Cornelia de Lange syndrome 2

Summary

Cornelia de Lange syndrome 2 (MONDO:0010370) is a disease caused by SMC1A (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: SMC1A (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 867

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Cornelia de Lange syndrome 2
Mondo ID	MONDO:0010370
OMIM	300590
DOID	DOID:0080506
NCIT	C75485
UMLS	C1802395
MedGen	315658
GARD	0015259
Is cancer (heuristic)	no

Also known as: CDLS2 · Cornelia de Lange syndrome 2 · Cornelia de Lange syndrome 2, X-linked dominant · Cornelia de Lange syndrome caused by mutation in SMC1A · Cornelia De Lange syndrome type 2 · SMC1A Cornelia de Lange syndrome · X-linked Cornelia De Lange syndrome

Data availability: 867 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 2

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

249 likely benign, 158 uncertain significance, 68 pathogenic, 36 benign, 32 conflicting classifications of pathogenicity, 32 likely pathogenic, 16 benign/likely benign, 9 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
212267	NM_006306.4(SMC1A):c.2369G>A (p.Arg790Gln)	MIR6857	Pathogenic	criteria provided, multiple submitters, no conflicts
2425562	NC_000023.10:g.(?53222149)(55057617_?)del	MIR98	Pathogenic	criteria provided, single submitter
1032427	NM_006306.4(SMC1A):c.157dup (p.Thr53fs)	SMC1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068642	NM_006306.4(SMC1A):c.3145C>T (p.Arg1049Ter)	SMC1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1068693	NM_006306.4(SMC1A):c.2842_2845dup (p.Asp949delinsGlyTer)	SMC1A	Pathogenic	criteria provided, single submitter
1069931	NM_006306.4(SMC1A):c.10del (p.Phe3_Leu4insTer)	SMC1A	Pathogenic	criteria provided, single submitter
1069969	NM_006306.4(SMC1A):c.2398C>T (p.Gln800Ter)	SMC1A	Pathogenic	criteria provided, single submitter
1072544	NC_000023.10:g.(?53449431)(53449549_?)del	SMC1A	Pathogenic	criteria provided, single submitter
1074295	NM_006306.4(SMC1A):c.2923C>T (p.Arg975Ter)	SMC1A	Pathogenic	criteria provided, single submitter
1075881	NM_006306.4(SMC1A):c.481del (p.Ser161fs)	SMC1A	Pathogenic	criteria provided, single submitter
1076178	NM_006306.4(SMC1A):c.586C>G (p.Arg196Gly)	SMC1A	Pathogenic	criteria provided, single submitter
1076799	NM_006306.4(SMC1A):c.2132G>A (p.Arg711Gln)	SMC1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1164033	NM_006306.4(SMC1A):c.2341T>C (p.Cys781Arg)	SMC1A	Pathogenic	no assertion criteria provided
1164034	NM_006306.4(SMC1A):c.1171C>T (p.Gln391Ter)	SMC1A	Pathogenic	criteria provided, single submitter
11672	NM_006306.4(SMC1A):c.2493_2495del (p.Asp831_Gln832delinsGlu)	SMC1A	Pathogenic	no assertion criteria provided
11673	NM_006306.4(SMC1A):c.1478A>C (p.Glu493Ala)	SMC1A	Pathogenic	no assertion criteria provided
11674	NM_006306.4(SMC1A):c.173_187del (p.Val58_Arg62del)	SMC1A	Pathogenic	no assertion criteria provided
11675	NM_006306.4(SMC1A):c.1487G>A (p.Arg496His)	SMC1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1320145	NM_006306.4(SMC1A):c.109+575dup	SMC1A	Pathogenic	criteria provided, single submitter
1346682	NM_006306.4(SMC1A):c.1607A>G (p.Lys536Arg)	SMC1A	Pathogenic	criteria provided, single submitter
1351039	NM_006306.4(SMC1A):c.2437C>T (p.Gln813Ter)	SMC1A	Pathogenic	criteria provided, single submitter
1351269	NM_006306.4(SMC1A):c.2173C>T (p.Arg725Ter)	SMC1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1378122	NM_006306.4(SMC1A):c.302del (p.Gly101fs)	SMC1A	Pathogenic	criteria provided, single submitter
1398517	NM_006306.4(SMC1A):c.628C>T (p.Gln210Ter)	SMC1A	Pathogenic	criteria provided, single submitter
1418836	NM_006306.4(SMC1A):c.2899C>T (p.Gln967Ter)	SMC1A	Pathogenic	criteria provided, single submitter
1419270	NM_006306.4(SMC1A):c.286C>T (p.Arg96Cys)	SMC1A	Pathogenic	criteria provided, single submitter
1446827	NM_006306.4(SMC1A):c.761del (p.Lys254fs)	SMC1A	Pathogenic	criteria provided, single submitter
1453732	NM_006306.4(SMC1A):c.547_548del (p.Gln183fs)	SMC1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1455114	NM_006306.4(SMC1A):c.733_734del (p.Lys245fs)	SMC1A	Pathogenic	criteria provided, single submitter
1455891	NM_006306.4(SMC1A):c.2132_2139del (p.Arg711fs)	SMC1A	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 10 · 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
SMC1A	Definitive	X-linked	Cornelia de Lange syndrome 2	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
IQSEC2	Orphanet:217377	Microduplication Xp11.22p11.23 syndrome
IQSEC2	Orphanet:397933	Severe intellectual disability-progressive postnatal microcephaly-midline stereotypic hand movements syndrome
IQSEC2	Orphanet:819	Smith-Magenis syndrome
HSD17B10	Orphanet:391428	HSD10 disease, infantile type
HSD17B10	Orphanet:391457	HSD10 disease, neonatal type
HSD17B10	Orphanet:85295	HSD10 disease, atypical type

