Beemer-Langer syndrome

Summary

Beemer-Langer syndrome (MONDO:0010024) is a disease with 7 cohort genes. The dominant Reactome pathway is Intraflagellar transport (4 cohort genes).

At a glance

• Cohort genes: 7
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Beemer-Langer syndrome
Mondo ID	MONDO:0010024
MeSH	C537599
OMIM	269860
Orphanet	93268
DOID	DOID:9249
SNOMED CT	254052001
UMLS	C0432198
MedGen	96578
GARD	0004832
Is cancer (heuristic)	no

Also known as: Beemer Langer syndrome · Beemer-Langer syndrome · short rib polydactyly syndrome Beemer-Langer type · short rib-polydactyly syndrome Beemer type · short rib-polydactyly syndrome type 4 · short rib-polydactyly syndrome type IV · short-rib thoracic dysplasia 12 · SRPS type 4 · SRTD12

Data availability: 11 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › ciliopathy › Jeune syndrome › Beemer-Langer syndrome

Related subtypes (23): asphyxiating thoracic dystrophy 1, Ellis-van Creveld syndrome, short-rib thoracic dysplasia 6 with or without polydactyly, short-rib thoracic dysplasia 9 with or without polydactyly, asphyxiating thoracic dystrophy 2, asphyxiating thoracic dystrophy 3, asphyxiating thoracic dystrophy 4, short-rib thoracic dysplasia 7 with or without polydactyly, asphyxiating thoracic dystrophy 5, short-rib thoracic dysplasia 8 with or without polydactyly, short-rib thoracic dysplasia 10 with or without polydactyly, short-rib thoracic dysplasia 11 with or without polydactyly, short-rib thoracic dysplasia 13 with or without polydactyly, short-rib thoracic dysplasia 14 with polydactyly, short-rib thoracic dysplasia 15 with polydactyly, short-rib thoracic dysplasia 16 with or without polydactyly, short-rib thoracic dysplasia 21 without polydactyly, short-rib thoracic dysplasia 19 with or without polydactyly, short-rib thoracic dysplasia 18 with polydactyly, short-rib thoracic dysplasia 20 with polydactyly, short-rib thoracic dysplasia 17 with or without polydactyly, Jeune syndrome - GRK2-related, short-rib thoracic dysplasia 22 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

ClinVar germline variants

11 retrieved; paginated sample, class counts are floors:

5 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
446664	NM_147127.5(EVC2):c.1708C>T (p.Gln570Ter)	EVC2	Pathogenic	criteria provided, multiple submitters, no conflicts
446685	NM_147127.5(EVC2):c.3121C>T (p.Gln1041Ter)	EVC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446652	NM_020800.3(IFT80):c.487_490del (p.Leu163fs)	IFT80	Pathogenic/Likely pathogenic	no assertion criteria provided
446650	NM_024753.5(TTC21B):c.1320del (p.Phe440fs)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446651	NM_024753.5(TTC21B):c.3605T>C (p.Leu1202Pro)	TTC21B	Pathogenic/Likely pathogenic	no assertion criteria provided
446637	NM_025132.4(WDR19):c.475G>A (p.Asp159Asn)	WDR19	Pathogenic/Likely pathogenic	no assertion criteria provided
446636	NM_025132.4(WDR19):c.3484-2A>C	WDR19	Likely pathogenic	criteria provided, single submitter
216490	NM_001377.3(DYNC2H1):c.6047A>G (p.Tyr2016Cys)	DYNC2H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
281122	NM_147127.5(EVC2):c.1823G>A (p.Arg608His)	EVC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
446674	NM_001199397.3(NEK1):c.418G>A (p.Gly140Arg)	NEK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
406217	NM_020800.3(IFT80):c.1093A>G (p.Thr365Ala)	TRIM59-IFT80	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 18 · 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
IFT80	Supportive	Autosomal recessive	Beemer-Langer syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IFT80	Orphanet:474	Jeune syndrome
IFT80	Orphanet:93268	Short rib-polydactyly syndrome, Beemer-Langer type
IFT80	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type
WDR19	Orphanet:1515	Cranioectodermal dysplasia
WDR19	Orphanet:3156	Senior-Loken syndrome
WDR19	Orphanet:474	Jeune syndrome
WDR19	Orphanet:93592	Juvenile nephronophthisis
EVC2	Orphanet:289	Ellis Van Creveld syndrome
EVC2	Orphanet:952	Acrofacial dysostosis, Weyers type
TTC21B	Orphanet:474	Jeune syndrome
TTC21B	Orphanet:93591	Infantile nephronophthisis
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

