WDR35

Summary

WDR35 (WD repeat domain 35, HGNC:29250) is a protein-coding gene on chromosome 2p24.1, encoding WD repeat-containing protein 35 (Q9P2L0). As a 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 ciliogenesis and ciliary protein trafficking.

This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. Two patients with Sensenbrenner syndrome / cranioectodermal dysplasia (CED) were identified with mutations in this gene, consistent with a possible ciliary function.

Source: NCBI Gene 57539 — RefSeq curated summary.

At a glance

• Gene–disease (curated): short-rib thoracic dysplasia 7 with or without polydactyly (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 886 total — 38 pathogenic, 31 likely-pathogenic
• Phenotypes (HPO): 149
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_020779

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29250
Approved symbol	WDR35
Name	WD repeat domain 35
Location	2p24.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC33196, KIAA1336, IFT121, IFTA1, FAP118, CFAP118
Ensembl gene	ENSG00000118965
Ensembl biotype	protein_coding
OMIM	613602
Entrez	57539

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000281405, ENST00000345530, ENST00000414212, ENST00000445063, ENST00000453014, ENST00000494964, ENST00000917695, ENST00000968993

RefSeq mRNA: 2 — MANE Select: NM_020779 NM_001006657, NM_020779

CCDS: CCDS1695, CCDS33152

Canonical transcript exons

ENST00000281405 — 27 exons

Exon	Start	End
ENSE00000000090	19910263	19913708
ENSE00000714125	19932283	19932447
ENSE00001621996	19978751	19978879
ENSE00001640448	19960554	19960614
ENSE00001647780	19989165	19989282
ENSE00001738158	19982463	19982534
ENSE00001744886	19975530	19975663
ENSE00001747691	19980691	19980783
ENSE00001872281	19989992	19990105
ENSE00003460420	19914037	19914277
ENSE00003495781	19935471	19935603
ENSE00003497197	19973563	19973708
ENSE00003516523	19946461	19946570
ENSE00003525036	19941759	19941839
ENSE00003531841	19930396	19930552
ENSE00003534905	19937743	19937946
ENSE00003545142	19931269	19931409
ENSE00003545631	19933401	19933511
ENSE00003571621	19945786	19945996
ENSE00003575269	19936219	19936365
ENSE00003587750	19969480	19969605
ENSE00003592498	19951415	19951484
ENSE00003666659	19948164	19948217
ENSE00003668703	19953834	19953978
ENSE00003671402	19966724	19966909
ENSE00003686174	19974468	19974633
ENSE00003687539	19938265	19938401

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 93.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.8112 / max 211.4608, expressed in 1664 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27071	10.8112	1664

Top tissues by expression

260 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	93.48	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.03	gold quality
bronchus	UBERON:0002185	92.87	gold quality
tibia	UBERON:0000979	92.59	gold quality
germinal epithelium of ovary	UBERON:0001304	92.51	gold quality
epithelial cell of pancreas	CL:0000083	91.66	silver quality
kidney epithelium	UBERON:0004819	91.47	gold quality
cardiac muscle of right atrium	UBERON:0003379	88.05	silver quality
left ventricle myocardium	UBERON:0006566	87.93	silver quality
calcaneal tendon	UBERON:0003701	87.83	gold quality
upper arm skin	UBERON:0004263	87.77	gold quality
pigmented layer of retina	UBERON:0001782	87.28	gold quality
retina	UBERON:0000966	87.26	gold quality
renal medulla	UBERON:0000362	87.17	gold quality
right uterine tube	UBERON:0001302	86.43	gold quality
vena cava	UBERON:0004087	85.70	silver quality
ventricular zone	UBERON:0003053	85.25	gold quality
parietal pleura	UBERON:0002400	84.57	gold quality
caput epididymis	UBERON:0004358	84.55	gold quality
corpus callosum	UBERON:0002336	84.29	gold quality
subthalamic nucleus	UBERON:0001906	84.26	gold quality
dorsal plus ventral thalamus	UBERON:0001897	84.22	gold quality
ventral tegmental area	UBERON:0002691	84.04	gold quality
superior vestibular nucleus	UBERON:0007227	83.89	gold quality
layer of synovial tissue	UBERON:0007616	83.64	gold quality
pons	UBERON:0000988	83.50	gold quality
nasal cavity epithelium	UBERON:0005384	83.42	silver quality
endometrium	UBERON:0001295	83.36	gold quality
substantia nigra pars reticulata	UBERON:0001966	83.07	gold quality
cardia of stomach	UBERON:0001162	83.06	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.65
E-GEOD-36552	no	67.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

