Cornelia de Lange syndrome 6

Summary

Cornelia de Lange syndrome 6 (MONDO:0957921) is a disease caused by BRD4 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: BRD4 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Cornelia de Lange syndrome 6
Mondo ID	MONDO:0957921
OMIM	620568
DOID	DOID:0060970
UMLS	C5882712
MedGen	1848930
GARD	0026892
Is cancer (heuristic)	no

Data availability: 18 ClinVar variants · 2 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 6

Related subtypes (5): Cornelia de Lange syndrome 1, Cornelia de Lange syndrome 2, Cornelia de Lange syndrome 5, Cornelia de Lange syndrome 3, Cornelia de Lange syndrome 4

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

18 retrieved; paginated sample, class counts are floors:

9 likely pathogenic, 4 pathogenic, 4 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2671881	NM_001379291.1(BRD4):c.1224delinsCA (p.Glu408fs)	BRD4	Pathogenic	no assertion criteria provided
2671882	NM_001379291.1(BRD4):c.2753_2754insT (p.Pro919fs)	BRD4	Pathogenic	no assertion criteria provided
4538455	NM_001379291.1(BRD4):c.1552-1G>A	BRD4	Pathogenic	criteria provided, single submitter
4820175	NM_001379291.1(BRD4):c.285+1G>T	BRD4	Pathogenic	criteria provided, single submitter
2443328	NM_001379291.1(BRD4):c.1289A>G (p.Tyr430Cys)	BRD4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2920692	NM_001379291.1(BRD4):c.3312_3319del (p.Gln1105fs)	BRD4	Likely pathogenic	criteria provided, single submitter
2920709	NM_001379291.1(BRD4):c.2728dup (p.Gln910fs)	BRD4	Likely pathogenic	criteria provided, single submitter
3629461	NM_001379291.1(BRD4):c.1698_1701dup (p.Pro568fs)	BRD4	Likely pathogenic	criteria provided, single submitter
3775476	NM_001379291.1(BRD4):c.394_395del (p.Met132fs)	BRD4	Likely pathogenic	criteria provided, single submitter
4293038	NM_001379291.1(BRD4):c.1315dup (p.Val439fs)	BRD4	Likely pathogenic	criteria provided, single submitter
4755534	NM_001379291.1(BRD4):c.3710_3719del (p.Arg1237fs)	BRD4	Likely pathogenic	criteria provided, single submitter
4796708	NM_001379291.1(BRD4):c.2211+2T>C	BRD4	Likely pathogenic	criteria provided, single submitter
977428	NM_001379291.1(BRD4):c.710_711del (p.Pro237fs)	BRD4	Likely pathogenic	criteria provided, single submitter
2418246	NM_001379291.1(BRD4):c.2194G>A (p.Gly732Arg)	BRD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3779237	NM_014423.4(AFF4):c.2480A>G (p.Glu827Gly)	AFF4	Uncertain significance	criteria provided, single submitter
2671883	NM_001379291.1(BRD4):c.883A>C (p.Thr295Pro)	BRD4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3393157	NM_001379291.1(BRD4):c.3889CAGCAA[3] (p.Gln1300_Ala1301insGlnGln)	BRD4	Uncertain significance	criteria provided, single submitter
3775808	NM_001379291.1(BRD4):c.4020+1G>C	BRD4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · 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
BRD4	Strong	Autosomal dominant	Cornelia de Lange syndrome 6	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRD4	Orphanet:199	Cornelia de Lange syndrome
BRD4	Orphanet:443167	NUT midline carcinoma
AFF4	Orphanet:444077	Cognitive impairment-coarse facies-heart defects-obesity-pulmonary involvement-short stature-skeletal dysplasia syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRD4	HGNC:13575	ENSG00000141867	O60885	Bromodomain-containing protein 4	gencc,clinvar
AFF4	HGNC:17869	ENSG00000072364	Q9UHB7	AF4/FMR2 family member 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
AFF4	AF4/FMR2 family member 4	Key component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRD4	Other/Unknown	no		Bromodomain, Bromodomain_CS, NET_dom
AFF4	Other/Unknown	no		AF4/FMR2, AF4_int, AF4/FMR2_CHD

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
sural nerve	1
tendon of biceps brachii	1
esophagus squamous epithelium	1
germinal epithelium of ovary	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRD4	300	ubiquitous	marker	buccal mucosa cell, sural nerve, tendon of biceps brachii
AFF4	271	ubiquitous	marker	esophagus squamous epithelium, germinal epithelium of ovary, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRD4	7,883
AFF4	2,471

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRD4	O60885	619
AFF4	Q9UHB7	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

