Cornelia de Lange syndrome 4

Summary

Cornelia de Lange syndrome 4 (MONDO:0013864) is a disease caused by RAD21 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: RAD21 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 295

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Cornelia de Lange syndrome 4
Mondo ID	MONDO:0013864
OMIM	614701
DOID	DOID:0080508
UMLS	C3553517
MedGen	766431
GARD	0015837
Is cancer (heuristic)	no

Also known as: CDLS4 · Cornelia de Lange syndrome 4 · Cornelia de Lange syndrome caused by mutation in RAD21 · Cornelia De Lange syndrome type 4 · RAD21 Cornelia de Lange syndrome

Data availability: 295 ClinVar variants · 4 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 4

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 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

295 retrieved; paginated sample, class counts are floors:

111 likely benign, 104 uncertain significance, 28 pathogenic, 16 conflicting classifications of pathogenicity, 12 benign, 11 benign/likely benign, 9 likely pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1034259	NM_006265.3(RAD21):c.85delinsCCT (p.Lys29fs)	RAD21	Pathogenic	criteria provided, single submitter
1185047	NM_006265.3(RAD21):c.1621-384_1704+199del	RAD21	Pathogenic	no assertion criteria provided
1185048	NM_006265.3(RAD21):c.593dup (p.Ser198fs)	RAD21	Pathogenic	no assertion criteria provided
1185049	NM_006265.3(RAD21):c.943_946del (p.Glu315fs)	RAD21	Pathogenic	criteria provided, single submitter
1805433	NM_006265.3(RAD21):c.1635del (p.Gly547fs)	RAD21	Pathogenic	criteria provided, multiple submitters, no conflicts
2001811	NM_006265.3(RAD21):c.1045dup (p.Thr349fs)	RAD21	Pathogenic	criteria provided, single submitter
211993	NM_006265.3(RAD21):c.56_62del (p.Leu19fs)	RAD21	Pathogenic	criteria provided, single submitter
211994	NM_006265.3(RAD21):c.579dup (p.Glu194fs)	RAD21	Pathogenic	criteria provided, single submitter
211995	NM_006265.3(RAD21):c.592_593dup (p.Ser198fs)	RAD21	Pathogenic	criteria provided, single submitter
2584420	NM_006265.3(RAD21):c.193C>T (p.Arg65Ter)	RAD21	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2738121	NM_006265.3(RAD21):c.683del (p.Ile228fs)	RAD21	Pathogenic	criteria provided, single submitter
3064208	NM_006265.3(RAD21):c.68G>A (p.Trp23Ter)	RAD21	Pathogenic	criteria provided, single submitter
3066324	NM_006265.3(RAD21):c.464del (p.Leu155fs)	RAD21	Pathogenic	criteria provided, single submitter
35459	NM_006265.3(RAD21):c.1127C>G (p.Pro376Arg)	RAD21	Pathogenic	no assertion criteria provided
3632951	NM_006265.3(RAD21):c.839C>G (p.Ser280Ter)	RAD21	Pathogenic	criteria provided, single submitter
436481	NM_006265.3(RAD21):c.181_182dup (p.Gly62fs)	RAD21	Pathogenic	criteria provided, single submitter
523217	NM_006265.3(RAD21):c.1550dup (p.Glu518fs)	RAD21	Pathogenic	criteria provided, single submitter
523218	NM_006265.3(RAD21):c.1161+1G>A	RAD21	Pathogenic	criteria provided, single submitter
545121	NM_006265.3(RAD21):c.1774_1776del (p.Gln592del)	RAD21	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
559920	NM_006265.3(RAD21):c.208A>T (p.Lys70Ter)	RAD21	Pathogenic	criteria provided, single submitter
620426	NM_006265.3(RAD21):c.1306C>T (p.Gln436Ter)	RAD21	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802434	NM_006265.3(RAD21):c.144+1G>A	RAD21	Pathogenic	criteria provided, multiple submitters, no conflicts
807668	NM_006265.3(RAD21):c.3G>A (p.Met1Ile)	RAD21	Pathogenic	criteria provided, single submitter
816920	NM_006265.3(RAD21):c.1432C>T (p.Arg478Ter)	RAD21	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
830828	NC_000008.11:g.(?116857267)(116863259_?)del	RAD21	Pathogenic	criteria provided, single submitter
848764	NM_006265.3(RAD21):c.466C>T (p.Gln156Ter)	RAD21	Pathogenic	criteria provided, single submitter
864834	NM_006265.3(RAD21):c.1548delinsTC (p.Glu518fs)	RAD21	Pathogenic	no assertion criteria provided
864835	NM_006265.3(RAD21):c.589C>T (p.Gln197Ter)	RAD21	Pathogenic	criteria provided, single submitter
864836	NM_006265.3(RAD21):c.1217_1224del (p.Lys406fs)	RAD21	Pathogenic	criteria provided, single submitter
981439	NM_006265.3(RAD21):c.1843G>T (p.Glu615Ter)	RAD21	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RAD21	Definitive	Autosomal dominant	Cornelia de Lange syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAD21	Orphanet:199	Cornelia de Lange syndrome
RAD21	Orphanet:502	Trichorhinophalangeal syndrome type 2