153 targeting WDR35, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 17)

• These results indicated that naofen may function as a novel modulator activating caspase-3, and promoting TNF-alpha-stimulated apoptosis. (PMID:20193664)
• WDR35 is homologous to TULP4 (from the Tubby superfamily) and has previously been characterized as an intraflagellar transport component, confirming that Sensenbrenner syndrome is a ciliary disorder. (PMID:20817137)
• Through structural modeling, we show that WDR35 has strong homology to the COPI coatamers involved in vesicular trafficking and that short-rib polydactyly mutations affect key structural elements in WDR35. (PMID:21473986)
• report on the detection of novel WDR35 mutations in two unrelated cranioectodermal dysplasia patients (PMID:22486404)
• A pathogenic WDR35 mutation was identified in a family with a complex clinical presentation that includes significant overlap of the phenotypes described in Sensenbrenner syndrome and the unclassified short-rib polydactyly syndromes. (PMID:22987818)
• Splicing variants in WDR35, and possibly in other IFT-A components, underlie a number of Ellis-van Creveld syndrome cases by disrupting targeting of both the EvC complex and Smoothened to cilia. (PMID:25908617)
• Wdr35 regulates cilium assembly by selectively regulating transport of distinct cargoes. (PMID:27806291)
• Psychomotor development was apparently normal. Molecular analysis in one of the affected individuals identified compound heterozygosity for a nonsense (c.1922T>G, p.(Leu641*)) and missense (c.2522A>T, p.(Asp841Val)) variants in WDR35. We (PMID:28332779)
• A differential diagnosis of Sensenbrenner Syndrome was made after a novel homozygous missense mutation in WDR35 was identified in a patient with initial diagnosis of Jeune syndrome. (PMID:28870638)
• The observations of the Sensenbrenner syndrome patient in this study provide additional clinical data and expand the molecular spectrum of Sensenbrenner syndrome. Moreover, the two variants identified in the proband provide further evidence for the WDR35 mutations as the most common cause of this rare syndrome. (PMID:29134781)
• Homozygous missense mutation in WDR35 gene is associated with multiple congenital anomalies, including brain malformations and skeletal dysplasia suggestive of cranioectodermal dysplasia ciliopathy. (PMID:29174089)
• Over-expression of WDR35 results in decreased phosphorylation of ribosome S6 protein in a RagA-, RagB- and RagC-dependent manner. Thus, WDR35 is associated with RagA, RagB and RagC and might negatively influence mTORC1 activity. (PMID:30570184)
• Results demonstrated that copy number variation (CNV) of WDR35 may lead to skeletal dysplasia and fetal anomaly, and that down-regulated WDR35 may damage the cilia formation and sequentially indirectly regulate Gli signal, which would eventually result in negative regulation of osteogenic differentiation. (PMID:30790652)
• Prenatal genetic diagnosis of cranioectodermal dysplasia in a Polish family with compound heterozygous variants in WDR35. (PMID:32804427)
• Association study of genetic variants at TTC32-WDR35 gene cluster with coronary artery disease in Chinese Han population. (PMID:33009702)
• Interfamilial clinical variability in four Polish families with cranioectodermal dysplasia and identical compound heterozygous variants in WDR35. (PMID:33421337)
• WDR35 is involved in subcellular localization of acetylated tubulin in 293T cells. (PMID:33610917)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	wdr35	ENSDARG00000069269
mus_musculus	Wdr35	ENSMUSG00000066643
rattus_norvegicus	Wdr35	ENSRNOG00000028783
drosophila_melanogaster	Oseg4	FBGN0035264
caenorhabditis_elegans		WBGENE00016935

Paralogs (5): TULP3 (ENSG00000078246), TULP2 (ENSG00000104804), TULP1 (ENSG00000112041), TULP4 (ENSG00000130338), TUB (ENSG00000166402)

Protein

Protein identifiers

WD repeat-containing protein 35 — Q9P2L0 (reviewed: Q9P2L0)

Alternative names: Intraflagellar transport protein 121 homolog

All UniProt accessions (4): Q9P2L0, F8WB94, H0Y6C0, H7BZK8

UniProt curated annotations — full annotation on UniProt →

Function. As a 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 ciliogenesis and ciliary protein trafficking. May promote CASP3 activation and TNF-stimulated apoptosis.

