808	Calpain-15	clinvar
SPOCK1	HGNC:11251	ENSG00000152377	Q08629	Testican-1	clinvar
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 1	clinvar
SPTLC1	HGNC:11277	ENSG00000090054	O15269	Serine palmitoyltransferase 1	clinvar
PLK4	HGNC:11397	ENSG00000142731	O00444	Serine/threonine-protein kinase PLK4	clinvar
STXBP1	HGNC:11444	ENSG00000136854	P61764	Syntaxin-binding protein 1	clinvar
BUB1B	HGNC:1149	ENSG00000156970	O60566	Mitotic checkpoint serine/threonine-protein kinase BUB1 beta	clinvar
SYNGAP1	HGNC:11497	ENSG00000197283	Q96PV0	Ras/Rap GTPase-activating protein SynGAP	clinvar
TAF2	HGNC:11536	ENSG00000064313	Q6P1X5	Transcription initiation factor TFIID subunit 2	clinvar
TALDO1	HGNC:11559	ENSG00000177156	P37837	Transaldolase	clinvar
TBX2	HGNC:11597	ENSG00000121068	Q13207	T-box transcription factor TBX2	clinvar
TCF4	HGNC:11634	ENSG00000196628	P15884	Transcription factor 4	clinvar
TCOF1	HGNC:11654	ENSG00000070814	Q13428	Treacle protein	clinvar
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	clinvar
TFAP2C	HGNC:11744	ENSG00000087510	Q92754	Transcription factor AP-2 gamma	clinvar
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	clinvar
TRIO	HGNC:12303	ENSG00000038382	O75962	Triple functional domain protein	clinvar
TRPS1	HGNC:12340	ENSG00000104447	Q9UHF7	Zinc finger transcription factor Trps1	clinvar
TUBA8	HGNC:12410	ENSG00000183785	Q9NY65	Tubulin alpha-8 chain	clinvar
VAPA	HGNC:12648	ENSG00000101558	Q9P0L0	Vesicle-associated membrane protein-associated protein A	clinvar
VARS1	HGNC:12651	ENSG00000204394	P26640	Valine–tRNA ligase	clinvar
VLDLR	HGNC:12698	ENSG00000147852	P98155	Very low-density lipoprotein receptor	clinvar
VPS33B	HGNC:12712	ENSG00000184056	Q9H267	Vacuolar protein sorting-associated protein 33B	clinvar
NSD2	HGNC:12766	ENSG00000109685	O96028	Histone-lysine N-methyltransferase NSD2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LMNB1	Lamin-B1	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.
TEDC1	Tubulin epsilon and delta complex protein 1	Acts as a positive regulator of ciliary hedgehog signaling.
SPDL1	Protein Spindly	Required for the localization of dynein and dynactin to the mitotic kinetochore.
TTI1	TELO2-interacting protein 1 homolog	Regulator of the DNA damage response (DDR).
BCS1L	Mitochondrial chaperone BCS1	Chaperone necessary for the incorporation of Rieske iron-sulfur protein UQCRFS1 into the mitochondrial respiratory chain complex III.
RREB1	Ras-responsive element-binding protein 1	Transcription factor that binds specifically to the RAS-responsive elements (RRE) of gene promoters.
SALL1	Sal-like protein 1	Transcriptional repressor involved in organogenesis.
SBF1	Myotubularin-related protein 5	Acts as an adapter for the phosphatase MTMR2 to regulate MTMR2 catalytic activity and subcellular location.
BLM	RecQ-like DNA helicase BLM	ATP-dependent DNA helicase that unwinds double-stranded (ds)DNA in a 3’-5’ direction.
SCN1A	Sodium channel protein type 1 subunit alpha	Pore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SCN4A	Sodium channel protein type 4 subunit alpha	Pore-forming subunit of Nav1.4, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SDHD	Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial	Membrane-anchoring subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
SEC24C	Protein transport protein Sec24C	Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).
SEM1	26S proteasome complex subunit SEM1	Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins.
SIM1	Single-minded homolog 1	Transcriptional factor that may have pleiotropic effects during embryogenesis and in the adult.
SLC1A4	Neutral amino acid transporter A	Sodium-coupled antiporter of neutral amino acids.
SLC2A1	Solute carrier family 2, facilitated glucose transporter member 1	Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake.
SLC9A6	Sodium/hydrogen exchanger 6	Endosomal Na(+), K(+)/H(+) antiporter.
