NEK9-related lethal skeletal dysplasia

Summary

NEK9-related lethal skeletal dysplasia (MONDO:0014870) is a disease caused by NEK9 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NEK9 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	NEK9-related lethal skeletal dysplasia
Mondo ID	MONDO:0014870
OMIM	617022
Orphanet	464366
DOID	DOID:0061266
UMLS	C5568141
MedGen	1799564
GARD	0017818
Is cancer (heuristic)	no

Also known as: LCCS10 · lethal congenital contracture syndrome 10 · lethal congenital contracture syndrome type 10 · lethal skeletal dysplasia-fetal akinesia-contractures-thoracic dysplasia-pulmonary hypoplasia syndrome

Data availability: 13 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › respiratory or thoracic malformation › thoracic malformation › NEK9-related lethal skeletal dysplasia

Related subtypes (14): Acropectorovertebral dysplasia, congenitally short costocoracoid ligament, Sprengel deformity, thoracolaryngopelvic dysplasia, fetal akinesia deformation sequence, lethal congenital contracture syndrome 1, orofaciodigital syndrome IV, thoracic dysplasia-hydrocephalus syndrome, thoracomelic dysplasia, Matthew-Wood syndrome, short rib-polydactyly syndrome, shoulder and thorax deformity-congenital heart disease syndrome, sternal cleft, ossification anomalies-psychomotor developmental delay syndrome

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

13 retrieved; paginated sample, class counts are floors:

3 benign, 3 uncertain significance, 3 likely pathogenic, 2 pathogenic, 1 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
242929	NM_033116.6(NEK9):c.1489C>T (p.Arg497Ter)	NEK9	Pathogenic	criteria provided, single submitter
4277741	NM_033116.6(NEK9):c.2801T>G (p.Leu934Ter)	NEK9	Pathogenic	criteria provided, single submitter
2692319	NM_033116.6(NEK9):c.1367G>A (p.Gly456Asp)	NEK9	Likely pathogenic	criteria provided, single submitter
2692321	NM_033116.6(NEK9):c.1327+2T>C	NEK9	Likely pathogenic	criteria provided, single submitter
4294505	NM_033116.6(NEK9):c.1019del (p.Ala340fs)	NEK9	Likely pathogenic	criteria provided, single submitter
2038281	NM_033116.6(NEK9):c.1840+2T>C	NEK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242930	NM_033116.6(NEK9):c.2042G>A (p.Arg681His)	NEK9	Uncertain significance	criteria provided, single submitter
4279885	NM_033116.6(NEK9):c.2783A>G (p.Gln928Arg)	NEK9	Uncertain significance	criteria provided, single submitter
830039	NM_033116.6(NEK9):c.190G>A (p.Gly64Arg)	NEK9	Uncertain significance	no assertion criteria provided
1181094	NM_033116.6(NEK9):c.324C>T (p.His108=)	NEK9	Benign	criteria provided, multiple submitters, no conflicts
1253709	NM_033116.6(NEK9):c.300T>A (p.Ile100=)	NEK9	Benign	criteria provided, multiple submitters, no conflicts
1325899	NM_033116.6(NEK9):c.*13G>A	NEK9	Benign	criteria provided, multiple submitters, no conflicts
982714	NM_033116.6(NEK9):c.1126G>A (p.Ala376Thr)	NEK9	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
NEK9	Definitive	Autosomal recessive	renal-hepatic-pancreatic dysplasia 2	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NEK9	Orphanet:464366	NEK9-related lethal skeletal dysplasia
NEK9	Orphanet:64754	Nevus comedonicus 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
NEK9	HGNC:18591	ENSG00000119638	Q8TD19	Serine/threonine-protein kinase Nek9	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NEK9	Serine/threonine-protein kinase Nek9	Pleiotropic regulator of mitotic progression, participating in the control of spindle dynamics and chromosome separation.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NEK9	Kinase	yes		Reg_chr_condens, Prot_kinase_dom, Ser/Thr_kinase_AS

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
left ovary	1
right uterine tube	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NEK9	296	ubiquitous	marker	tibia, right uterine tube, left ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NEK9	2,341

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NEK9	Q8TD19	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Activation of NIMA Kinases NEK9, NEK6, NEK7	1	1427.5×	0.006	NEK9
Nuclear Envelope Breakdown	1	456.8×	0.007	NEK9
Mitotic Prophase	1	368.4×	0.007	NEK9
Nuclear Pore Complex (NPC) Disassembly	1	308.6×	0.007	NEK9
EML4 and NUDC in mitotic spindle formation	1	92.8×	0.019	NEK9
Mitotic Prometaphase	1	69.2×	0.019	NEK9
M Phase	1	66.0×	0.019	NEK9
Cell Cycle, Mitotic	1	48.2×	0.023	NEK9
Cell Cycle	1	36.0×	0.028	NEK9

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
regulation of mitotic cell cycle	1	240.7×	0.011	NEK9
mitotic cell cycle	1	133.8×	0.011	NEK9
cell division	1	46.2×	0.022	NEK9

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
NEK9	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NEK9	21	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	NEK9
FEDRATINIB	4	NEK9
DABRAFENIB	4	NEK9
PACRITINIB	4	NEK9
FOSTAMATINIB	4	NEK9
CRIZOTINIB	4	NEK9
DOVITINIB	3	NEK9
LESTAURTINIB	3	NEK9
FORETINIB	2	NEK9
REBASTINIB	2	NEK9
DANUSERTIB	2	NEK9
R-406	2	NEK9
ENMD-2076	2	NEK9
AT-9283	2	NEK9
MILCICLIB	2	NEK9
BMS-754807	2	NEK9
GSK-461364	1	NEK9
KW-2449	1	NEK9
XL-019	1	NEK9
CYC-116	1	NEK9
AST-487	1	NEK9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NEK9	254	Binding:254

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NEK9	254

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

21 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)
MOMELOTINIB	4	NEK9
FEDRATINIB	4	NEK9
DABRAFENIB	4	NEK9
PACRITINIB	4	NEK9
FOSTAMATINIB	4	NEK9
CRIZOTINIB	4	NEK9
DOVITINIB	3	NEK9
LESTAURTINIB	3	NEK9
FORETINIB	2	NEK9
REBASTINIB	2	NEK9
DANUSERTIB	2	NEK9
R-406	2	NEK9
ENMD-2076	2	NEK9
AT-9283	2	NEK9
MILCICLIB	2	NEK9
BMS-754807	2	NEK9
GSK-461364	1	NEK9
KW-2449	1	NEK9
XL-019	1	NEK9
CYC-116	1	NEK9
AST-487	1	NEK9

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NEK9
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	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.