short rib-polydactyly syndrome, Majewski type

Summary

short rib-polydactyly syndrome, Majewski type (MONDO:0019662) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		34	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	short rib-polydactyly syndrome, Majewski type
Mondo ID	MONDO:0019662
Orphanet	93269
ICD-11	132740256
SNOMED CT	72922008
GARD	0004833
Is cancer (heuristic)	no

Also known as: polydactyly with neonatal chondrodystrophy type 2 · short rib-polydactyly syndrome Majewski type · short rib-polydactyly syndrome type 2 · SRPS type 2

Data availability: 3 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › syndromic disease › short rib-polydactyly syndrome › short rib-polydactyly syndrome, Majewski type

Related subtypes (3): cranioectodermal dysplasia, Joubert syndrome with Jeune asphyxiating thoracic dystrophy, Jeune syndrome

Subtypes (1): short-rib thoracic dysplasia 6 with or without polydactyly

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 9 · 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
NEK1	Definitive	Autosomal recessive	short-rib thoracic dysplasia 6 with or without polydactyly	9
DYNC2H1	Supportive	Autosomal recessive	short rib-polydactyly syndrome, Majewski type	9
IFT54	Supportive	Autosomal recessive	short rib-polydactyly syndrome, Majewski type	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IFT54	Orphanet:3156	Senior-Loken syndrome
IFT54	Orphanet:93269	Short rib-polydactyly syndrome, Majewski type
DYNC2H1	Orphanet:474	Jeune syndrome
DYNC2H1	Orphanet:93269	Short rib-polydactyly syndrome, Majewski type
DYNC2H1	Orphanet:93270	Short rib-polydactyly syndrome, Saldino-Noonan type
DYNC2H1	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type
NEK1	Orphanet:2751	Orofaciodigital syndrome type 2
NEK1	Orphanet:803	Amyotrophic lateral sclerosis
NEK1	Orphanet:93269	Short rib-polydactyly syndrome, Majewski type

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
IFT54	HGNC:17861	ENSG00000204104	Q8TDR0	TRAF3-interacting protein 1	gencc
DYNC2H1	HGNC:2962	ENSG00000187240	Q8NCM8	Cytoplasmic dynein 2 heavy chain 1	gencc
NEK1	HGNC:7744	ENSG00000137601	Q96PY6	Serine/threonine-protein kinase Nek1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IFT54	TRAF3-interacting protein 1	Plays an inhibitory role on IL13 signaling by binding to IL13RA1.
DYNC2H1	Cytoplasmic dynein 2 heavy chain 1	May function as a motor for intraflagellar retrograde transport.
NEK1	Serine/threonine-protein kinase Nek1	Phosphorylates serines and threonines, but also appears to possess tyrosine kinase activity.

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IFT54	Other/Unknown	no		TRAF3IP1, TRAF3IP1_N, TRAF3IP1_C
DYNC2H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
NEK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 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
bronchial epithelial cell	2
oocyte	2
secondary oocyte	2
sural nerve	1
right uterine tube	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IFT54	265	ubiquitous	marker	oocyte, bronchial epithelial cell, sural nerve
DYNC2H1	230	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, right uterine tube
NEK1	288	ubiquitous	marker	secondary oocyte, trigeminal ganglion, oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DYNC2H1	1,885
NEK1	1,512
IFT54	1,363

Intra-cohort edges

A	B	Sources
DYNC2H1	NEK1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC2H1	Q8NCM8	4
IFT54	Q8TDR0	2
NEK1	Q96PY6	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Intraflagellar transport	2	133.6×	6e-04	IFT54, DYNC2H1
Regulation of pyruvate metabolism	1	190.3×	0.020	NEK1
Pyruvate metabolism	1	135.9×	0.020	NEK1
Hedgehog ‘off’ state	1	59.5×	0.033	DYNC2H1
Cilium Assembly	1	36.2×	0.044	IFT54
Aerobic respiration and respiratory electron transport	1	29.5×	0.045	NEK1
Organelle biogenesis and maintenance	1	22.0×	0.051	IFT54
Metabolism	1	3.9×	0.237	NEK1

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
cilium assembly	3	73.6×	8e-05	IFT54, DYNC2H1, NEK1
kidney development	2	93.6×	0.002	IFT54, DYNC2H1
morphogenesis of a polarized epithelium	1	1404.3×	0.008	IFT54
negative regulation of defense response to virus	1	432.1×	0.010	IFT54
embryonic camera-type eye development	1	401.2×	0.010	IFT54
intraciliary retrograde transport	1	374.5×	0.010	DYNC2H1
negative regulation of interferon-beta production	1	351.1×	0.010	IFT54
spinal cord motor neuron differentiation	1	312.1×	0.010	DYNC2H1
intraciliary anterograde transport	1	295.6×	0.010	IFT54
dorsal/ventral neural tube patterning	1	267.5×	0.010	IFT54
embryonic heart tube development	1	255.3×	0.010	IFT54
post-anal tail morphogenesis	1	244.2×	0.010	IFT54
cilium movement involved in cell motility	1	224.7×	0.010	DYNC2H1
coronary vasculature development	1	208.1×	0.010	DYNC2H1
negative regulation of protein phosphorylation	1	193.7×	0.010	IFT54
intraciliary transport	1	187.2×	0.010	IFT54
regulation of microtubule cytoskeleton organization	1	181.2×	0.010	IFT54
negative regulation of type I interferon production	1	165.2×	0.010	IFT54
negative regulation of protein-containing complex assembly	1	151.8×	0.010	IFT54
negative regulation of smoothened signaling pathway	1	151.8×	0.010	IFT54
dorsal/ventral pattern formation	1	140.4×	0.010	DYNC2H1
positive regulation of smoothened signaling pathway	1	140.4×	0.010	DYNC2H1
embryonic limb morphogenesis	1	133.8×	0.010	DYNC2H1
protein localization to cilium	1	133.8×	0.010	DYNC2H1
forebrain development	1	117.0×	0.011	DYNC2H1
embryonic digit morphogenesis	1	100.3×	0.013	IFT54
non-motile cilium assembly	1	96.8×	0.013	DYNC2H1
determination of left/right symmetry	1	85.1×	0.014	DYNC2H1
protein processing	1	56.7×	0.020	DYNC2H1
Golgi organization	1	44.6×	0.024	DYNC2H1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
NEK1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NEK1	12	4
IFT54	0	0
DYNC2H1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	NEK1
DABRAFENIB	4	NEK1
LESTAURTINIB	3	NEK1
TG100-115	2	NEK1
R-406	2	NEK1
PELITINIB	2	NEK1
GSK-461364	1	NEK1
KW-2449	1	NEK1
AMG-900	1	NEK1
TAK-593	1	NEK1
CYC-116	1	NEK1
AST-487	1	NEK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NEK1	288	Binding:288

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NEK1	288

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

12 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)
FEDRATINIB	4	NEK1
DABRAFENIB	4	NEK1
LESTAURTINIB	3	NEK1
TG100-115	2	NEK1
R-406	2	NEK1
PELITINIB	2	NEK1
GSK-461364	1	NEK1
KW-2449	1	NEK1
AMG-900	1	NEK1
TAK-593	1	NEK1
CYC-116	1	NEK1
AST-487	1	NEK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NEK1
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	2	IFT54, DYNC2H1

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)
DYNC2H1	0	NEK1
IFT54	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.