SMARCA2	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SMARCA4	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SMARCA5	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5	ATPase that possesses intrinsic ATP-dependent nucleosome-remodeling activity.
SMARCAL1	SNF2 related chromatin remodeling annealing helicase 1	ATP-dependent annealing helicase that binds selectively to fork DNA relative to ssDNA or dsDNA and catalyzes the rewinding of the stably unwound DNA.
ARID1A	AT-rich interactive domain-containing protein 1A	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SMC1A	Structural maintenance of chromosomes protein 1A	Involved in chromosome cohesion during cell cycle and in DNA repair.
SMO	Protein smoothened	G protein-coupled receptor which associates with the patched protein (PTCH) to transduce hedgehog protein signaling.
SNAP25	Synaptosomal-associated protein 25	t-SNARE involved in the molecular regulation of neurotransmitter release.
SPOCK1	Testican-1	May play a role in cell-cell and cell-matrix interactions.
SPTAN1	Spectrin alpha chain, non-erythrocytic 1	Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.
SPTLC1	Serine palmitoyltransferase 1	Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-…
PLK4	Serine/threonine-protein kinase PLK4	Serine/threonine-protein kinase that plays a central role in centriole duplication.
STXBP1	Syntaxin-binding protein 1	Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins.
BUB1B	Mitotic checkpoint serine/threonine-protein kinase BUB1 beta	Essential component of the mitotic checkpoint.
SYNGAP1	Ras/Rap GTPase-activating protein SynGAP	Major constituent of the PSD essential for postsynaptic signaling.
TAF2	Transcription initiation factor TFIID subunit 2	The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription.
TALDO1	Transaldolase	Catalyzes the rate-limiting step of the non-oxidative phase in the pentose phosphate pathway.
TBX2	T-box transcription factor TBX2	Transcription factor which acts as a transcriptional repressor.
TCF4	Transcription factor 4	Transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5-motif.
TCOF1	Treacle protein	Nucleolar protein that acts as a regulator of RNA polymerase I by connecting RNA polymerase I with enzymes responsible for ribosomal processing and modification.
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
TFAP2C	Transcription factor AP-2 gamma	Sequence-specific DNA-binding transcription factor that interacts with cellular enhancer elements to regulate transcription of selected genes, and which plays a key role in early embryonic development.
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
TRIO	Triple functional domain protein	Guanine nucleotide exchange factor (GEF) for RHOA and RAC1 GTPases.
TRPS1	Zinc finger transcription factor Trps1	Transcriptional repressor.
TUBA8	Tubulin alpha-8 chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
VAPA	Vesicle-associated membrane protein-associated protein A	Endoplasmic reticulum (ER)-anchored protein that mediates the formation of contact sites between the ER and endosomes via interaction with FFAT motif-containing proteins such as STARD3 or WDR44.
VARS1	Valine–tRNA ligase	Catalyzes the attachment of valine to tRNA(Val).
VLDLR	Very low-density lipoprotein receptor	Multifunctional cell surface receptor that binds VLDL and transports it into cells by endocytosis and therefore plays an important role in energy metabolism.
VPS33B	Vacuolar protein sorting-associated protein 33B	May play a role in vesicle-mediated protein trafficking to lysosomal compartments and in membrane docking/fusion reactions of late endosomes/lysosomes.
NSD2	Histone-lysine N-methyltransferase NSD2	Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at ‘Lys-36’ (H3K36me2).
YME1L1	ATP-dependent zinc metalloprotease YME1L1	ATP-dependent metalloprotease that catalyzes the degradation of folded and unfolded proteins with a suitable degron sequence in the mitochondrial intermembrane region.

