CK syndrome

Summary

CK syndrome (MONDO:0010441) is a disease caused by NSDHL (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NSDHL (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 42
• Phenotypes (HPO): 35

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		24	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000272	Malar flattening	Very frequent (80-99%)
HP:0000275	Narrow face	Very frequent (80-99%)
HP:0000276	Long face	Very frequent (80-99%)
HP:0000286	Epicanthus	Very frequent (80-99%)
HP:0000308	Microretrognathia	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000426	Prominent nasal bridge	Very frequent (80-99%)
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0000582	Upslanted palpebral fissure	Very frequent (80-99%)
HP:0000678	Dental crowding	Very frequent (80-99%)
HP:0000737	Irritability	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001302	Pachygyria	Very frequent (80-99%)
HP:0001533	Slender build	Very frequent (80-99%)
HP:0002126	Polymicrogyria	Very frequent (80-99%)
HP:0002360	Sleep abnormality	Very frequent (80-99%)
HP:0002381	Aphasia	Very frequent (80-99%)
HP:0002538	Abnormality of the cerebral cortex	Very frequent (80-99%)
HP:0002751	Kyphoscoliosis	Very frequent (80-99%)
HP:0002938	Lumbar hyperlordosis	Very frequent (80-99%)
HP:0007874	Almond-shaped palpebral fissure	Very frequent (80-99%)
HP:0010511	Long toe	Very frequent (80-99%)
HP:0025406	Asthenia	Very frequent (80-99%)
HP:0100807	Long fingers	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000718	Aggressive behavior	Frequent (30-79%)
HP:0000752	Hyperactivity	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0003107	Abnormality of cholesterol metabolism	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	CK syndrome
Mondo ID	MONDO:0010441
OMIM	300831
Orphanet	251383
DOID	DOID:0111898
UMLS	C3151781
MedGen	463131
GARD	0017210
Is cancer (heuristic)	no

Also known as: CK syndrome · CK syndrome, X-linked recessive · mental retardation, X-linked, with thin body habitus and cortical malformation · X-linked intellectual disability-microcephaly-cortical malformation-thin habitus syndrome

Data availability: 42 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › CK syndrome

Related subtypes (16): Smith-Magenis syndrome, intellectual disability, Buenos-Aires type, intellectual disability, Wolff type, AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome, 7p22.1 microduplication syndrome, 9p13 microdeletion syndrome, 3q27.3 microdeletion syndrome, 9q31.1q31.3 microdeletion syndrome, Rubinstein-Taybi syndrome, X-linked syndromic intellectual disability, 9q33.3q34.11 microdeletion syndrome, autosomal recessive syndromic intellectual disability, autosomal dominant syndromic intellectual disability, aplasia cutis-enamel dysplasia syndrome, 2p25.3 microduplication syndrome, dyneinopathy