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

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of RNA Pol II elongation complex	1	96.8×	0.040	AFF4
RNA Polymerase II Transcription Elongation	1	96.8×	0.040	AFF4
RNA Polymerase II Pre-transcription Events	1	68.8×	0.040	AFF4
Potential therapeutics for SARS	1	57.1×	0.040	BRD4
Regulation of PD-L1(CD274) transcription	1	54.4×	0.040	BRD4
SARS-CoV Infections	1	27.7×	0.066	BRD4
Viral Infection Pathways	1	15.4×	0.100	BRD4
Infectious disease	1	12.4×	0.106	BRD4
RNA Polymerase II Transcription	1	11.3×	0.106	AFF4
Gene expression (Transcription)	1	8.9×	0.120	AFF4
Disease	1	6.5×	0.147	BRD4

GO biological processes by enrichment

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

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of DNA damage checkpoint	1	2808.7×	0.005	BRD4
positive regulation of T-helper 17 cell lineage commitment	1	1053.2×	0.007	BRD4
host-mediated suppression of viral transcription	1	648.1×	0.008	BRD4
positive regulation of G2/M transition of mitotic cell cycle	1	300.9×	0.012	BRD4
positive regulation of transcription elongation by RNA polymerase II	1	150.5×	0.020	BRD4
regulation of inflammatory response	1	84.3×	0.026	BRD4
response to endoplasmic reticulum stress	1	83.4×	0.026	AFF4
spermatid development	1	72.6×	0.026	AFF4
regulation of gene expression	1	41.7×	0.037	AFF4
chromatin remodeling	1	36.5×	0.037	BRD4
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.037	BRD4
DNA damage response	1	26.8×	0.046	BRD4
positive regulation of DNA-templated transcription	1	14.0×	0.081	BRD4
positive regulation of transcription by RNA polymerase II	1	7.4×	0.139	BRD4
regulation of transcription by RNA polymerase II	1	5.8×	0.164	BRD4

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
BRD4	ACETAMINOPHEN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRD4	31	4
AFF4	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ACETAMINOPHEN	4	BRD4
FEDRATINIB	4	BRD4
NITROXOLINE	4	BRD4
ROMIDEPSIN	4	BRD4
BELINOSTAT	4	BRD4
PANOBINOSTAT	4	BRD4
ALPRAZOLAM	4	BRD4
LENALIDOMIDE	4	BRD4
NORFLOXACIN	4	BRD4
VORINOSTAT	4	BRD4
VOLASERTIB	3	BRD4
DINACICLIB	3	BRD4
TACEDINALINE	3	BRD4
APABETALONE	3	BRD4
PELABRESIB	3	BRD4
MOLIBRESIB	2	AFF4, BRD4
CLOXYQUIN	2	BRD4
SF-1126	2	BRD4
BIRABRESIB	2	BRD4
AMREDOBRESIB	2	BRD4
ALOBRESIB	2	BRD4
MIVEBRESIB	2	BRD4
EZOBRESIB	2	BRD4
BI-2536	2	BRD4
7-ETHYL-10-HYDROXYCAMPTOTHECIN	2	BRD4
METHYLPYRROLIDONE	1	BRD4
AZD-5153	1	BRD4
RO-6870810	1	BRD4
ABBV-744	1	BRD4
PLX-51107	1	BRD4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
BRD4	4,603	Binding:4569, Functional:30, ADMET:4
AFF4	9	Binding:9

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BRD4	4,603

Pharmacogenomics

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

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

Chemical tractability of cohort targets

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)
ACETAMINOPHEN	4	BRD4
FEDRATINIB	4	BRD4
NITROXOLINE	4	BRD4
ROMIDEPSIN	4	BRD4
BELINOSTAT	4	BRD4
PANOBINOSTAT	4	BRD4
ALPRAZOLAM	4	BRD4
LENALIDOMIDE	4	BRD4
NORFLOXACIN	4	BRD4
VORINOSTAT	4	BRD4
VOLASERTIB	3	BRD4
DINACICLIB	3	BRD4
TACEDINALINE	3	BRD4
APABETALONE	3	BRD4
PELABRESIB	3	BRD4
MOLIBRESIB	2	AFF4, BRD4
CLOXYQUIN	2	BRD4
SF-1126	2	BRD4
BIRABRESIB	2	BRD4
AMREDOBRESIB	2	BRD4
ALOBRESIB	2	BRD4
MIVEBRESIB	2	BRD4
EZOBRESIB	2	BRD4
BI-2536	2	BRD4
7-ETHYL-10-HYDROXYCAMPTOTHECIN	2	BRD4
METHYLPYRROLIDONE	1	BRD4
AZD-5153	1	BRD4
RO-6870810	1	BRD4
ABBV-744	1	BRD4
PLX-51107	1	BRD4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BRD4
B	Phased (≥1) drug, not yet approved	1	AFF4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.