Protein-family classification

Druggable: 18 · Difficult: 22 · Unknown: 30 · Druggable fraction: 0.26

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
Transcription factor	17	2.0×	0.039
Ion channel	2	3.2×	0.717
Protease	3	1.6×	0.820
Scaffold/PPI	5	1.2×	0.820
Phosphatase	1	1.2×	0.820
Kinase	3	1.2×	0.820
Transporter	1	1.1×	0.820
Enzyme (other)	6	1.0×	0.820
Other/Unknown	30	0.8×	0.989
Antibody/Immunoglobulin	1	0.4×	0.989
GPCR	1	0.3×	0.989

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LMNB1	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf
TEDC1	Other/Unknown	no		TEDC1_dom, TEDC1
SPDL1	Other/Unknown	no		SPDLY_chordates, Spindly/BICDR_Dynein_Adapter
TTI1	Other/Unknown	no		ARM-like, ARM-type_fold, Tti1
BCS1L	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
RREB1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, RREB1
SALL1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Sal_C2H2-zinc-finger
SBF1	Phosphatase	yes	3.1.3.16	cDENN_dom, PH_domain, GRAM
BLM	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, HRDC_dom, DNA/RNA_helicase_DEAH_CS
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
SCN4A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a4su_mammal
SDHD	Other/Unknown	no		CybS, SQR/QFR_C/D
SEC24C	Transcription factor	no		Znf_Sec23_Sec24, Sec23/24_trunk_dom, Sec23/24_helical_dom
SEM1	Other/Unknown	no		DSS1_SEM1, DUF5543
SIM1	Transcription factor	no		PAS, PAC, SIM_C
SLC1A4	Other/Unknown	no		Na-dicarboxylate_symporter, Na-dicarboxylate_symporter_CS, Na:dicarbo_symporter_sf
SLC2A1	Transporter	yes		Glu_transpt_1, Sugar/inositol_transpt, MFS_sugar_transport-like
SLC9A6	Other/Unknown	no		NHE-6/7/9, NaH_exchanger, Cation/H_exchanger_TM
SMARCA2	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
SMARCA4	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
SMARCA5	Transcription factor	no		SNF2_N, SANT/Myb, Helicase_C-like
SMARCAL1	Other/Unknown	no		SNF2_N, Helicase_C-like, HARP_dom
ARID1A	Other/Unknown	no		ARID_dom, ARM-like, ARM-type_fold
SMC1A	Other/Unknown	no		RecF/RecN/SMC_N, SMC_hinge, SMC
SMO	GPCR	yes		Frizzled/Smoothened_7TM, Frizzled/SFRP, GPCR_2-like_7TM
SNAP25	Other/Unknown	no		T_SNARE_dom, SNAP-25_dom, SNAP-25_N_SNARE_chord
CAPN15	Protease	yes	3.4.22.B35	Pept_cys_AS, Peptidase_C2_calpain_cat, Znf_RanBP2
SPOCK1	Other/Unknown	no		Thyroglobulin_1, Kazal_dom, EF-hand-dom_pair
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
SPTLC1	Enzyme (other)	yes	2.3.1.50	Aminotransferase_I/II_large, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small
PLK4	Kinase	yes	2.7.11.21	Prot_kinase_dom, POLO_box_dom, Tyr_kinase_AS
STXBP1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
BUB1B	Kinase	yes	2.7.11.1	Kinase-like_dom_sf, Mad3/Bub1_I, Bub1/Mad3
SYNGAP1	Scaffold/PPI	no		C2_dom, PH_domain, RasGAP_dom
TAF2	Protease	yes		ARM-type_fold, Peptidase_M4/M1_CTD_sf, TAF2
TALDO1	Other/Unknown	no		TAL/FSA, Transaldolase_1, Aldolase_TIM
TBX2	Transcription factor	no		TF_T-box, TF_Brachyury, p53-like_TF_DNA-bd_sf
TCF4	Transcription factor	no	7.6.2.3	bHLH_dom, HLH_DNA-bd_sf, NeuroDiff_E-box_TFs
TCOF1	Other/Unknown	no		Treacle_dom, LisH, Treacle
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
TFAP2C	Transcription factor	no		TF_AP2, TF_AP2_gamma, TF_AP2_C
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
TRIO	Kinase	yes		DH_dom, Prot_kinase_dom, CRAL-TRIO_dom
TRPS1	Transcription factor	no		Znf_GATA, Znf_C2H2_type, Znf_NHR/GATA
TUBA8	Other/Unknown	no		Tubulin, Alpha_tubulin, Tubulin_FtsZ_GTPase
VAPA	Antibody/Immunoglobulin	yes		MSP_dom, PapD-like_sf, Ig-like_fold
VARS1	Enzyme (other)	yes	6.1.1.9	aa-tRNA-synth_I_CS, aa-tRNA-synth_Ia, Valyl-tRNA_ligase
VLDLR	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF
VPS33B	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
NSD2	Transcription factor	no	2.1.1.356	PWWP_dom, SET_dom, Znf_RING

Expression context

Cohort genes with no expression data: 0.

