Cornelia de Lange syndrome 1
diseaseOn this page
Also known as CDLS1Cornelia de Lange syndrome caused by mutation in NIPBLCornelia De Lange syndrome type 1NIPBL Cornelia de Lange syndrome
Summary
Cornelia de Lange syndrome 1 (MONDO:0007387) is a disease caused by NIPBL (GenCC Definitive), with 11 cohort genes. The dominant Reactome pathway is Cohesin Loading onto Chromatin (4 cohort genes).
At a glance
- Causal gene: NIPBL (GenCC Definitive)
- Cohort genes: 11
- ClinVar variants: 1,698
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | Cornelia de Lange syndrome 1 |
| Mondo ID | MONDO:0007387 |
| OMIM | 122470 |
| DOID | DOID:0080505 |
| SNOMED CT | 40354009 |
| UMLS | C4551851 |
| MedGen | 1645760 |
| GARD | 0024555 |
| Is cancer (heuristic) | no |
Also known as: CDLS1 · Cornelia de Lange syndrome 1 · Cornelia de Lange syndrome caused by mutation in NIPBL · Cornelia De Lange syndrome type 1 · NIPBL Cornelia de Lange syndrome
Data availability: 1,698 ClinVar variants · 3 GenCC gene-disease records.
Disease family
Classification path: disease › human disease › disease by body system or component › syndromic disease › Cornelia de Lange syndrome › Cornelia de Lange syndrome 1
Related subtypes (5): Cornelia de Lange syndrome 2, Cornelia de Lange syndrome 5, Cornelia de Lange syndrome 3, Cornelia de Lange syndrome 4, Cornelia de Lange syndrome 6
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:
208 pathogenic, 134 uncertain significance, 85 likely benign, 67 conflicting classifications of pathogenicity, 63 likely pathogenic, 15 pathogenic/likely pathogenic, 14 benign/likely benign, 14 benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1459695 | NC_000005.9:g.(?36970958)(37371079_?)del | CPLANE1 | Pathogenic | criteria provided, single submitter |
| 180201 | NM_001197104.2(KMT2A):c.2233C>T (p.Arg745Ter) | KMT2A | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1000617 | NM_133433.4(NIPBL):c.7199G>C (p.Arg2400Pro) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1066128 | NM_133433.4(NIPBL):c.5808+2T>C | NIPBL | Pathogenic | criteria provided, single submitter |
| 1070037 | NM_133433.4(NIPBL):c.7854del (p.Tyr2618_Leu2619insTer) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1071194 | NM_133433.4(NIPBL):c.5269del (p.Val1757fs) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1072674 | NM_133433.4(NIPBL):c.4675_4750dup (p.Leu1584delinsGlnThrThrValTer) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1074354 | NM_133433.4(NIPBL):c.4643+1G>A | NIPBL | Pathogenic | criteria provided, single submitter |
| 1075044 | NM_133433.4(NIPBL):c.2837dup (p.Leu946fs) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1075076 | NC_000005.9:g.(?36953799)(37064994_?)del | NIPBL | Pathogenic | criteria provided, single submitter |
| 1075092 | NM_133433.4(NIPBL):c.7013del (p.Ala2338fs) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1075290 | NM_133433.4(NIPBL):c.1942del (p.Thr648fs) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1076020 | NM_133433.4(NIPBL):c.4335T>G (p.Tyr1445Ter) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1076024 | NM_133433.4(NIPBL):c.8326del (p.Ile2776fs) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1076298 | NM_133433.4(NIPBL):c.2207del (p.Pro736fs) | NIPBL | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1195876 | NM_133433.4(NIPBL):c.-467C>T | NIPBL | Pathogenic/Likely pathogenic | no assertion criteria provided |
| 1319902 | NM_133433.4(NIPBL):c.5808+5G>A | NIPBL | Pathogenic/Likely pathogenic | no assertion criteria provided |