Cohort genes → proteins

5 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMC1A	HGNC:11111	ENSG00000072501	Q14683	Structural maintenance of chromosomes protein 1A	gencc,clinvar
IQSEC2	HGNC:29059	ENSG00000124313	Q5JU85	IQ motif and SEC7 domain-containing protein 2	clinvar
MIR98	HGNC:31649	ENSG00000271886		microRNA 98	clinvar
HSD17B10	HGNC:4800	ENSG00000072506	Q99714	3-hydroxyacyl-CoA dehydrogenase type-2	clinvar
MIR6857	HGNC:50263	ENSG00000278204		microRNA 6857	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMC1A	Structural maintenance of chromosomes protein 1A	Involved in chromosome cohesion during cell cycle and in DNA repair.
IQSEC2	IQ motif and SEC7 domain-containing protein 2	Is a guanine nucleotide exchange factor for the ARF GTP-binding proteins.
HSD17B10	3-hydroxyacyl-CoA dehydrogenase type-2	Mitochondrial dehydrogenase involved in pathways of fatty acid, branched-chain amino acid and steroid metabolism.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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
Scaffold/PPI	1	3.5×	0.530
Enzyme (other)	1	2.4×	0.530
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMC1A	Other/Unknown	no		RecF/RecN/SMC_N, SMC_hinge, SMC
IQSEC2	Scaffold/PPI	no		Sec7_dom, PH_domain, PH-like_dom_sf
MIR98	Other/Unknown	no
HSD17B10	Enzyme (other)	yes	1.1.1.135	SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf
MIR6857	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)	1
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	2
embryo	1
trabecular bone tissue	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
endometrium	1
olfactory segment of nasal mucosa	1
liver	1
right adrenal gland	1
right lobe of liver	1
adult mammalian kidney	1
blood	1
esophagogastric junction muscularis propria	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMC1A	289	ubiquitous	marker	sural nerve, trabecular bone tissue, embryo
IQSEC2	236	ubiquitous	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
MIR98	61		yes	olfactory segment of nasal mucosa, sural nerve, endometrium
HSD17B10	155	ubiquitous	marker	right lobe of liver, liver, right adrenal gland
MIR6857	17		yes	blood, adult mammalian kidney, esophagogastric junction muscularis propria

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMC1A	5,246
HSD17B10	2,961
IQSEC2	1,296
MIR98	0
MIR6857	0