63 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)	70
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	10
calcaneal tendon	7
sural nerve	7
lateral nuclear group of thalamus	6
cortical plate	6
oocyte	5
secondary oocyte	5
embryo	4
ganglionic eminence	4
buccal mucosa cell	4
left testis	4
right testis	4
Brodmann (1909) area 23	4
middle temporal gyrus	4
stromal cell of endometrium	4
cerebellar cortex	4
adrenal tissue	4
apex of heart	3
primordial germ cell in gonad	3
gastrocnemius	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LMNB1	226	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo
TEDC1	169	ubiquitous	yes	tendon of biceps brachii, granulocyte, mucosa of transverse colon
SPDL1	229	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
TTI1	287	ubiquitous	marker	secondary oocyte, cardia of stomach, embryo
BCS1L	279	ubiquitous	marker	body of pancreas, metanephros cortex, apex of heart
RREB1	278	ubiquitous	marker	buccal mucosa cell, epithelium of nasopharynx, oral cavity
SALL1	195	broad	marker	ventricular zone, inferior vagus X ganglion, renal medulla
SBF1	278	ubiquitous	yes	left testis, right testis, right lobe of thyroid gland
BLM	199	ubiquitous	marker	parotid gland, primordial germ cell in gonad, secondary oocyte
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
SCN4A	153	tissue_specific	yes	hindlimb stylopod muscle, gastrocnemius, skeletal muscle tissue of rectus abdominis
SDHD	287	ubiquitous	marker	jejunal mucosa, rectum, jejunum
SEC24C	290	ubiquitous	marker	lower esophagus mucosa, esophagus squamous epithelium, epithelium of esophagus
SEM1	285	ubiquitous	marker	calcaneal tendon, tendon, tendon of biceps brachii
SIM1	76	broad	yes	renal medulla, skeletal muscle tissue of biceps brachii, biceps brachii
SLC1A4	294	ubiquitous	marker	buccal mucosa cell, sperm, gluteal muscle
SLC2A1	250	ubiquitous	marker	tibial nerve, sural nerve, skin of abdomen
SLC9A6	286	ubiquitous	yes	lateral nuclear group of thalamus, middle temporal gyrus, pons
SMARCA2	301	ubiquitous	marker	calcaneal tendon, colonic epithelium, cortical plate
SMARCA4	295	ubiquitous	marker	ganglionic eminence, cortical plate, cervix squamous epithelium
SMARCA5	300	ubiquitous	marker	ventricular zone, calcaneal tendon, buccal mucosa cell
SMARCAL1	264	ubiquitous	marker	primordial germ cell in gonad, stromal cell of endometrium, sural nerve
ARID1A	286	ubiquitous	marker	bone marrow cell, ventricular zone, embryo
SMC1A	289	ubiquitous	marker	sural nerve, trabecular bone tissue, embryo
SMO	225	ubiquitous	marker	ventricular zone, left ovary, right ovary
SNAP25	220	broad	marker	pons, cerebellar cortex, cerebellum
CAPN15	235	ubiquitous	marker	lower esophagus mucosa, granulocyte, mucosa of transverse colon
SPOCK1	273	ubiquitous	marker	stromal cell of endometrium, lateral nuclear group of thalamus, decidua
SPTAN1	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
SPTLC1	300	ubiquitous	marker	esophagus squamous epithelium, oral cavity, epithelium of esophagus

Protein interactions among cohort

Intra-cohort edges: 21.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCA4	8,138
SMARCA5	6,214
VARS1	5,848
TERT	5,717
SLC2A1	5,711
SMC1A	5,246
LMNB1	5,226
HDAC4	4,771
TUBA8	4,465
VAPA	4,386

Intra-cohort edges

A	B	Sources
ARID1A	SMARCA2	biogrid_interaction, string_interaction
ARID1A	SMARCA4	biogrid_interaction, intact, string_interaction
BCS1L	VAPA	biogrid_interaction
BUB1B	PLK4	string_interaction
HDAC4	TRPS1	string_interaction
HDAC4	YWHAG	biogrid_interaction, intact
HDAC8	SMC1A	string_interaction
MAK16	TUBA8	biogrid_interaction, intact
NSD2	SALL1	string_interaction
PRDM16	WDR11	biogrid_interaction
SBF1	YWHAG	intact
SCN1A	STXBP1	string_interaction
SDHD	SMARCA4	intact
SEC24C	SYNGAP1	intact
SEM1	SPTLC1	intact
SMARCA2	SMARCA4	string_interaction
SMARCA4	SMARCA5	string_interaction
SMARCA4	TERT	intact, string_interaction
SNAP25	STXBP1	biogrid_interaction, intact
SPTAN1	STXBP1	string_interaction
SYNGAP1	TRIO	intact