Subunit / interactions. Component of the IFT complex A (IFT-A) complex. IFT-A complex is divided into a core subcomplex composed of IFT122:IFT140:WDR19 which is associated with TULP3 and a peripheral subcomplex composed of IFT43:WDR35:TTC21B. Interacts directy with IFT122, ITF43 and TTC21B. Interacts with IFT43. Interacts with CFAP61. Interacts with CFAP65.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Cilium axoneme. Cilium basal body.

Disease relevance. Cranioectodermal dysplasia 2 (CED2) [MIM:613610] A disorder characterized by craniofacial, skeletal and ectodermal abnormalities. Clinical features include short stature, dolichocephaly, craniosynostosis, narrow thorax with pectus excavatum, short limbs, brachydactyly, joint laxity, narrow palpebral fissures, telecanthus with hypertelorism, low-set simple ears, everted lower lip, and short neck. Teeth abnormalities include widely spaced, hypoplastic and fused teeth. The disease is caused by variants affecting the gene represented in this entry. Short-rib thoracic dysplasia 7 with or without polydactyly (SRTD7) [MIM:614091] A form of short-rib thoracic dysplasia, a group of autosomal recessive ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a ’trident’ appearance of the acetabular roof. Polydactyly is variably present. Non-skeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of the disease are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Disease spectrum encompasses Ellis-van Creveld syndrome, asphyxiating thoracic dystrophy (Jeune syndrome), Mainzer-Saldino syndrome, and short rib-polydactyly syndrome. SRTD7 hallmarks are acromesomelic hypomineralization, campomelia, polysyndactyly, laterality defects, and cystic kidneys. The disease is caused by variants affecting the gene represented in this entry. WDR35 mutations cause short rib-polydactyly syndrome through impaired cilia formation. Primary fibroblasts from SRTD7 patients lacking WDR35 fail to produce cilia. Short-rib thoracic dysplasia 7/20 with polydactyly, digenic (SRTD7/20) [MIM:614091] A digenic form of short-rib thoracic dysplasia caused by double heterozygosity for a mutation in the WDR35 gene and a mutation in the INTU gene. Short-rib thoracic dysplasia is part of a group of ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a ’trident’ appearance of the acetabular roof. Polydactyly is variably present. Non-skeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of the disease are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Disease spectrum encompasses Ellis-van Creveld syndrome, asphyxiating thoracic dystrophy (Jeune syndrome), Mainzer-Saldino syndrome, and short rib-polydactyly syndrome. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. SRTD7/20 can be caused by co-occurrence of WDR35 variant p.Trp311Leu and INTU p.Gln276Ter. One such patient has been reported.

Induction. By TNF.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9P2L0-1	1	yes
Q9P2L0-2	2

RefSeq proteins (2): NP_001006658, NP_065830* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR017233	WDR35	Family
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR039857	Ift122/121	Family
IPR056157	TPR_IFT80_172_dom	Domain
IPR056158	Beta-prop_IFT121_2nd	Domain
IPR056159	Beta-prop_IFT121_TULP_N	Domain
IPR056170	Znf_IFT121-like	Domain
IPR057361	TPR_WDR35	Repeat
IPR057979	TPR_IFT121	Domain

Pfam: PF23145, PF23387, PF23390, PF24797, PF25170, PF25768

UniProt features (123 total): strand 58, helix 36, sequence variant 10, turn 9, repeat 6, sequence conflict 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8BBE	ELECTRON MICROSCOPY	3.5
8BBG	ELECTRON MICROSCOPY	3.5
8FGW	ELECTRON MICROSCOPY	3.7
8FH3	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2L0-F1	85.93	0.52

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-5620924	Intraflagellar transport

MSigDB gene sets: 0 (showing top):

