Cornelia de Lange syndrome 5

Summary

Cornelia de Lange syndrome 5 (MONDO:0010471) is a disease caused by HDAC8 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: HDAC8 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 298

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Cornelia de Lange syndrome 5
Mondo ID	MONDO:0010471
OMIM	300882
DOID	DOID:0080509
UMLS	C3550903
MedGen	763817
GARD	0015271
Is cancer (heuristic)	no

Also known as: CDLS5 · Cornelia de Lange syndrome 5 · Cornelia de Lange syndrome 5, X-linked dominant · Cornelia De Lange syndrome type 5

Data availability: 298 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 5

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

298 retrieved; paginated sample, class counts are floors:

105 likely benign, 76 uncertain significance, 34 pathogenic, 34 likely pathogenic, 28 benign, 10 conflicting classifications of pathogenicity, 8 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
209109	NC_000023.10:g.71681853_72434328del752476	DMRTC1	Pathogenic	no assertion criteria provided
1072722	NM_018486.3(HDAC8):c.164+2dup	HDAC8	Pathogenic	criteria provided, single submitter
1076180	NM_018486.3(HDAC8):c.522C>G (p.Tyr174Ter)	HDAC8	Pathogenic	criteria provided, single submitter
1164056	NM_018486.3(HDAC8):c.471T>G (p.Asp157Glu)	HDAC8	Pathogenic	no assertion criteria provided
1323053	NM_018486.3(HDAC8):c.75_82del (p.Val25_Ser26insTer)	HDAC8	Pathogenic	criteria provided, single submitter
1333326	NM_018486.3(HDAC8):c.881G>A (p.Trp294Ter)	HDAC8	Pathogenic	criteria provided, single submitter
1417489	NM_018486.3(HDAC8):c.956C>T (p.Thr319Ile)	HDAC8	Pathogenic	criteria provided, single submitter
158658	NM_018486.3(HDAC8):c.131del (p.Ser43_Leu44insTer)	HDAC8	Pathogenic	criteria provided, single submitter
1676874	NM_018486.3(HDAC8):c.110G>A (p.Arg37Gln)	HDAC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1742375	NM_018486.3(HDAC8):c.467A>G (p.Asn156Ser)	HDAC8	Pathogenic	criteria provided, multiple submitters, no conflicts
2029945	NM_018486.3(HDAC8):c.748del (p.Glu250fs)	HDAC8	Pathogenic	criteria provided, single submitter
211139	NM_018486.3(HDAC8):c.134_137del (p.Ile45fs)	HDAC8	Pathogenic	criteria provided, multiple submitters, no conflicts
211141	NM_018486.3(HDAC8):c.229C>T (p.Gln77Ter)	HDAC8	Pathogenic	criteria provided, single submitter
2426477	NC_000023.10:g.(?71681834)(71681968_?)del	HDAC8	Pathogenic	criteria provided, single submitter
2445981	NM_018486.3(HDAC8):c.75_82dup (p.Cys28fs)	HDAC8	Pathogenic	no assertion criteria provided
2691318	NM_018486.3(HDAC8):c.1010dup (p.Thr338fs)	HDAC8	Pathogenic	criteria provided, single submitter
280671	NM_018486.3(HDAC8):c.787C>T (p.Gln263Ter)	HDAC8	Pathogenic	criteria provided, multiple submitters, no conflicts
2819953	NM_018486.3(HDAC8):c.738-2A>G	HDAC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3237489	NM_018486.3(HDAC8):c.550+1G>T	HDAC8	Pathogenic	criteria provided, single submitter
3245515	NC_000023.10:g.(?71571563)(71571708_?)del	HDAC8	Pathogenic	criteria provided, single submitter
3245526	NC_000023.10:g.(?71710759)(71715138_?)del	HDAC8	Pathogenic	criteria provided, single submitter
37252	NM_018486.3(HDAC8):c.164+5G>A	HDAC8	Pathogenic	criteria provided, single submitter
39710	NM_018486.3(HDAC8):c.490C>T (p.Arg164Ter)	HDAC8	Pathogenic	criteria provided, multiple submitters, no conflicts
39711	NM_018486.3(HDAC8):c.539A>G (p.His180Arg)	HDAC8	Pathogenic	no assertion criteria provided
39712	NM_018486.3(HDAC8):c.932C>T (p.Thr311Met)	HDAC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39714	NM_018486.3(HDAC8):c.1001A>G (p.His334Arg)	HDAC8	Pathogenic	no assertion criteria provided
419411	NM_018486.3(HDAC8):c.165-2A>G	HDAC8	Pathogenic	criteria provided, multiple submitters, no conflicts
446297	NM_018486.3(HDAC8):c.522C>A (p.Tyr174Ter)	HDAC8	Pathogenic	no assertion criteria provided
4526865	NM_018486.3(HDAC8):c.165-1G>A	HDAC8	Pathogenic	criteria provided, single submitter
4531349	NM_018486.3(HDAC8):c.206_207insTGATGCTTATCTGCAG (p.Phe70fs)	HDAC8	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
HDAC8	Definitive	X-linked	Cornelia de Lange syndrome 5	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HDAC8	Orphanet:199	Cornelia de Lange syndrome
HDAC8	Orphanet:3459	Wilson-Turner syndrome
PHKA1	Orphanet:715	Glycogen storage disease due to muscle phosphorylase kinase deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HDAC8	HGNC:13315	ENSG00000147099	Q9BY41	Histone deacetylase 8	gencc,clinvar
DMRTC1	HGNC:13910	ENSG00000269502	Q5HYR2	Doublesex- and mab-3-related transcription factor C1	clinvar
PHKA1	HGNC:8925	ENSG00000067177	P46020	Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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).
PHKA1	Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform	Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Enzyme (other)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HDAC8	Enzyme (other)	yes	3.5.1.98	HDACs, HDAC_I/II, Ureohydrolase_dom_sf
DMRTC1	Other/Unknown	no		DMRT, DMRT-C1/C2_C
PHKA1	Enzyme (other)	yes	2.7.11.19	PHK_A/B_su, 6-hairpin_glycosidase_sf, GH15-like