| 1320125 | NM_133433.4(NIPBL):c.10dup (p.Asp4fs) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1328515 | NM_133433.4(NIPBL):c.7948dup (p.Ile2650fs) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1351385 | NM_133433.4(NIPBL):c.3178del (p.Glu1060fs) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1359106 | NM_133433.4(NIPBL):c.6359T>G (p.Leu2120Ter) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1366117 | NM_133433.4(NIPBL):c.4455_4456dup (p.Tyr1486fs) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1379181 | NM_133433.4(NIPBL):c.1786_1790del (p.Asn595_His596insTer) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1382932 | NM_133433.4(NIPBL):c.3040del (p.Gln1014fs) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1383143 | NM_133433.4(NIPBL):c.3100A>T (p.Lys1034Ter) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1390979 | NM_133433.4(NIPBL):c.4502_4503dup (p.Val1502fs) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1395044 | NM_133433.4(NIPBL):c.373C>T (p.Gln125Ter) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1399376 | NM_133433.4(NIPBL):c.6080_6083dup (p.Gln2028fs) | NIPBL | Pathogenic | criteria provided, single submitter |
| 1402649 | NM_133433.4(NIPBL):c.8326dup (p.Ile2776fs) | NIPBL | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1406195 | NM_133433.4(NIPBL):c.5725dup (p.Thr1909fs) | NIPBL | Pathogenic | criteria provided, single submitter |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 4 · Orphanet: 27 · 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 |
|---|---|---|---|---|
| NIPBL | Definitive | Autosomal dominant | Cornelia de Lange syndrome 1 | 4 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| NIPBL | Orphanet:199 | Cornelia de Lange syndrome |
| NIPBL | Orphanet:329802 | 5p13 microduplication syndrome |
| SMC1A | Orphanet:199 | Cornelia de Lange syndrome |
| SMC1A | Orphanet:220386 | Semilobar holoprosencephaly |
| SMC1A | Orphanet:3095 | Atypical Rett syndrome |
| SMC1A | Orphanet:708203 | Intellectual disability-small hands and feet-drug-resistant epilepsy syndrome |
| TAF6 | Orphanet:694946 | Alazami-Yuan syndrome |
| HDAC8 | Orphanet:199 | Cornelia de Lange syndrome |
| HDAC8 | Orphanet:3459 | Wilson-Turner syndrome |
| BRD4 | Orphanet:199 | Cornelia de Lange syndrome |
| BRD4 | Orphanet:443167 | NUT midline carcinoma |
| ANTXR1 | Orphanet:2067 | GAPO syndrome |
| SMC3 | Orphanet:199 | Cornelia de Lange syndrome |
| CPLANE1 | Orphanet:2754 | Orofaciodigital syndrome type 6 |
| CPLANE1 | Orphanet:475 | Isolated Joubert syndrome |
| CPLANE1 | Orphanet:65684 | Monomelic amyotrophy |
| KMT2A | Orphanet:319182 | Wiedemann-Steiner syndrome |
| KMT2A | Orphanet:402017 | Acute myeloid leukemia with t(9;11)(p22;q23) |
| KMT2A | Orphanet:585918 | B-lymphoblastic leukemia/lymphoma with t(v;11q23.3) |
| KMT2A | Orphanet:589534 | Mixed phenotype acute leukemia with t(9;22)(q34.1;q11.2) |
| KMT2A | Orphanet:589595 | Mixed phenotype acute leukemia with t(v;11q23.3) |
| KMT2A | Orphanet:98831 | Acute myeloid leukemia with 11q23 abnormalities |
| KMT2A | Orphanet:98835 | Acute undifferentiated leukemia |
| ATR | Orphanet:313846 | Familial cutaneous telangiectasia and oropharyngeal cancer predisposition syndrome |
| ATR | Orphanet:808 | Seckel syndrome |
| RAD21 | Orphanet:199 | Cornelia de Lange syndrome |
| RAD21 | Orphanet:502 | Trichorhinophalangeal syndrome type 2 |
Cohort genes → proteins
11 cohort genes, 11 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 11 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| NIPBL | HGNC:28862 | ENSG00000164190 | Q6KC79 | Nipped-B-like protein | gencc,clinvar |
| SMC1A | HGNC:11111 | ENSG00000072501 | Q14683 | Structural maintenance of chromosomes protein 1A | clinvar |