Intra-cohort edges

A	B	Sources
IQSEC2	SMC1A	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMC1A	Q14683	18
HSD17B10	Q99714	15
IQSEC2	Q5JU85	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 5 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
tRNA processing in the mitochondrion	1	1142.0×	0.009	HSD17B10
Mitotic Telophase/Cytokinesis	1	713.8×	0.009	SMC1A
rRNA processing in the mitochondrion	1	634.4×	0.009	HSD17B10
Cohesin Loading onto Chromatin	1	571.0×	0.009	SMC1A
Establishment of Sister Chromatid Cohesion	1	519.1×	0.009	SMC1A
tRNA modification in the mitochondrion	1	519.1×	0.009	HSD17B10
Branched-chain amino acid catabolism	1	237.9×	0.017	HSD17B10
Meiosis	1	142.8×	0.025	SMC1A
Reproduction	1	95.2×	0.029	SMC1A
S Phase	1	90.6×	0.029	SMC1A
SUMO E3 ligases SUMOylate target proteins	1	89.2×	0.029	SMC1A
SUMOylation	1	81.6×	0.029	SMC1A
SUMOylation of DNA damage response and repair proteins	1	73.2×	0.029	SMC1A
Meiotic synapsis	1	70.5×	0.029	SMC1A
ESR-mediated signaling	1	64.2×	0.030	SMC1A
Mitochondrial protein degradation	1	57.1×	0.031	HSD17B10
Signaling by Nuclear Receptors	1	51.0×	0.031	SMC1A
Mitotic Metaphase and Anaphase	1	48.4×	0.031	SMC1A
Mitotic Anaphase	1	48.4×	0.031	SMC1A
Resolution of Sister Chromatid Cohesion	1	43.3×	0.033	SMC1A
Estrogen-dependent gene expression	1	37.8×	0.036	SMC1A
Mitotic Prometaphase	1	34.6×	0.038	SMC1A
M Phase	1	33.0×	0.038	SMC1A
Separation of Sister Chromatids	1	30.4×	0.039	SMC1A
Cell Cycle, Mitotic	1	24.1×	0.048	SMC1A
Cell Cycle	1	18.0×	0.061	SMC1A
Post-translational protein modification	1	9.6×	0.109	SMC1A
Metabolism of proteins	1	6.2×	0.161	SMC1A
Signal Transduction	1	5.1×	0.187	SMC1A

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
brexanolone metabolic process	1	5617.3×	0.004	HSD17B10
response to DNA damage checkpoint signaling	1	2808.7×	0.004	SMC1A
mitochondrial tRNA methylation	1	1872.4×	0.004	HSD17B10
mitochondrial tRNA 5’-end processing	1	1872.4×	0.004	HSD17B10
establishment of meiotic sister chromatid cohesion	1	1404.3×	0.004	SMC1A
mitochondrial tRNA 3’-end processing	1	1404.3×	0.004	HSD17B10
C21-steroid hormone metabolic process	1	1123.5×	0.004	HSD17B10
L-isoleucine catabolic process	1	936.2×	0.004	HSD17B10
establishment of mitotic sister chromatid cohesion	1	802.5×	0.005	SMC1A
positive regulation of long-term synaptic depression	1	624.1×	0.005	IQSEC2
response to radiation	1	401.2×	0.007	SMC1A
mitotic sister chromatid cohesion	1	374.5×	0.007	SMC1A
androgen metabolic process	1	295.6×	0.007	HSD17B10
regulation of ARF protein signal transduction	1	295.6×	0.007	IQSEC2
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	1	295.6×	0.007	IQSEC2
sister chromatid cohesion	1	255.3×	0.008	SMC1A
bile acid biosynthetic process	1	208.1×	0.008	HSD17B10
estrogen metabolic process	1	208.1×	0.008	HSD17B10
positive regulation of synaptic transmission, glutamatergic	1	208.1×	0.008	IQSEC2
mitotic sister chromatid segregation	1	160.5×	0.010	SMC1A
fatty acid beta-oxidation	1	124.8×	0.013	HSD17B10
mitotic spindle assembly	1	114.6×	0.013	SMC1A
somatic stem cell population maintenance	1	82.6×	0.016	SMC1A
meiotic cell cycle	1	81.4×	0.016	SMC1A
positive regulation of synapse assembly	1	81.4×	0.016	IQSEC2
protein homotetramerization	1	79.1×	0.016	HSD17B10
fatty acid metabolic process	1	64.6×	0.019	HSD17B10
modulation of chemical synaptic transmission	1	61.1×	0.019	IQSEC2
mitochondrion organization	1	50.6×	0.022	HSD17B10
lipid metabolic process	1	30.5×	0.036	HSD17B10