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IFT80	HGNC:29262	ENSG00000068885	Q9P2H3	Intraflagellar transport protein 80 homolog	gencc,clinvar
WDR19	HGNC:18340	ENSG00000157796	Q8NEZ3	WD repeat-containing protein 19	clinvar
EVC2	HGNC:19747	ENSG00000173040	Q86UK5	Limbin	clinvar
TTC21B	HGNC:25660	ENSG00000123607	Q7Z4L5	Tetratricopeptide repeat protein 21B	clinvar
DYNC2H1	HGNC:2962	ENSG00000187240	Q8NCM8	Cytoplasmic dynein 2 heavy chain 1	clinvar
TRIM59-IFT80	HGNC:56756	ENSG00000248710		TRIM59-IFT80 readthrough (NMD candidate)	clinvar
NEK1	HGNC:7744	ENSG00000137601	Q96PY6	Serine/threonine-protein kinase Nek1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IFT80	Intraflagellar transport protein 80 homolog	Component of the intraflagellar transport (IFT) complex B, which is essential for the development and maintenance of motile and sensory cilia.
WDR19	WD repeat-containing protein 19	As component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is involved in cilia function and/or assembly.
EVC2	Limbin	Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling.
TTC21B	Tetratricopeptide repeat protein 21B	Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs).
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: 2 · Unknown: 4 · Druggable fraction: 0.14

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	4.0×	0.626
Scaffold/PPI	1	2.5×	0.626
Transcription factor	1	1.2×	0.626
Other/Unknown	4	1.0×	0.626

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IFT80	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
WDR19	Transcription factor	no		WD40_rpt, TPR-like_helical_dom_sf, WD40/YVTN_repeat-like_dom_sf
EVC2	Other/Unknown	no		Limbin, Limbin/EVC
TTC21B	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC21A/TTC21B
DYNC2H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
TRIM59-IFT80	Other/Unknown	no
NEK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

6 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	3
bronchial epithelial cell	2
calcaneal tendon	2
primordial germ cell in gonad	2
secondary oocyte	2
colonic epithelium	1
endothelial cell	1
oviduct epithelium	1
adenohypophysis	1
pancreatic ductal cell	1
cerebellar hemisphere	1
corpus callosum	1
male germ line stem cell (sensu Vertebrata) in testis	1
oocyte	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IFT80	256	ubiquitous	marker	colonic epithelium, oviduct epithelium, endothelial cell
WDR19	269	ubiquitous	marker	right uterine tube, bronchial epithelial cell, adenohypophysis
EVC2	182	ubiquitous	marker	pancreatic ductal cell, calcaneal tendon, primordial germ cell in gonad
TTC21B	179	ubiquitous	marker	right uterine tube, calcaneal tendon, cerebellar hemisphere
DYNC2H1	230	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, right uterine tube
TRIM59-IFT80	68	tissue_specific	yes	corpus callosum, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
NEK1	288	ubiquitous	marker	secondary oocyte, trigeminal ganglion, oocyte

Protein interactions among cohort

Intra-cohort edges: 9.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IFT80	2,582
DYNC2H1	1,885
TTC21B	1,588
NEK1	1,512
WDR19	1,251
EVC2	913
TRIM59-IFT80	0