| TAF6 | HGNC:11540 | ENSG00000106290 | P49848 | Transcription initiation factor TFIID subunit 6 | clinvar |
| HDAC8 | HGNC:13315 | ENSG00000147099 | Q9BY41 | Histone deacetylase 8 | clinvar |
| BRD4 | HGNC:13575 | ENSG00000141867 | O60885 | Bromodomain-containing protein 4 | clinvar |
| ANTXR1 | HGNC:21014 | ENSG00000169604 | Q9H6X2 | Anthrax toxin receptor 1 | clinvar |
| SMC3 | HGNC:2468 | ENSG00000108055 | Q9UQE7 | Structural maintenance of chromosomes protein 3 | clinvar |
| CPLANE1 | HGNC:25801 | ENSG00000197603 | Q9H799 | Ciliogenesis and planar polarity effector 1 | clinvar |
| KMT2A | HGNC:7132 | ENSG00000118058 | Q03164 | Histone-lysine N-methyltransferase 2A | clinvar |
| ATR | HGNC:882 | ENSG00000175054 | Q13535 | Serine/threonine-protein kinase ATR | clinvar |
| RAD21 | HGNC:9811 | ENSG00000164754 | O60216 | Double-strand-break repair protein rad21 homolog | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| NIPBL | Nipped-B-like protein | Plays an important role in the loading of the cohesin complex on to DNA. |
| SMC1A | Structural maintenance of chromosomes protein 1A | Involved in chromosome cohesion during cell cycle and in DNA repair. |
| TAF6 | Transcription initiation factor TFIID subunit 6 | The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription. |
| HDAC8 | Histone deacetylase 8 | Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). |
| BRD4 | Bromodomain-containing protein 4 | Chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation. |
| ANTXR1 | Anthrax toxin receptor 1 | Plays a role in cell attachment and migration. |
| SMC3 | Structural maintenance of chromosomes protein 3 | Central component of cohesin, a complex required for chromosome cohesion during the cell cycle. |
| CPLANE1 | Ciliogenesis and planar polarity effector 1 | Involved in ciliogenesis. |
| KMT2A | Histone-lysine N-methyltransferase 2A | Histone methyltransferase that plays an essential role in early development and hematopoiesis. |
| ATR | Serine/threonine-protein kinase ATR | Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. |
| RAD21 | Double-strand-break repair protein rad21 homolog | As a member of the cohesin complex, involved in sister chromatid cohesion from the time of DNA replication in S phase to their segregation in mitosis, a function that is essential for proper chromosome segregation, post-replicative DNA rep… |
Protein-family classification
Druggable: 2 · Difficult: 2 · Unknown: 7 · Druggable fraction: 0.18
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 | 1 | 2.5× | 0.758 |
| Scaffold/PPI | 1 | 1.6× | 0.758 |
| Other/Unknown | 7 | 1.1× | 0.758 |
| Enzyme (other) | 1 | 1.1× | 0.758 |
| Transcription factor | 1 | 0.8× | 0.758 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| NIPBL | Other/Unknown | no | ARM-like, ARM-type_fold, Nipped-B_C | |
| SMC1A | Other/Unknown | no | RecF/RecN/SMC_N, SMC_hinge, SMC | |
| TAF6 | Other/Unknown | no | TAF_TATA-bd_Histone-like_dom, Histone-fold, TAF6_C | |
| HDAC8 | Enzyme (other) | yes | 3.5.1.98 | HDACs, HDAC_I/II, Ureohydrolase_dom_sf |
| BRD4 | Other/Unknown | no | Bromodomain, Bromodomain_CS, NET_dom | |
| ANTXR1 | Other/Unknown | no | VWF_A, Anthrax_toxin_rcpt_C, Anthrax_toxin_rcpt_extracel | |
| SMC3 | Other/Unknown | no | RecF/RecN/SMC_N, SMC_hinge, SMC | |
| CPLANE1 | Scaffold/PPI | no | CPLANE1, WD40_repeat_dom_sf | |
| KMT2A | Transcription factor | no | SET_dom, Bromodomain, Znf_PHD | |
| ATR | Kinase | yes | 2.7.11.1 | PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom |
| RAD21 | Other/Unknown | no | Rad21/Rec8_C_eu, Rad21_Rec8_N, ScpA-like_C |
Expression context
Cohort genes with no expression data: 0.