GO Biological Process (6): intraciliary retrograde transport (GO:0035721), intraciliary transport (GO:0042073), cilium assembly (GO:0060271), protein localization to cilium (GO:0061512), cellular response to leukemia inhibitory factor (GO:1990830), cell projection organization (GO:0030030)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (9): centrosome (GO:0005813), cilium (GO:0005929), axoneme (GO:0005930), intraciliary transport particle A (GO:0030991), ciliary basal body (GO:0036064), ciliary tip (GO:0097542), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by Hedgehog	1
Assembly of the 9+0 primary cilium	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cilium	3
cilium organization	2
microtubule organizing center	2
intraciliary transport particle	2
intraciliary transport	1
transport along microtubule	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
protein localization to organelle	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
cellular component organization	1
binding	1
centriole	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cytoskeleton	1
microtubule	1
ciliary plasm	1
protein-containing complex	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

930 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WDR35	IFT43	Q96FT9	997
WDR35	TTC21B	Q7Z4L5	997
WDR35	WDR19	Q8NEZ3	997
WDR35	IFT140	Q96RY7	996
WDR35	ELMO3	Q96BJ8	993
WDR35	DOCK1	Q14185	991
WDR35	IFT122	Q9HBG6	986
WDR35	ELMO1	Q92556	986
WDR35	ELMO2	Q96JJ3	983
WDR35	CRK	P46108	926
WDR35	IFT80	Q9P2H3	810
WDR35	IFT22	Q9H7X7	776
WDR35	IFT52	Q9Y366	776
WDR35	GULP1	Q9UBP9	766
WDR35	IFT172	Q9UG01	760
WDR35	DYNC2LI1	Q8TCX1	760

IntAct

45 interactions, top by confidence:

A	B	Type	Score
WDR19	TULP3	psi-mi:“MI:0914”(association)	0.860
IFT122	IFT43	psi-mi:“MI:0915”(physical association)	0.800
TULP3	FOXK2	psi-mi:“MI:0914”(association)	0.790
IFT43	TULP3	psi-mi:“MI:0914”(association)	0.790
TTC21B	IFT43	psi-mi:“MI:0915”(physical association)	0.770
TTC21B	IFT43	psi-mi:“MI:0914”(association)	0.770
IFT43	WDR35	psi-mi:“MI:0915”(physical association)	0.740
WDR35	IFT43	psi-mi:“MI:0915”(physical association)	0.740
IFT122	TTC21B	psi-mi:“MI:0915”(physical association)	0.700
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
IFTAP	PLK1	psi-mi:“MI:0914”(association)	0.640
TULP3	GGPS1	psi-mi:“MI:0914”(association)	0.640
IFT43	TTC21B	psi-mi:“MI:0914”(association)	0.530
IFT122	DNAJA2	psi-mi:“MI:0914”(association)	0.530
TULP3	HSPG2	psi-mi:“MI:0914”(association)	0.530
IFTAP	WDR19	psi-mi:“MI:0914”(association)	0.530
IFT122	CDC7	psi-mi:“MI:0914”(association)	0.510
IFT140	ACSL3	psi-mi:“MI:0914”(association)	0.510
IFT122	IFT43	psi-mi:“MI:0915”(physical association)	0.400
IFT122	TTC21B	psi-mi:“MI:0915”(physical association)	0.400
IFT43	PLK1	psi-mi:“MI:0914”(association)	0.350
	TTC21B	psi-mi:“MI:0914”(association)	0.350
TULP3	PPM1G	psi-mi:“MI:0914”(association)	0.350
hspa1a_hspa1b_human-1	SHTN1	psi-mi:“MI:0914”(association)	0.350
PPP4R1L	IFT56	psi-mi:“MI:0914”(association)	0.350
DUSP16	MEIOC	psi-mi:“MI:0914”(association)	0.350
NPTN	RTL8C	psi-mi:“MI:0914”(association)	0.350
TULP2	ZSWIM8	psi-mi:“MI:0914”(association)	0.350

BioGRID (57): WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS), WDR35 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IC37, A4QNS7, A5PJZ5, A6N6J5, E9PY46, F1QEB7, F4IDS7, O75694, O75717, P37199, P59328, Q05B17, Q08D69, Q1RMS6, Q2YDS1, Q32PG3, Q3ZC98, Q4QQS8, Q5F3K4, Q5R822, Q5RAW8, Q5RCA2, Q5U5D4, Q5ZL91, Q5ZLG9, Q66HC5, Q68FJ0, Q6DK84, Q6PFM9, Q6PJI9, Q7TQK1, Q802U2, Q8BGQ1, Q8BH57, Q8BJ71, Q8BND3, Q8C0M0, Q8K1X1, Q8N1F7, Q8R480