Intra-cohort edges

A	B	Sources
DYNC2H1	IFT80	string_interaction
DYNC2H1	NEK1	string_interaction
DYNC2H1	TTC21B	string_interaction
DYNC2H1	WDR19	string_interaction
EVC2	IFT80	string_interaction
EVC2	WDR19	string_interaction
IFT80	NEK1	string_interaction
IFT80	WDR19	string_interaction
TTC21B	WDR19	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WDR19	Q8NEZ3	4
DYNC2H1	Q8NCM8	4
TTC21B	Q7Z4L5	3
NEK1	Q96PY6	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IFT80	Q9P2H3	92.50
EVC2	Q86UK5	73.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 7 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Intraflagellar transport	4	133.6×	8e-08	IFT80, WDR19, TTC21B, DYNC2H1
Hedgehog ‘off’ state	3	89.2×	2e-05	WDR19, TTC21B, DYNC2H1
Activation of SMO	1	105.7×	0.026	EVC2
Regulation of pyruvate metabolism	1	95.2×	0.026	NEK1
Pyruvate metabolism	1	68.0×	0.029	NEK1
Signaling by Hedgehog	1	30.7×	0.053	EVC2
Hedgehog ‘on’ state	1	26.4×	0.053	EVC2
Aerobic respiration and respiratory electron transport	1	14.8×	0.082	NEK1
Metabolism	1	1.9×	0.463	NEK1
Signal Transduction	1	1.7×	0.463	EVC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 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	5	61.3×	2e-07	IFT80, WDR19, TTC21B, DYNC2H1, NEK1
intraciliary retrograde transport	3	561.7×	4e-07	WDR19, TTC21B, DYNC2H1
smoothened signaling pathway	3	90.6×	8e-05	IFT80, EVC2, TTC21B
embryonic limb morphogenesis	2	133.8×	0.001	WDR19, DYNC2H1
protein localization to cilium	2	133.8×	0.001	TTC21B, DYNC2H1
non-motile cilium assembly	2	96.8×	0.002	IFT80, DYNC2H1
regulation of intraciliary retrograde transport	1	1404.3×	0.007	TTC21B
growth plate cartilage chondrocyte differentiation	1	702.2×	0.007	IFT80
ear morphogenesis	1	702.2×	0.007	WDR19
smoothened signaling pathway involved in dorsal/ventral neural tube patterning	1	702.2×	0.007	WDR19
myotome development	1	702.2×	0.007	WDR19
protein localization to non-motile cilium	1	702.2×	0.007	TTC21B
response to inositol	1	702.2×	0.007	IFT80
tooth eruption	1	561.7×	0.007	IFT80
digestive system development	1	561.7×	0.007	WDR19
receptor localization to non-motile cilium	1	561.7×	0.007	IFT80
protein localization to ciliary membrane	1	561.7×	0.007	WDR19
cartilage homeostasis	1	561.7×	0.007	IFT80
negative regulation of non-canonical Wnt signaling pathway	1	561.7×	0.007	IFT80
bone mineralization involved in bone maturation	1	468.1×	0.007	IFT80
negative regulation of eating behavior	1	468.1×	0.007	TTC21B
articular cartilage development	1	401.2×	0.008	IFT80
forebrain dorsal/ventral pattern formation	1	351.1×	0.009	TTC21B
odontoblast differentiation	1	351.1×	0.009	IFT80
Bergmann glial cell differentiation	1	255.3×	0.011	TTC21B
osteoblast proliferation	1	234.1×	0.012	IFT80
embryonic camera-type eye development	1	200.6×	0.013	WDR19
nervous system process	1	200.6×	0.013	WDR19
gonad development	1	187.2×	0.013	WDR19
cerebellar Purkinje cell differentiation	1	175.5×	0.014	TTC21B

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 6

Druggability breadth: 1 of 7 evidence-associated genes (14%) 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
IFT80	0	0
WDR19	0	0
EVC2	0	0
TTC21B	0	0
DYNC2H1	0	0
TRIM59-IFT80	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: 6; 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	6	IFT80, WDR19, EVC2, TTC21B, DYNC2H1, TRIM59-IFT80

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DYNC2H1	0	NEK1
IFT80	0	—
WDR19	0	—
EVC2	0	—
TTC21B	0	—
TRIM59-IFT80	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.