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
adrenal tissue	1
colonic epithelium	1
left adrenal gland	1
adenohypophysis	1
pituitary gland	1
right hemisphere of cerebellum	1
biceps brachii	1
gastrocnemius	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HDAC8	244	ubiquitous	marker	colonic epithelium, adrenal tissue, left adrenal gland
DMRTC1	114		yes	adenohypophysis, pituitary gland, right hemisphere of cerebellum
PHKA1	227	ubiquitous	marker	gastrocnemius, skeletal muscle tissue of rectus abdominis, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HDAC8	3,087
PHKA1	973
DMRTC1	256

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HDAC8	Q9BY41	53
PHKA1	P46020	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DMRTC1	Q5HYR2	63.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Glycogen metabolism	1	951.7×	0.013	PHKA1
Glycogen breakdown (glycogenolysis)	1	380.7×	0.016	PHKA1
Notch-HLH transcription pathway	1	203.9×	0.020	HDAC8
NOTCH1 Intracellular Domain Regulates Transcription	1	119.0×	0.020	HDAC8
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	98.5×	0.020	HDAC8
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	98.5×	0.020	HDAC8
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	73.2×	0.022	HDAC8
HDACs deacetylate histones	1	60.1×	0.022	HDAC8
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.022	PHKA1
Resolution of Sister Chromatid Cohesion	1	43.3×	0.028	HDAC8
Separation of Sister Chromatids	1	30.4×	0.036	HDAC8
Metabolism	1	5.8×	0.165	PHKA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of glycogen catabolic process	1	1404.3×	0.008	PHKA1
mitotic sister chromatid cohesion	1	374.5×	0.013	HDAC8
regulation of telomere maintenance	1	280.9×	0.013	HDAC8
glycogen metabolic process	1	175.5×	0.016	PHKA1
generation of precursor metabolites and energy	1	114.6×	0.018	PHKA1
negative regulation of protein ubiquitination	1	95.2×	0.018	HDAC8
heterochromatin formation	1	85.1×	0.018	HDAC8
regulation of protein stability	1	41.9×	0.033	HDAC8
chromatin organization	1	33.0×	0.037	HDAC8
regulation of DNA-templated transcription	1	10.5×	0.101	DMRTC1
negative regulation of transcription by RNA polymerase II	1	5.9×	0.160	HDAC8