11 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) | 11 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| sural nerve | 4 |
| colonic epithelium | 3 |
| ventricular zone | 3 |
| calcaneal tendon | 2 |
| male germ line stem cell (sensu Vertebrata) in testis | 2 |
| stromal cell of endometrium | 2 |
| adrenal tissue | 2 |
| tendon of biceps brachii | 2 |
| embryo | 1 |
| trabecular bone tissue | 1 |
| right frontal lobe | 1 |
| right hemisphere of cerebellum | 1 |
| left adrenal gland | 1 |
| buccal mucosa cell | 1 |
| decidua | 1 |
| palpebral conjunctiva | 1 |
| oocyte | 1 |
| Brodmann (1909) area 23 | 1 |
| epithelium of nasopharynx | 1 |
| ganglionic eminence | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| NIPBL | 288 | ubiquitous | marker | male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon, colonic epithelium |
| SMC1A | 289 | ubiquitous | marker | sural nerve, trabecular bone tissue, embryo |
| TAF6 | 290 | ubiquitous | marker | stromal cell of endometrium, right hemisphere of cerebellum, right frontal lobe |
| HDAC8 | 244 | ubiquitous | marker | colonic epithelium, adrenal tissue, left adrenal gland |
| BRD4 | 300 | ubiquitous | marker | buccal mucosa cell, sural nerve, tendon of biceps brachii |
| ANTXR1 | 270 | ubiquitous | marker | stromal cell of endometrium, decidua, palpebral conjunctiva |
| SMC3 | 276 | ubiquitous | marker | tendon of biceps brachii, ventricular zone, oocyte |
| CPLANE1 | 195 | ubiquitous | marker | sural nerve, calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis |
| KMT2A | 285 | ubiquitous | marker | ventricular zone, colonic epithelium, sural nerve |
| ATR | 289 | ubiquitous | marker | Brodmann (1909) area 23, epithelium of nasopharynx, adrenal tissue |
| RAD21 | 301 | ubiquitous | marker | ventricular zone, ganglionic eminence, superficial temporal artery |
Protein interactions among cohort
Intra-cohort edges: 12.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| BRD4 | 7,883 |
| SMC1A | 5,246 |
| SMC3 | 5,056 |
| RAD21 | 5,042 |
| KMT2A | 4,314 |
| ATR | 3,541 |
| NIPBL | 3,278 |
| HDAC8 | 3,087 |
| TAF6 | 2,598 |
| ANTXR1 | 2,039 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| BRD4 | NIPBL | string_interaction |
| CPLANE1 | NIPBL | string_interaction |
| HDAC8 | NIPBL | string_interaction |
| HDAC8 | SMC1A | string_interaction |
| HDAC8 | SMC3 | string_interaction |
| KMT2A | TAF6 | biogrid_interaction |
| NIPBL | RAD21 | intact, string_interaction |
| NIPBL | SMC1A | intact, string_interaction |
| NIPBL | SMC3 | string_interaction |
| RAD21 | SMC1A | biogrid_interaction, intact, string_interaction |
| RAD21 | SMC3 | biogrid_interaction, intact, string_interaction |
| SMC1A | SMC3 | biogrid_interaction, intact, string_interaction |
Structural data
PDB: 10 · AlphaFold-only: 1 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| BRD4 | O60885 | 619 |
| KMT2A | Q03164 | 60 |