Diamond homologs: A6N6J5, Q8BND3, Q9P2L0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
WDR35	“form complex”	“ITF complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 38 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Intraflagellar transport	6	40.1×	1e-06
Hedgehog ‘off’ state	5	29.7×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
intraciliary retrograde transport	5	165.2×	2e-08
protein localization to cilium	6	70.8×	4e-08
cilium assembly	6	13.0×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

886 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	38
Likely pathogenic	31
Uncertain significance	430
Likely benign	213
Benign	79

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323764	NM_020779.4(WDR35):c.570+1G>C	Pathogenic
1360910	NM_020779.4(WDR35):c.1954_1955insAAAC (p.Leu652fs)	Pathogenic
1368965	NM_020779.4(WDR35):c.1694_1695dup (p.Thr566Ter)	Pathogenic
1415290	NM_020779.4(WDR35):c.297del (p.Met99fs)	Pathogenic
1459665	NC_000002.11:g.(?20153575)(20153759_?)del	Pathogenic
1978470	NM_020779.4(WDR35):c.2701G>T (p.Glu901Ter)	Pathogenic
20	NM_020779.4(WDR35):c.25-2A>G	Pathogenic
21	NM_020779.4(WDR35):c.1844A>G (p.Glu615Gly)	Pathogenic
22	NM_020779.4(WDR35):c.2858del (p.Pro953fs)	Pathogenic
2423459	NC_000002.11:g.(?20188906)(20189063_?)del	Pathogenic
286127	NM_020779.4(WDR35):c.2998G>T (p.Glu1000Ter)	Pathogenic
2939861	NM_020779.4(WDR35):c.1554C>G (p.Tyr518Ter)	Pathogenic
2948787	NM_020779.4(WDR35):c.1322G>A (p.Trp441Ter)	Pathogenic
2951856	NM_020779.4(WDR35):c.1609C>T (p.Gln537Ter)	Pathogenic
2952744	NM_020779.4(WDR35):c.171_178del (p.Ser59fs)	Pathogenic
31043	NM_020779.4(WDR35):c.307+214_436+1120del	Pathogenic
31044	NM_020779.4(WDR35):c.1600C>T (p.Arg534Ter)	Pathogenic
31045	NM_020779.4(WDR35):c.781T>C (p.Trp261Arg)	Pathogenic
3751016	NM_020779.4(WDR35):c.2713_2714del (p.Leu905fs)	Pathogenic
3759851	NM_020779.4(WDR35):c.1714C>T (p.Gln572Ter)	Pathogenic
3762513	NM_020779.4(WDR35):c.519del (p.Phe173fs)	Pathogenic
3764724	NM_020779.4(WDR35):c.1137del (p.Thr380fs)	Pathogenic
446645	NM_020779.4(WDR35):c.2489A>T (p.Asp830Val)	Pathogenic
4783901	NM_020779.4(WDR35):c.721_727del (p.His241fs)	Pathogenic
4785065	NM_020779.4(WDR35):c.2306G>A (p.Trp769Ter)	Pathogenic
4788990	NM_020779.4(WDR35):c.2956del (p.Ser986fs)	Pathogenic
4793548	NM_020779.4(WDR35):c.1525-2_1527dup	Pathogenic
4796627	NM_020779.4(WDR35):c.1990C>T (p.Arg664Ter)	Pathogenic
488656	NM_020779.4(WDR35):c.143-18T>A	Pathogenic
488657	NM_020779.4(WDR35):c.3426G>T (p.Trp1142Cys)	Pathogenic

SpliceAI

5017 predictions. Top by Δscore:

Variant	Effect	Δscore
2:19914035:AC:A	donor_gain	1.0000
2:19914036:CC:C	donor_gain	1.0000
2:19931263:CTTTA:C	donor_loss	1.0000
2:19931264:TTTA:T	donor_loss	1.0000
2:19931265:TTACC:T	donor_loss	1.0000
2:19931266:TAC:T	donor_loss	1.0000
2:19931268:C:A	donor_loss	1.0000
2:19931268:CCT:C	donor_gain	1.0000
2:19931270:TCTGA:T	donor_gain	1.0000
2:19931281:T:TA	donor_gain	1.0000
2:19931411:T:C	acceptor_gain	1.0000
2:19931411:T:TC	acceptor_gain	1.0000
2:19932277:CATTA:C	donor_loss	1.0000
2:19932278:ATTAC:A	donor_loss	1.0000
2:19932279:TTAC:T	donor_loss	1.0000
2:19932280:TACCT:T	donor_loss	1.0000
2:19932281:A:C	donor_loss	1.0000
2:19932282:CCTT:C	donor_loss	1.0000
2:19932443:TTCCA:T	acceptor_gain	1.0000
2:19932444:TCCA:T	acceptor_gain	1.0000
2:19932445:CCA:C	acceptor_gain	1.0000
2:19932445:CCAC:C	acceptor_gain	1.0000
2:19932446:CA:C	acceptor_gain	1.0000
2:19932446:CAC:C	acceptor_gain	1.0000
2:19932448:C:CC	acceptor_gain	1.0000
2:19932448:C:T	acceptor_loss	1.0000
2:19933399:A:AC	donor_gain	1.0000
2:19933400:C:CC	donor_gain	1.0000
2:19935466:CCTA:C	donor_gain	1.0000
2:19935467:CTA:C	donor_loss	1.0000

AlphaMissense

7731 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:19932447:A:G	W898R	0.999
2:19932447:A:T	W898R	0.999
2:19945863:A:G	W601R	0.999
2:19945863:A:T	W601R	0.999
2:19973664:A:G	W261R	0.999
2:19973664:A:T	W261R	0.999
2:19978820:A:G	W123R	0.999
2:19978820:A:T	W123R	0.999
2:19932445:C:A	W898C	0.998
2:19932445:C:G	W898C	0.998
2:19933469:C:G	A875P	0.998
2:19975610:A:G	W164R	0.998
2:19975610:A:T	W164R	0.998
2:19978794:G:C	C131W	0.998
2:19980706:A:G	W98R	0.998
2:19980706:A:T	W98R	0.998
2:19980763:A:G	W79R	0.998
2:19980763:A:T	W79R	0.998
2:19932332:A:G	L936P	0.997
2:19936246:C:T	G807E	0.997
2:19953913:A:G	W452R	0.997
2:19953913:A:T	W452R	0.997
2:19969557:A:G	W311R	0.997
2:19969557:A:T	W311R	0.997
2:19978796:A:G	C131R	0.997
2:19978818:C:A	W123C	0.997
2:19978818:C:G	W123C	0.997
2:19978874:A:G	W105R	0.997
2:19978874:A:T	W105R	0.997
2:19980777:A:T	V74D	0.997

dbSNP variants (sampled 300 via entrez): RS1000102031 (2:19973042 C>G,T), RS1000136680 (2:19981165 G>A), RS1000208289 (2:19988308 T>C), RS1000222948 (2:19921263 T>C), RS1000296686 (2:19920854 C>A,T), RS1000350770 (2:19947540 G>C,T), RS1000402338 (2:19980707 C>T), RS1000412092 (2:19940682 T>G), RS1000451771 (2:19945789 A>G), RS1000487934 (2:19947972 G>A), RS1000512874 (2:19986321 T>C), RS1000513611 (2:19927327 A>G), RS1000570105 (2:19931841 A>C), RS1000578900 (2:19940791 C>G), RS1000588080 (2:19945483 A>C)

Disease associations

OMIM: gene MIM:613602 | disease phenotypes: MIM:613610, MIM:614091, MIM:263520, MIM:208500, MIM:225500, MIM:218330

GenCC curated gene-disease

Disease	Classification	Inheritance
cranioectodermal dysplasia 2	Definitive	Autosomal recessive
short-rib thoracic dysplasia 7 with or without polydactyly	Strong	Autosomal recessive
cranioectodermal dysplasia	Supportive	Autosomal recessive
short rib-polydactyly syndrome, Verma-Naumoff type	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
short-rib thoracic dysplasia 7 with or without polydactyly	Definitive	AR
cranioectodermal dysplasia 2	Definitive	AR