Structural data

PDB: 48 · AlphaFold-only: 22 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SEM1	P60896	129
ACTB	P60709	88
HDAC8	Q9BY41	53
SMARCA2	P51531	32
SMARCA4	P51532	31
TAF2	Q6P1X5	28
VLDLR	P98155	27
TERT	O14746	23
NSD2	O96028	22
YWHAG	P61981	22
PLK4	O00444	19
HDAC4	P56524	19
SMC1A	Q14683	18
SPTLC1	O15269	17
BLM	P54132	15
SMARCA5	O60264	15
SMO	Q99835	15
SNAP25	P60880	14
ELAC2	Q9BQ52	10
BUB1B	O60566	9
KMT2C	Q8NEZ4	9
LMNB1	P20700	7
ARID1A	O14497	7
SPTAN1	Q13813	7
SLC2A1	P11166	5
TCF4	P15884	5
IFT122	Q9HBG6	5
TRIO	O75962	4
KDM2B	Q8NHM5	4
MAK16	Q9BXY0	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VPS33B	Q9H267	91.82
TUBA8	Q9NY65	91.24
VARS1	P26640	88.12
BCS1L	Q9Y276	87.10
SAMD9L	Q8IVG5	83.85
SBF1	O95248	74.72
ZNF91	Q05481	72.09
CAPN15	O75808	71.65
YME1L1	Q96TA2	70.79
SLC9A6	Q92581	70.61
TFAP2C	Q92754	66.37
SPOCK1	Q08629	63.80
TEDC1	Q86SX3	63.08
SIM1	P81133	60.70
SYNGAP1	Q96PV0	60.43
TBX2	Q13207	58.13
BCL11B	Q9C0K0	51.76
ZIC2	O95409	51.36
SALL1	Q9NSC2	49.54
TRPS1	Q9UHF7	49.12
RREB1	Q92766	48.28
TCOF1	Q13428	41.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 833. Enrichment computed across 250 evidence-associated genes (179 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 179 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Anchoring of the basal body to the plasma membrane	14	8.8×	4e-07	PLK4, YWHAG, PCNT, CLASP1, CPAP, CDK5RAP2, TUBB4A, TMEM216 (+6 more)
Recruitment of NuMA to mitotic centrosomes	12	7.8×	2e-05	PLK4, TUBA8, YWHAG, PCNT, CLASP1, CPAP, TUBGCP6, TUBGCP5 (+4 more)
Recruitment of mitotic centrosome proteins and complexes	11	8.3×	2e-05	PLK4, YWHAG, PCNT, CLASP1, CPAP, TUBGCP6, TUBGCP5, CDK5RAP2 (+3 more)
Cell Cycle	20	4.0×	2e-05	LMNB1, BLM, SEM1, SMARCA5, SMC1A, BUB1B, TERT, TUBA8 (+12 more)
M Phase	14	5.2×	9e-05	LMNB1, SEM1, SMC1A, BUB1B, TUBA8, YWHAG, AAAS, KNTC1 (+6 more)
Cell Cycle, Mitotic	16	4.3×	1e-04	LMNB1, SEM1, SMC1A, BUB1B, TUBA8, YWHAG, AAAS, KNTC1 (+8 more)
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	6	15.3×	2e-04	SMARCA2, SMARCA4, ARID1A, ACTB, BCL11B, ARID1B
Loss of Nlp from mitotic centrosomes	9	8.0×	2e-04	PLK4, YWHAG, PCNT, CLASP1, CPAP, CDK5RAP2, TUBB4A, CEP290 (+1 more)
Loss of proteins required for interphase microtubule organization from the centrosome	9	8.0×	2e-04	PLK4, YWHAG, PCNT, CLASP1, CPAP, CDK5RAP2, TUBB4A, CEP290 (+1 more)
AURKA Activation by TPX2	9	7.7×	2e-04	PLK4, YWHAG, PCNT, CLASP1, CPAP, CDK5RAP2, TUBB4A, CEP290 (+1 more)
Mitotic Metaphase and Anaphase	11	6.0×	2e-04	LMNB1, SEM1, SMC1A, BUB1B, TUBA8, KNTC1, CENPF, TUBB4A (+3 more)
Mitotic Anaphase	11	6.0×	2e-04	LMNB1, SEM1, SMC1A, BUB1B, TUBA8, KNTC1, CENPF, TUBB4A (+3 more)
RHO GTPases Activate Formins	12	5.2×	2e-04	BUB1B, TUBA8, ACTB, ACTG1, NUF2, CLASP1, KNTC1, CENPF (+4 more)
Formation of the canonical BAF (cBAF) complex	5	17.7×	4e-04	SMARCA2, SMARCA4, ARID1A, ACTB, ARID1B
Resolution of Sister Chromatid Cohesion	11	5.3×	4e-04	SMC1A, BUB1B, TUBA8, HDAC8, NUF2, CLASP1, KNTC1, CENPF (+3 more)
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	18	3.4×	4e-04	LMNB1, SPTAN1, BUB1B, TUBA8, YWHAG, ACTB, AAAS, ACTG1 (+10 more)
Regulation of PLK1 Activity at G2/M Transition	9	6.4×	5e-04	PLK4, YWHAG, PCNT, CLASP1, CPAP, CDK5RAP2, TUBB4A, CEP290 (+1 more)
Mitotic Prometaphase	12	4.6×	5e-04	SMC1A, BUB1B, TUBA8, YWHAG, NUF2, CLASP1, KNTC1, CENPF (+4 more)
Signaling by Rho GTPases	17	3.2×	8e-04	LMNB1, SPTAN1, BUB1B, TUBA8, YWHAG, ACTB, AAAS, ACTG1 (+9 more)
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	6	10.1×	0.001	SMARCA2, SMARCA4, ARID1A, AUTS2, ARID2, ARID1B
Transcriptional regulation by RUNX1	8	6.5×	0.001	SEM1, SMARCA2, SMARCA4, ARID1A, KMT2C, AUTS2, ARID2, ARID1B