| HDAC8 | Q9BY41 | 53 |
| RAD21 | O60216 | 36 |
| TAF6 | P49848 | 32 |
| SMC1A | Q14683 | 18 |
| SMC3 | Q9UQE7 | 12 |
| ATR | Q13535 | 10 |
| ANTXR1 | Q9H6X2 | 5 |
| NIPBL | Q6KC79 | 3 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| CPLANE1 | Q9H799 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 92. Enrichment computed across 11 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Cohesin Loading onto Chromatin | 4 | 456.8× | 6e-09 | NIPBL, SMC1A, SMC3, RAD21 |
| Establishment of Sister Chromatid Cohesion | 3 | 311.4× | 4e-06 | SMC1A, SMC3, RAD21 |
| Meiotic synapsis | 4 | 56.4× | 1e-05 | SMC1A, SMC3, ATR, RAD21 |
| Resolution of Sister Chromatid Cohesion | 4 | 34.6× | 8e-05 | SMC1A, HDAC8, SMC3, RAD21 |
| Meiosis | 3 | 85.7× | 9e-05 | SMC1A, SMC3, ATR |
| Reproduction | 3 | 57.1× | 2e-04 | SMC1A, SMC3, ATR |
| Separation of Sister Chromatids | 4 | 24.3× | 2e-04 | SMC1A, HDAC8, SMC3, RAD21 |
| Mitotic Telophase/Cytokinesis | 2 | 285.5× | 2e-04 | SMC1A, SMC3 |
| SUMOylation of DNA damage response and repair proteins | 3 | 43.9× | 4e-04 | SMC1A, SMC3, RAD21 |
| Estrogen-dependent gene expression | 3 | 22.7× | 0.002 | SMC1A, SMC3, RAD21 |
| S Phase | 2 | 36.2× | 0.010 | SMC1A, SMC3 |
| SUMO E3 ligases SUMOylate target proteins | 2 | 35.7× | 0.010 | SMC1A, SMC3 |
| SUMOylation | 2 | 32.6× | 0.011 | SMC1A, SMC3 |
| Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells) | 2 | 29.3× | 0.013 | HDAC8, KMT2A |
| Cell Cycle | 3 | 10.8× | 0.013 | SMC1A, SMC3, ATR |
| Regulation of TP53 Activity | 2 | 26.6× | 0.014 | TAF6, ATR |
| ESR-mediated signaling | 2 | 25.7× | 0.014 | SMC1A, SMC3 |
| Regulation of TP53 Activity through Phosphorylation | 2 | 23.6× | 0.016 | TAF6, ATR |
| Regulation of PD-L1(CD274) transcription | 2 | 21.8× | 0.017 | BRD4, KMT2A |
| Signaling by Nuclear Receptors | 2 | 20.4× | 0.019 | SMC1A, SMC3 |
| Mitotic Metaphase and Anaphase | 2 | 19.4× | 0.019 | SMC1A, SMC3 |
| Mitotic Anaphase | 2 | 19.4× | 0.019 | SMC1A, SMC3 |
| RNA Polymerase II Transcription | 3 | 6.8× | 0.033 | TAF6, KMT2A, ATR |
| Mitotic Prometaphase | 2 | 13.8× | 0.033 | SMC1A, SMC3 |
| M Phase | 2 | 13.2× | 0.035 | SMC1A, SMC3 |
| Uptake and function of anthrax toxins | 1 | 95.2× | 0.036 | ANTXR1 |
| Transcriptional Regulation by TP53 | 2 | 12.4× | 0.036 | TAF6, ATR |
| Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters | 1 | 87.8× | 0.037 | KMT2A |
| Diseases of DNA Double-Strand Break Repair | 1 | 81.6× | 0.037 | ATR |
| Defective homologous recombination repair (HRR) due to BRCA2 loss of function | 1 | 81.6× | 0.037 | ATR |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| establishment of mitotic sister chromatid cohesion | 4 | 875.4× | 5e-10 | NIPBL, SMC1A, SMC3, RAD21 |
| mitotic sister chromatid cohesion | 4 | 408.5× | 9e-09 | NIPBL, SMC1A, HDAC8, SMC3 |
| establishment of meiotic sister chromatid cohesion | 3 | 1149.0× | 4e-08 | SMC1A, SMC3, RAD21 |