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
HDAC8	CELECOXIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HDAC8	37	4
DMRTC1	0	0
PHKA1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CELECOXIB	4	HDAC8
PHENYLBUTANOIC ACID	4	HDAC8
SODIUM PHENYLBUTYRATE	4	HDAC8
ROMIDEPSIN	4	HDAC8
BELINOSTAT	4	HDAC8
PANOBINOSTAT	4	HDAC8
VORINOSTAT	4	HDAC8
GIVINOSTAT	4	HDAC8
DAUNORUBICIN	4	HDAC8
BORTEZOMIB	4	HDAC8
BENDAMUSTINE	4	HDAC8
CURCUMIN	3	HDAC8
CAFFEIC ACID	3	HDAC8
PRACINOSTAT	3	HDAC8
TACEDINALINE	3	HDAC8
ENTINOSTAT	3	HDAC8
TUCIDINOSTAT	3	HDAC8
ABEXINOSTAT	3	HDAC8
NANATINOSTAT	2	HDAC8
AR-42	2	HDAC8
CHLOROGENIC ACID	2	HDAC8
DACINOSTAT	2	HDAC8
FIMEPINOSTAT	2	HDAC8
BUTYRIC ACID	2	HDAC8
QUISINOSTAT	2	HDAC8
RICOLINOSTAT	2	HDAC8
MOCETINOSTAT	2	HDAC8
CITARINOSTAT	2	HDAC8
SODIUM BUTYRATE	2	HDAC8
BAICALEIN	2	HDAC8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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
PHKA1	20	Binding:20

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HDAC8	3.5.1.98	histone deacetylase
PHKA1	2.7.11.19	phosphorylase 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

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
CELECOXIB	4	HDAC8
PHENYLBUTANOIC ACID	4	HDAC8
SODIUM PHENYLBUTYRATE	4	HDAC8
ROMIDEPSIN	4	HDAC8
BELINOSTAT	4	HDAC8
PANOBINOSTAT	4	HDAC8
VORINOSTAT	4	HDAC8
GIVINOSTAT	4	HDAC8
DAUNORUBICIN	4	HDAC8
BORTEZOMIB	4	HDAC8
BENDAMUSTINE	4	HDAC8
CURCUMIN	3	HDAC8
CAFFEIC ACID	3	HDAC8
PRACINOSTAT	3	HDAC8
TACEDINALINE	3	HDAC8
ENTINOSTAT	3	HDAC8
TUCIDINOSTAT	3	HDAC8
ABEXINOSTAT	3	HDAC8
NANATINOSTAT	2	HDAC8
AR-42	2	HDAC8
CHLOROGENIC ACID	2	HDAC8
DACINOSTAT	2	HDAC8
FIMEPINOSTAT	2	HDAC8
BUTYRIC ACID	2	HDAC8
QUISINOSTAT	2	HDAC8
RICOLINOSTAT	2	HDAC8
MOCETINOSTAT	2	HDAC8
CITARINOSTAT	2	HDAC8
SODIUM BUTYRATE	2	HDAC8
BAICALEIN	2	HDAC8

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HDAC8
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PHKA1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DMRTC1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DMRTC1	0	—
PHKA1	20	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.