Separation of Sister Chromatids	12	4.1×	0.001	SEM1, SMC1A, BUB1B, TUBA8, HDAC8, NUF2, CLASP1, KNTC1 (+4 more)
Regulation of MITF-M-dependent genes involved in pigmentation	6	8.9×	0.002	SMARCA2, SMARCA4, ARID1A, ACTB, ARID1B, CTNNB1
MITF-M-dependent gene expression	7	7.1×	0.002	SMARCA2, SMARCA4, ARID1A, TBX2, TERT, ACTB, ARID1B
Interaction between L1 and Ankyrins	5	10.3×	0.003	SCN1A, SCN4A, SPTAN1, ACTB, ACTG1
Regulation of endogenous retroelements	5	10.3×	0.003	SMARCA2, SMARCA4, ARID1A, ACTB, ARID1B
EML4 and NUDC in mitotic spindle formation	9	4.7×	0.004	BUB1B, TUBA8, NUF2, CLASP1, KNTC1, CENPF, TUBB4A, SPDL1 (+1 more)
Resolution of D-Loop Structures	4	14.2×	0.004	BLM, SEM1, RTEL1, SLX4
Formation of the polybromo-BAF (pBAF) complex	4	14.2×	0.004	SMARCA2, SMARCA4, ACTB, ARID2
RHO GTPases activate IQGAPs	5	9.7×	0.004	TUBA8, ACTB, ACTG1, TUBB4A, CTNNB1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 243 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
non-motile cilium assembly	12	14.3×	5e-08	RPGRIP1, IFT122, CPAP, CLCN4, IFT74, TBC1D32, POC1A, TMEM216 (+4 more)
regulation of mitotic metaphase/anaphase transition	7	14.3×	4e-04	SMARCA2, SMARCA4, ARID1A, ACTB, CDC6, ARID2, ARID1B
regulation of G0 to G1 transition	6	16.6×	6e-04	SMARCA2, SMARCA4, ARID1A, ACTB, ARID2, ARID1B
replication fork processing	7	12.1×	6e-04	BLM, SMARCAL1, RTEL1, ASF1A, FAM111A, DDX11, DONSON
regulation of nucleotide-excision repair	6	14.9×	8e-04	SMARCA2, SMARCA4, ARID1A, ACTB, ARID2, ARID1B
positive regulation of double-strand break repair	7	9.9×	0.002	SMARCA2, SMARCA4, ARID1A, ACTB, ARID2, ARID1B, DDX11
chromatin remodeling	14	4.2×	0.002	SMARCA2, SMARCA4, SMARCA5, ARID1A, ACTB, KDM2B, HDAC4, SRCAP (+6 more)
positive regulation of DNA damage checkpoint	3	52.0×	0.002	TTI2, TTI1, TELO2
positive regulation of T cell differentiation	6	11.2×	0.002	SMARCA2, SMARCA4, ARID1A, ACTB, ARID2, ARID1B
centriole replication	5	15.1×	0.003	PLK4, CPAP, RTTN, CDK5RAP2, WDR62
t-circle formation	4	23.1×	0.003	BLM, SMARCAL1, SLX4, DNA2
mitotic spindle organization	7	7.8×	0.004	NUF2, PCNT, CLASP1, SBDS, POC1A, WDR62, DYNC1H1
cilium assembly	13	3.9×	0.004	PLK4, IFT122, WDR11, PCNT, CPAP, IFT74, POC1A, TMEM216 (+5 more)
positive regulation of cell differentiation	7	7.7×	0.004	SMARCA2, SMARCA4, ARID1A, ACTB, ARID2, ARID1B, CTNNB1
microtubule nucleation	5	12.8×	0.004	PCNT, CLASP1, CPAP, TUBGCP6, TUBGCP5
mitotic sister chromatid cohesion	4	18.5×	0.005	SMC1A, HDAC8, POGZ, NIPBL
positive regulation of neuroblast proliferation	5	12.0×	0.005	SMO, CDON, ASPM, WDR62, CTNNB1
positive regulation of myoblast differentiation	6	9.1×	0.005	SMARCA2, SMARCA4, ARID1A, ACTB, ARID2, ARID1B
mitotic spindle assembly checkpoint signaling	5	11.6×	0.005	BUB1B, NUF2, KNTC1, CENPF, SPDL1
positive regulation of DNA-templated transcription	22	2.5×	0.005	RREB1, SALL1, BLM, SMARCA2, SMARCA4, ARID1A, TAF2, TCF4 (+14 more)
nervous system development	16	3.0×	0.007	SIM1, SMARCA2, SMARCA4, ARID1A, SPOCK1, TCF4, VLDLR, HDAC4 (+8 more)
regulation of G1/S transition of mitotic cell cycle	6	7.6×	0.010	SMARCA2, SMARCA4, ARID1A, ACTB, ARID2, ARID1B
embryonic digit morphogenesis	6	7.4×	0.010	SALL1, TBX2, TBC1D32, CTNNB1, FREM2, IFT140
cerebral cortex development	7	5.9×	0.012	SLC2A1, SMO, TFAP2C, CDON, ASPM, FAT4, WDR62
embryonic brain development	4	13.2×	0.012	MED12, CTNNB1, IFT140, CC2D2A
cognition	6	7.0×	0.012	SLC1A4, CHRNB2, CHD7, SETD5, MFSD2A, NIPBL
mitochondrion organization	8	5.0×	0.012	BCS1L, TERT, YME1L1, AFG1L, CERT1, MFF, WDR81, CLUH
cell division	15	2.9×	0.016	SMC1A, BUB1B, NUF2, CLASP1, KNTC1, CPAP, CDC6, SPART (+7 more)
regulation of neuron differentiation	4	12.1×	0.016	YWHAG, BCL11B, CDK5RAP2, WDR62
regulation of synapse assembly	4	11.6×	0.018	VLDLR, CHRNB2, CTNNB1, SETD5