| sister chromatid cohesion | 3 | 208.9× | 1e-05 | SMC1A, SMC3, RAD21 |
| replication-born double-strand break repair via sister chromatid exchange | 2 | 510.7× | 2e-04 | NIPBL, RAD21 |
| chromatin looping | 2 | 218.9× | 8e-04 | NIPBL, RAD21 |
| mitotic sister chromatid segregation | 2 | 87.5× | 0.005 | NIPBL, SMC1A |
| mitotic spindle assembly | 2 | 62.5× | 0.008 | SMC1A, SMC3 |
| external genitalia morphogenesis | 1 | 1532.0× | 0.009 | NIPBL |
| regulation of developmental growth | 1 | 766.0× | 0.009 | NIPBL |
| gallbladder development | 1 | 766.0× | 0.009 | NIPBL |
| response to DNA damage checkpoint signaling | 1 | 766.0× | 0.009 | SMC1A |
| negative regulation of DNA methylation-dependent heterochromatin formation | 1 | 766.0× | 0.009 | KMT2A |
| establishment of RNA localization to telomere | 1 | 766.0× | 0.009 | ATR |
| establishment of protein-containing complex localization to telomere | 1 | 766.0× | 0.009 | ATR |
| positive regulation of telomerase catalytic core complex assembly | 1 | 766.0× | 0.009 | ATR |
| somatic stem cell population maintenance | 2 | 45.1× | 0.009 | NIPBL, SMC1A |
| meiotic cell cycle | 2 | 44.4× | 0.009 | SMC1A, SMC3 |
| double-strand break repair | 2 | 36.9× | 0.009 | ATR, RAD21 |
| DNA repair | 3 | 17.4× | 0.009 | SMC1A, SMC3, ATR |
| DNA damage response | 3 | 14.6× | 0.009 | NIPBL, BRD4, ATR |
| cell division | 3 | 12.6× | 0.009 | SMC1A, SMC3, RAD21 |
| nuclear membrane disassembly | 1 | 510.7× | 0.011 | ATR |
| negative regulation of DNA damage checkpoint | 1 | 510.7× | 0.011 | BRD4 |
| maintenance of mitotic sister chromatid cohesion | 1 | 383.0× | 0.013 | NIPBL |
| ear morphogenesis | 1 | 383.0× | 0.013 | NIPBL |
| negative regulation of mitotic metaphase/anaphase transition | 1 | 383.0× | 0.013 | RAD21 |
| eye morphogenesis | 1 | 383.0× | 0.013 | NIPBL |
| negative regulation of extracellular matrix assembly | 1 | 383.0× | 0.013 | ANTXR1 |
| positive regulation of sister chromatid cohesion | 1 | 306.4× | 0.015 | RAD21 |
Therapeutics
Drug target analysis
Approved (phase 4): 4 · Phase ≥3: 5 · Phased (≥1): 6 · Undrugged: 5
Druggability breadth: 7 of 11 evidence-associated genes (64%) 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 |
|---|---|
| SMC1A | SELUMETINIB |
| HDAC8 | CELECOXIB |
| BRD4 | ACETAMINOPHEN |
| KMT2A | FLUORESCEIN |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| KMT2A | 535 | 4 |
| HDAC8 | 37 | 4 |
| BRD4 | 31 | 4 |
| ATR | 8 | 3 |
| SMC1A | 2 | 4 |
| SMC3 | 1 | 2 |
| NIPBL | 0 | 0 |
| TAF6 | 0 | 0 |
| ANTXR1 | 0 | 0 |
| CPLANE1 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| SELUMETINIB | 4 | SMC1A |
| CELECOXIB | 4 | HDAC8 |
| PHENYLBUTANOIC ACID | 4 | HDAC8 |
| SODIUM PHENYLBUTYRATE | 4 | HDAC8 |
| ROMIDEPSIN | 4 | BRD4, HDAC8 |
| BELINOSTAT | 4 | BRD4, HDAC8 |
| PANOBINOSTAT | 4 | BRD4, HDAC8 |
| VORINOSTAT | 4 | BRD4, HDAC8 |
| GIVINOSTAT | 4 | HDAC8 |
| DAUNORUBICIN | 4 | HDAC8, KMT2A |