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
HSD17B10	LEVODOPA

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HSD17B10	249	4
SMC1A	2	4
IQSEC2	0	0
MIR98	0	0
MIR6857	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SELUMETINIB	4	SMC1A
LEVODOPA	4	HSD17B10
PHENYLBUTAZONE	4	HSD17B10
CANDESARTAN CILEXETIL	4	HSD17B10
TELMISARTAN	4	HSD17B10
DIENESTROL	4	HSD17B10
CHOLECALCIFEROL	4	HSD17B10
BUMETANIDE	4	HSD17B10
SALMETEROL XINAFOATE	4	HSD17B10
SULFAPHENAZOLE	4	HSD17B10
RALOXIFENE HYDROCHLORIDE	4	HSD17B10
DICYCLOMINE	4	HSD17B10
CISPLATIN	4	HSD17B10
TETRABENAZINE	4	HSD17B10
DECAMETHONIUM	4	HSD17B10
LABETALOL HYDROCHLORIDE	4	HSD17B10
DIMENHYDRINATE	4	HSD17B10
HYDROXYZINE PAMOATE	4	HSD17B10
MALATHION	4	HSD17B10
PYRITHIONE ZINC	4	HSD17B10
AVOBENZONE	4	HSD17B10
CEFOXITIN SODIUM	4	HSD17B10
OXYMETHOLONE	4	HSD17B10
FEXOFENADINE HYDROCHLORIDE	4	HSD17B10
GEMIFLOXACIN MESYLATE	4	HSD17B10
AMPICILLIN SODIUM	4	HSD17B10
CHLOROTRIANISENE	4	HSD17B10
TRAZODONE HYDROCHLORIDE	4	HSD17B10
ETHOPROPAZINE HYDROCHLORIDE	4	HSD17B10
PHENAZOPYRIDINE HYDROCHLORIDE	4	HSD17B10

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HSD17B10	41	Binding:39, Functional:2
SMC1A	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HSD17B10	1.1.1.135, 1.1.1.178, 1.1.1.35, 1.1.1.62	GDP-6-deoxy-D-talose 4-dehydrogenase, 3-hydroxy-2-methylbutyryl-CoA dehydrogenase, 3-hydroxyacyl-CoA dehydrogenase, 17beta-estradiol 17-dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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
LEVODOPA	4	HSD17B10
PHENYLBUTAZONE	4	HSD17B10
CANDESARTAN CILEXETIL	4	HSD17B10
TELMISARTAN	4	HSD17B10
DIENESTROL	4	HSD17B10
CHOLECALCIFEROL	4	HSD17B10
BUMETANIDE	4	HSD17B10
SALMETEROL XINAFOATE	4	HSD17B10
SULFAPHENAZOLE	4	HSD17B10
RALOXIFENE HYDROCHLORIDE	4	HSD17B10
DICYCLOMINE	4	HSD17B10
CISPLATIN	4	HSD17B10
TETRABENAZINE	4	HSD17B10
DECAMETHONIUM	4	HSD17B10
LABETALOL HYDROCHLORIDE	4	HSD17B10
DIMENHYDRINATE	4	HSD17B10
HYDROXYZINE PAMOATE	4	HSD17B10
MALATHION	4	HSD17B10
PYRITHIONE ZINC	4	HSD17B10
AVOBENZONE	4	HSD17B10
CEFOXITIN SODIUM	4	HSD17B10
OXYMETHOLONE	4	HSD17B10
FEXOFENADINE HYDROCHLORIDE	4	HSD17B10
GEMIFLOXACIN MESYLATE	4	HSD17B10
AMPICILLIN SODIUM	4	HSD17B10
CHLOROTRIANISENE	4	HSD17B10
TRAZODONE HYDROCHLORIDE	4	HSD17B10
ETHOPROPAZINE HYDROCHLORIDE	4	HSD17B10
PHENAZOPYRIDINE HYDROCHLORIDE	4	HSD17B10

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SMC1A, HSD17B10
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	IQSEC2, MIR98, MIR6857

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)
IQSEC2	0	SMC1A
MIR98	0	—
MIR6857	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.