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RAD21	HGNC:9811	ENSG00000164754	O60216	Double-strand-break repair protein rad21 homolog	gencc,clinvar
EIF3H	HGNC:3273	ENSG00000147677	O15372	Eukaryotic translation initiation factor 3 subunit H	clinvar
MIR3610	HGNC:38942	ENSG00000283956		microRNA 3610	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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…
EIF3H	Eukaryotic translation initiation factor 3 subunit H	Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Protease	1	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAD21	Other/Unknown	no		Rad21/Rec8_C_eu, Rad21_Rec8_N, ScpA-like_C
EIF3H	Protease	yes		JAMM/MPN+_dom, eIF3h, MPN
MIR3610	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	2
superficial temporal artery	1
ventricular zone	1
cortical plate	1
primordial germ cell in gonad	1
endometrium	1
lymph node	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAD21	301	ubiquitous	marker	ventricular zone, ganglionic eminence, superficial temporal artery
EIF3H	299	ubiquitous	marker	cortical plate, ganglionic eminence, primordial germ cell in gonad
MIR3610	55	ubiquitous	yes	endometrium, skeletal muscle tissue, lymph node

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAD21	5,042
EIF3H	3,091
MIR3610	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAD21	O60216	36
EIF3H	O15372	27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 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
Cohesin Loading onto Chromatin	1	571.0×	0.013	RAD21
Establishment of Sister Chromatid Cohesion	1	519.1×	0.013	RAD21
Formation of the ternary complex, and subsequently, the 43S complex	1	107.7×	0.026	EIF3H
Translation initiation complex formation	1	95.2×	0.026	EIF3H
Ribosomal scanning and start codon recognition	1	95.2×	0.026	EIF3H
SUMOylation of DNA damage response and repair proteins	1	73.2×	0.026	RAD21
Meiotic synapsis	1	70.5×	0.026	RAD21
Formation of a pool of free 40S subunits	1	56.0×	0.026	EIF3H
L13a-mediated translational silencing of Ceruloplasmin expression	1	50.5×	0.026	EIF3H
GTP hydrolysis and joining of the 60S ribosomal subunit	1	50.1×	0.026	EIF3H
Resolution of Sister Chromatid Cohesion	1	43.3×	0.027	RAD21
Estrogen-dependent gene expression	1	37.8×	0.028	RAD21
Separation of Sister Chromatids	1	30.4×	0.033	RAD21

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
establishment of meiotic sister chromatid cohesion	1	2106.5×	0.004	RAD21
negative regulation of mitotic metaphase/anaphase transition	1	2106.5×	0.004	RAD21
positive regulation of sister chromatid cohesion	1	1685.2×	0.004	RAD21
replication-born double-strand break repair via sister chromatid exchange	1	1404.3×	0.004	RAD21
establishment of mitotic sister chromatid cohesion	1	1203.7×	0.004	RAD21
negative regulation of glial cell apoptotic process	1	936.2×	0.005	RAD21
chromatin looping	1	601.9×	0.005	RAD21
formation of cytoplasmic translation initiation complex	1	561.7×	0.005	EIF3H
negative regulation of G2/M transition of mitotic cell cycle	1	561.7×	0.005	RAD21
sister chromatid cohesion	1	383.0×	0.007	RAD21
protein localization to chromatin	1	290.6×	0.008	RAD21
reciprocal meiotic recombination	1	280.9×	0.008	RAD21
negative regulation of interleukin-1 beta production	1	255.3×	0.008	RAD21
regulation of translational initiation	1	234.1×	0.008	EIF3H
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	200.6×	0.008	EIF3H
positive regulation of interleukin-10 production	1	200.6×	0.008	RAD21
translational initiation	1	179.3×	0.009	EIF3H
DNA recombination	1	168.5×	0.009	RAD21
negative regulation of tumor necrosis factor production	1	125.8×	0.011	RAD21
double-strand break repair	1	101.5×	0.013	RAD21
chromosome segregation	1	86.9×	0.014	RAD21
negative regulation of neuron apoptotic process	1	55.4×	0.021	RAD21
response to hypoxia	1	47.9×	0.023	RAD21
cell division	1	23.1×	0.046	RAD21
apoptotic process	1	14.3×	0.071	RAD21
regulation of transcription by RNA polymerase II	1	5.8×	0.164	RAD21

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RAD21	0	0
EIF3H	0	0
MIR3610	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
EIF3H	1	Binding:1

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	EIF3H
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	RAD21, MIR3610

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RAD21	0	—
EIF3H	1	—
MIR3610	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.