| BORTEZOMIB | 4 | HDAC8 |
| BENDAMUSTINE | 4 | HDAC8 |
| ACETAMINOPHEN | 4 | BRD4, KMT2A |
| FEDRATINIB | 4 | BRD4 |
| NITROXOLINE | 4 | BRD4 |
| ALPRAZOLAM | 4 | BRD4 |
| LENALIDOMIDE | 4 | BRD4 |
| NORFLOXACIN | 4 | BRD4 |
| FLUORESCEIN | 4 | KMT2A |
| METHYSERGIDE | 4 | KMT2A |
| OXCARBAZEPINE | 4 | KMT2A |
| TRYPAN BLUE FREE ACID | 4 | KMT2A |
| RALOXIFENE HYDROCHLORIDE | 4 | KMT2A |
| IDARUBICIN | 4 | KMT2A |
| DULOXETINE | 4 | KMT2A |
| PYRITHIONE ZINC | 4 | KMT2A |
| HYDROCORTISONE VALERATE | 4 | KMT2A |
| PROMETHAZINE HYDROCHLORIDE | 4 | KMT2A |
| THIORIDAZINE HYDROCHLORIDE | 4 | KMT2A |
| METHYSERGIDE MALEATE | 4 | KMT2A |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 2.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| BRD4 | 4,603 | Binding:4569, Functional:30, ADMET:4 |
| HDAC8 | 2,631 | Binding:2599, ADMET:25, Functional:6, Toxicity:1 |
| ATR | 231 | Binding:226, Functional:5 |
| KMT2A | 188 | Binding:180, Functional:8 |
| SMC1A | 10 | Binding:10 |
| SMC3 | 7 | Binding:7 |
| TAF6 | 1 | Binding:1 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| HDAC8 | 3.5.1.98 | histone deacetylase |
| ATR | 2.7.11.1 | non-specific serine/threonine protein kinase |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| HDAC8 | 2,631 |
| BRD4 | 4,603 |
| KMT2A | 188 |
| ATR | 231 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 11; 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) |
|---|---|---|
| SELUMETINIB | 4 | SMC1A |
| CELECOXIB | 4 | HDAC8 |
| PHENYLBUTANOIC ACID | 4 | HDAC8 |
| SODIUM PHENYLBUTYRATE | 4 | HDAC8 |
| ROMIDEPSIN | 4 | BRD4, HDAC8 |
| BELINOSTAT | 4 | BRD4, HDAC8 |
| PANOBINOSTAT | 4 | BRD4, HDAC8 |
| VORINOSTAT | 4 | BRD4, HDAC8 |
| GIVINOSTAT | 4 | HDAC8 |
| DAUNORUBICIN | 4 | HDAC8, KMT2A |
| BORTEZOMIB | 4 | HDAC8 |
| BENDAMUSTINE | 4 | HDAC8 |
| ACETAMINOPHEN | 4 | BRD4, KMT2A |
| FEDRATINIB | 4 | BRD4 |
| NITROXOLINE | 4 | BRD4 |
| ALPRAZOLAM | 4 | BRD4 |
| LENALIDOMIDE | 4 | BRD4 |
| NORFLOXACIN | 4 | BRD4 |
| FLUORESCEIN | 4 | KMT2A |
| METHYSERGIDE | 4 | KMT2A |
| OXCARBAZEPINE | 4 | KMT2A |
| TRYPAN BLUE FREE ACID | 4 | KMT2A |
| RALOXIFENE HYDROCHLORIDE | 4 | KMT2A |
| IDARUBICIN | 4 | KMT2A |
| DULOXETINE | 4 | KMT2A |
| PYRITHIONE ZINC | 4 | KMT2A |
| HYDROCORTISONE VALERATE | 4 | KMT2A |
| PROMETHAZINE HYDROCHLORIDE | 4 | KMT2A |
| THIORIDAZINE HYDROCHLORIDE | 4 | KMT2A |
| METHYSERGIDE MALEATE | 4 | KMT2A |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 4 | SMC1A, HDAC8, BRD4, KMT2A |
| B | Phased (≥1) drug, not yet approved | 2 | SMC3, ATR |
| C | Druggable family + PDB, no drug | 0 | |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 5 | NIPBL, TAF6, ANTXR1, CPLANE1, RAD21 |
Undrugged target profiles
5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| NIPBL | 0 | SMC1A, SMC3 |
| RAD21 | 0 | SMC1A, SMC3 |
| TAF6 | 1 | — |
| ANTXR1 | 0 | — |
| CPLANE1 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.