Therapeutics

Drug target analysis

Approved (phase 4): 14 · Phase ≥3: 14 · Phased (≥1): 23 · Undrugged: 47

Druggability breadth: 102 of 250 evidence-associated genes (41%) 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
BLM	AMIFOSTINE
SCN1A	MEXILETINE HYDROCHLORIDE
SCN4A	CARBAMAZEPINE
SEM1	BORTEZOMIB
SLC2A1	EMETINE
SMC1A	SELUMETINIB
SMO	INFIGRATINIB
PLK4	MOMELOTINIB
BUB1B	CERITINIB
TERT	BERBERINE
NSD2	VENETOCLAX
HDAC8	CELECOXIB
KDM2B	DEFERIPRONE
HDAC4	CELECOXIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BLM	284	4
SCN1A	94	4
PLK4	65	4
HDAC8	37	4
HDAC4	31	4
SCN4A	24	4
SMO	11	4
TERT	10	4
NSD2	8	4
SLC2A1	7	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMIFOSTINE	4	BLM
BEXAROTENE	4	BLM
DICLOFENAC SODIUM	4	BLM
CLOTRIMAZOLE	4	BLM
FLUORESCEIN	4	BLM
OXCARBAZEPINE	4	BLM
BUMETANIDE	4	BLM
GLIPIZIDE	4	BLM
SALMETEROL XINAFOATE	4	BLM
AMIODARONE HYDROCHLORIDE	4	BLM
INDIGOTINDISULFONATE	4	BLM
TRIHEXYPHENIDYL HYDROCHLORIDE	4	BLM
RALOXIFENE HYDROCHLORIDE	4	BLM
IDARUBICIN	4	BLM
EDROPHONIUM CHLORIDE	4	BLM
PINACIDIL ANHYDROUS	4	BLM
DITHIAZANINE	4	BLM
TRIMETREXATE	4	BLM
NICARDIPINE HYDROCHLORIDE	4	BLM
PILOCARPINE HYDROCHLORIDE	4	BLM
PHENYLEPHRINE HYDROCHLORIDE	4	BLM
APRACLONIDINE HYDROCHLORIDE	4	BLM
DOXYLAMINE SUCCINATE	4	BLM
ROPINIROLE HYDROCHLORIDE	4	BLM
TETRAHYDROZOLINE HYDROCHLORIDE	4	BLM
MOLINDONE HYDROCHLORIDE	4	BLM
PARGYLINE HYDROCHLORIDE	4	BLM
GUANFACINE HYDROCHLORIDE	4	BLM
BROMOCRIPTINE MESYLATE	4	BLM
DIHYDROERGOTAMINE MESYLATE	4	BLM

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 14.

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

Symbol	Assays	Type breakdown
HDAC8	2,631	Binding:2599, ADMET:25, Functional:6, Toxicity:1
HDAC4	1,941	Binding:1919, ADMET:13, Functional:6, Toxicity:3
TERT	391	Binding:389, Functional:2
SMARCA2	311	Binding:274, Functional:25, ADMET:12
PLK4	303	Binding:293, Functional:10
NSD2	264	Binding:256, Functional:8
SMARCA4	230	Binding:207, ADMET:12, Functional:11
SLC2A1	158	Binding:130, ADMET:24, Functional:4
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
SMO	131	Binding:111, Functional:20
SCN4A	95	Binding:69, Functional:18, ADMET:7, Toxicity:1
BLM	82	Binding:78, Functional:4
TUBA8	73	Binding:72, Functional:1
TCF4	31	Binding:31
KMT2C	29	Binding:29
KDM2B	28	Binding:28
SEM1	26	Binding:26
ACTB	21	Binding:21
BUB1B	12	Binding:12
YWHAG	12	Binding:11, Functional:1
SMC1A	10	Binding:10
TCOF1	8	Binding:8
LMNB1	7	Binding:7
SPTAN1	7	Binding:7
VARS1	7	Binding:7
AAAS	7	Binding:7
ARID1A	6	Binding:6
MED12	6	Binding:6
SLC12A5	6	Functional:4, Binding:2
SPTLC1	4	Binding:4
SLC1A4	2	Binding:2
TRIO	2	Binding:2
PRDM16	2	Binding:2
TTI1	1	Binding:1
SEC24C	1	Binding:1
SMARCA5	1	Binding:1
STXBP1	1	Binding:1
TALDO1	1	Binding:1
VAPA	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SBF1	3.1.3.16	protein-serine/threonine phosphatase
BLM	3.6.4.12	DNA helicase
CAPN15	3.4.22.B35
SPTLC1	2.3.1.50	serine C-palmitoyltransferase
PLK4	2.7.11.21	polo kinase
BUB1B	2.7.11.1	non-specific serine/threonine protein kinase
TCF4	7.6.2.3	ABC-type glutathione-S-conjugate transporter
VARS1	6.1.1.9	valine-tRNA ligase
NSD2	2.1.1.356, 2.1.1.357, 2.1.1.359	[histone H3]-lysine27 N-trimethyltransferase, [histone H3]-lysine36 N-dimethyltransferase, [histone H3]-lysine36 N-trimethyltransferase
YME1L1	3.4.24.B18
HDAC8	3.5.1.98	histone deacetylase
PRDM16	2.1.1.367, 2.1.1.370	[histone H3]-lysine9 N-methyltransferase, [histone H3]-lysine4 N-dimethyltransferase
HDAC4	3.5.1.98	histone deacetylase
ELAC2	3.1.26.11	tRNase Z