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

42 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 8 conflicting classifications of pathogenicity, 8 benign/likely benign, 2 pathogenic, 2 likely benign, 1 benign, 1 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
21266	NM_015922.3(NSDHL):c.1098dup (p.Arg367fs)	NSDHL	Pathogenic	criteria provided, single submitter
21268	NM_015922.3(NSDHL):c.693GAA[1] (p.Lys232del)	NSDHL	Pathogenic	no assertion criteria provided
2441794	NM_015922.3(NSDHL):c.387del (p.Ile129fs)	NSDHL	Likely pathogenic	criteria provided, single submitter
1336685	NM_015922.3(NSDHL):c.265C>G (p.Gln89Glu)	NSDHL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1341846	NM_015922.3(NSDHL):c.44G>A (p.Arg15Gln)	NSDHL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1501081	NM_015922.3(NSDHL):c.790-9T>A	NSDHL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1800569	NM_015922.3(NSDHL):c.796C>T (p.His266Tyr)	NSDHL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2052304	NM_015922.3(NSDHL):c.842G>T (p.Arg281Leu)	NSDHL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3301142	NM_015922.3(NSDHL):c.19G>A (p.Glu7Lys)	NSDHL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3598149	NM_015922.3(NSDHL):c.656C>T (p.Ala219Val)	NSDHL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3598157	NM_015922.3(NSDHL):c.1100G>A (p.Arg367His)	NSDHL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1055356	NM_015922.3(NSDHL):c.1037C>G (p.Ala346Gly)	NSDHL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1297520	NM_015922.3(NSDHL):c.947C>G (p.Pro316Arg)	NSDHL	Uncertain significance	criteria provided, single submitter
1311669	NM_015922.3(NSDHL):c.263G>A (p.Arg88Gln)	NSDHL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1361740	NM_015922.3(NSDHL):c.560A>G (p.Asn187Ser)	NSDHL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1468939	NM_015922.3(NSDHL):c.1031A>G (p.Lys344Arg)	NSDHL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1801363	NM_015922.3(NSDHL):c.43C>T (p.Arg15Trp)	NSDHL	Uncertain significance	criteria provided, multiple submitters, no conflicts
2515548	NM_015922.3(NSDHL):c.529A>G (p.Ile177Val)	NSDHL	Uncertain significance	criteria provided, multiple submitters, no conflicts
2687770	NM_015922.3(NSDHL):c.1010A>G (p.Tyr337Cys)	NSDHL	Uncertain significance	criteria provided, single submitter
3377357	NM_015922.3(NSDHL):c.457G>A (p.Val153Ile)	NSDHL	Uncertain significance	criteria provided, multiple submitters, no conflicts
3598146	NM_015922.3(NSDHL):c.74T>C (p.Val25Ala)	NSDHL	Uncertain significance	criteria provided, single submitter
3598150	NM_015922.3(NSDHL):c.691G>A (p.Gly231Arg)	NSDHL	Uncertain significance	criteria provided, single submitter
3598151	NM_015922.3(NSDHL):c.754G>C (p.Glu252Gln)	NSDHL	Uncertain significance	criteria provided, single submitter
3598152	NM_015922.3(NSDHL):c.770A>G (p.Asp257Gly)	NSDHL	Uncertain significance	criteria provided, single submitter
3598153	NM_015922.3(NSDHL):c.780G>A (p.Leu260=)	NSDHL	Uncertain significance	criteria provided, single submitter
3598154	NM_015922.3(NSDHL):c.830C>G (p.Thr277Arg)	NSDHL	Uncertain significance	criteria provided, single submitter
3598156	NM_015922.3(NSDHL):c.847C>G (p.Leu283Val)	NSDHL	Uncertain significance	criteria provided, single submitter
373975	NM_015922.3(NSDHL):c.1054C>G (p.Leu352Val)	NSDHL	Uncertain significance	criteria provided, multiple submitters, no conflicts
436069	NM_015922.3(NSDHL):c.565C>T (p.Pro189Ser)	NSDHL	Uncertain significance	criteria provided, multiple submitters, no conflicts
978118	NM_015922.3(NSDHL):c.1118A>G (p.Lys373Arg)	NSDHL	Uncertain significance	criteria provided, multiple submitters, no conflicts

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
NSDHL	Definitive	X-linked	CK syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NSDHL	Orphanet:139	CHILD syndrome
NSDHL	Orphanet:251383	CK syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NSDHL	HGNC:13398	ENSG00000147383	Q15738	Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NSDHL	Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating	Catalyzes the NAD(P)(+)-dependent oxidative decarboxylation of the C4 methyl groups of 4-alpha-carboxysterols in post-squalene cholesterol biosynthesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NSDHL	Enzyme (other)	yes	1.1.1.170	3Beta_OHSteriod_DH/Estase, NAD(P)-bd_dom_sf, Lipid_A_modif_metabolic_enz

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
cervix squamous epithelium	1
esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NSDHL	271	ubiquitous	marker	cervix squamous epithelium, adrenal tissue, esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NSDHL	3,566

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NSDHL	Q15738	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Zymostenol biosynthesis via lathosterol (Kandutsch-Russell pathway)	1	1268.9×	9e-04	NSDHL
Cholesterol biosynthesis via desmosterol (Bloch pathway)	1	1142.0×	9e-04	NSDHL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete cholesterol biosynthetic process via lathosterol	1	2106.5×	0.003	NSDHL
labyrinthine layer blood vessel development	1	802.5×	0.004	NSDHL
cholesterol biosynthetic process	1	421.3×	0.004	NSDHL
hair follicle development	1	383.0×	0.004	NSDHL
cholesterol metabolic process	1	195.9×	0.006	NSDHL
smoothened signaling pathway	1	181.2×	0.006	NSDHL

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NSDHL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NSDHL	1.1.1.170	3beta-hydroxysteroid-4alpha-carboxylate 3-dehydrogenase (decarboxylating)

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	NSDHL
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NSDHL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.