Mondo (10): cranioectodermal dysplasia 2 (MONDO:0013323), short-rib thoracic dysplasia 7 with or without polydactyly (MONDO:0013569), connective tissue disorder (MONDO:0003900), short-rib thoracic dysplasia 6 with or without polydactyly (MONDO:0009894), short rib-polydactyly syndrome (MONDO:0015461), Jeune syndrome (MONDO:0018770), short-rib thoracic dysplasia 7/20 with polydactyly, digenic (MONDO:0800356), Ellis-van Creveld syndrome (MONDO:0009162), cranioectodermal dysplasia (MONDO:0009032), (MONDO:0019664)

Orphanet (6): Cranioectodermal dysplasia (Orphanet:1515), Short rib-polydactyly syndrome type 5 (Orphanet:498497), Short rib-polydactyly syndrome, Verma-Naumoff type (Orphanet:93271), Short rib-polydactyly syndrome (Orphanet:1505), Jeune syndrome (Orphanet:474), Ellis Van Creveld syndrome (Orphanet:289)

HPO phenotypes

149 total (30 of 149 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000062	Ambiguous genitalia
HP:0000083	Renal insufficiency
HP:0000089	Renal hypoplasia
HP:0000107	Renal cyst
HP:0000113	Polycystic kidney dysplasia
HP:0000126	Hydronephrosis
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000200	Short lingual frenulum
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000269	Prominent occiput
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000289	Broad philtrum
HP:0000293	Full cheeks
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000369	Low-set ears

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001587_4	Coronary heart disease	7.000000e-11
GCST006108_3	Facial morphology	7.000000e-08
GCST006108_5	Facial morphology	3.000000e-08
GCST008478_60	Neurological blood protein biomarker levels	7.000000e-18
GCST012226_435	Waist circumference adjusted for body mass index	3.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004743	facial morphology
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
D004613	Ellis-Van Creveld Syndrome	C05.116.099.708.327; C16.131.077.350.398; C16.131.831.350.398; C16.320.850.250.398; C17.800.804.350.398; C17.800.827.250.398
D012779	Short Rib-Polydactyly Syndrome	C05.116.099.708.857; C05.660.585.600.750; C16.131.077.850; C16.131.621.585.600.750
C537571	Jeune syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, increases expression	1
Copper	affects binding, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Estradiol	increases expression	1
Methyl Methanesulfonate	increases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1

Clinical trials (associated diseases)

89 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT05516758	PHASE2	TERMINATED	A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis
NCT05998759	PHASE2	RECRUITING	Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia
NCT06104228	PHASE2	RECRUITING	129 Xenon MRI as a Biomarker for Diagnosis and Response to Therapy in Pulmonary Arterial Hypertension (PAH)
NCT01093911	PHASE1	COMPLETED	Safety Study of CDP7657 in Healthy Volunteers and Patients With Systemic Lupus Erythematosus (SLE)
NCT01764594	PHASE1	COMPLETED	Safety Study of CDP7657 in Patients With Systemic Lupus Erythematosus
NCT02392130	PHASE1	COMPLETED	A Clinical Trial to Assess the Potential of LEO 130852A Gel to Reduce Steroid Induced Skin Atrophy on Healthy Skin
NCT03337165	PHASE1	COMPLETED	Autologous Tolerogenic Dendritic Cells for Treatment of Patients With Rheumatoid Arthritis
NCT03929120	PHASE1	COMPLETED	Allogeneic Bone Marrow Mesenchymal Stem Cells for Patients With Interstitial Lung Disease (ILD) & Connective Tissue Disorders (CTD)
NCT04032756	Not specified	TERMINATED	Tofacitinib Registry of Patients With Ulcerative Colitis in Germany
NCT04184531	Not specified	UNKNOWN	Sensenbrenner Clinical Study
NCT06626282	Not specified	RECRUITING	Fertility and Ovarian Reserve in Female Childhood Cancer Survivors
NCT01424033	PHASE2/PHASE3	TERMINATED	A Clinical Trial for CTD-ILD Treatment
NCT04915482	PHASE2/PHASE3	UNKNOWN	TPO-RAs Combined With Anti-CD20 Antibody in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT06574581	PHASE1/PHASE2	RECRUITING	ADSCs Therapy in Patients With CTD-ILD
NCT00001330	Not specified	COMPLETED	Study of Silicone-Associated Connective Tissue Diseases
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00001978	Not specified	TERMINATED	Determination of Kidney Function
NCT00076830	Not specified	COMPLETED	Evaluation and Treatment of Patients With Connective Tissue Disease