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN1A	149
SLC2A1	158
SMARCA2	311
SMARCA4	230
SMO	131
PLK4	303
TERT	391
NSD2	264
HDAC8	2,631
HDAC4	1,941

Pharmacogenomics

Cohort genes with a PharmGKB record: 69; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
AMIFOSTINE	4	BLM
BEXAROTENE	4	BLM
DICLOFENAC SODIUM	4	BLM
CLOTRIMAZOLE	4	BLM
FLUORESCEIN	4	BLM
OXCARBAZEPINE	4	BLM
BUMETANIDE	4	BLM
GLIPIZIDE	4	BLM
SALMETEROL XINAFOATE	4	BLM
AMIODARONE HYDROCHLORIDE	4	BLM
INDIGOTINDISULFONATE	4	BLM
TRIHEXYPHENIDYL HYDROCHLORIDE	4	BLM
RALOXIFENE HYDROCHLORIDE	4	BLM
IDARUBICIN	4	BLM
EDROPHONIUM CHLORIDE	4	BLM
PINACIDIL ANHYDROUS	4	BLM
DITHIAZANINE	4	BLM
TRIMETREXATE	4	BLM
NICARDIPINE HYDROCHLORIDE	4	BLM
PILOCARPINE HYDROCHLORIDE	4	BLM
PHENYLEPHRINE HYDROCHLORIDE	4	BLM
APRACLONIDINE HYDROCHLORIDE	4	BLM
DOXYLAMINE SUCCINATE	4	BLM
ROPINIROLE HYDROCHLORIDE	4	BLM
TETRAHYDROZOLINE HYDROCHLORIDE	4	BLM
MOLINDONE HYDROCHLORIDE	4	BLM
PARGYLINE HYDROCHLORIDE	4	BLM
GUANFACINE HYDROCHLORIDE	4	BLM
BROMOCRIPTINE MESYLATE	4	BLM
DIHYDROERGOTAMINE MESYLATE	4	BLM

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	14	BLM, SCN1A, SCN4A, SEM1, SLC2A1, SMC1A, SMO, PLK4, BUB1B, TERT (+4 more)
B	Phased (≥1) drug, not yet approved	9	LMNB1, SMARCA2, SMARCA4, SPTAN1, TCF4, TCOF1, MED12, YWHAG, ACTB
C	Druggable family + PDB, no drug	5	SPTLC1, TAF2, TRIO, VAPA, ELAC2
D	Druggable family + AlphaFold only, no drug	4	SBF1, CAPN15, VARS1, YME1L1
E	Difficult family or no structure, no drug	38	TEDC1, SPDL1, TTI1, BCS1L, RREB1, SALL1, SDHD, SEC24C, SIM1, SLC1A4 (+28 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SALL1	0	NSD2
ARID1A	6	SMARCA4, SMARCA2
TEDC1	0	—
SPDL1	0	—
TTI1	1	—
BCS1L	0	—
RREB1	0	—
SBF1	0	—
SDHD	0	—
SEC24C	1	—
SIM1	0	—
SLC1A4	2	—
SLC9A6	0	—
SMARCA5	1	—
SMARCAL1	0	—
SNAP25	0	—
CAPN15	0	—
SPOCK1	0	—
SPTLC1	4	—
STXBP1	1	—
SYNGAP1	0	—
TAF2	0	—
TALDO1	1	—
TBX2	0	—
TFAP2C	0	—
TRIO	2	—
TRPS1	0	—
TUBA8	73	—
VAPA	1	—
VARS1	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 17.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	16
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less