WDR35

WD repeat domain 35, the group of WD repeat domain containing|IFT-A complex

Basic information

Region (hg38): 2:19910263-19990105

Links

ENSG00000118965 ∙ NCBI:57539 ∙ OMIM:613602 ∙ HGNC:29250 ∙ Uniprot:Q9P2L0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cranioectodermal dysplasia 2 (Definitive), mode of inheritance: AR
• cranioectodermal dysplasia 2 (Strong), mode of inheritance: AR
• cranioectodermal dysplasia (Supportive), mode of inheritance: AR
• short rib-polydactyly syndrome, Verma-Naumoff type (Supportive), mode of inheritance: AR
• short-rib thoracic dysplasia 7 with or without polydactyly (Supportive), mode of inheritance: AR
• short-rib thoracic dysplasia 7 with or without polydactyly (Strong), mode of inheritance: AR
• cranioectodermal dysplasia 2 (Definitive), mode of inheritance: AR
• short-rib thoracic dysplasia 7 with or without polydactyly (Definitive), mode of inheritance: AR
• cranioectodermal dysplasia 2 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cranioectodermal dysplasia 2; Short -rib thoracic dysplasia 7 with or without polydactyly	AR	General	The condition can include cardac defects and renal and hepatic disease, among other findings; Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Dermatologic; Musculoskeletal; Renal	20817137; 21378380; 21473986

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the WDR35 gene.

• Cranioectodermal dysplasia 2;Short-rib thoracic dysplasia 7 with or without polydactyly (8 variants)
• Short-rib thoracic dysplasia 7 with or without polydactyly;Cranioectodermal dysplasia 2 (7 variants)
• not provided (3 variants)
• Short rib-polydactyly syndrome (1 variants)
• Cranioectodermal dysplasia 2 (1 variants)
• Short-rib thoracic dysplasia 7 with or without polydactyly (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the WDR35 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	1		10	83	6	100
missense	1	5	215	12	4	237
nonsense	9	4	2			15
start loss						0
frameshift	7	5				12
inframe indel			1			1
splice donor/acceptor (+/-2bp)	1	9	1			11
splice region			11	10		21
non coding			56	74	69	199
Total	19	23	285	169	79

Highest pathogenic variant AF is 0.0000460

Variants in WDR35

This is a list of pathogenic ClinVar variants found in the WDR35 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-19910289-C-T		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Uncertain significance (Jan 12, 2018)
2-19910290-G-A		Cranioectodermal dysplasia 2 • Short-rib thoracic dysplasia 7 with or without polydactyly	Benign (Jan 13, 2018)
2-19910323-G-T		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Uncertain significance (Jan 13, 2018)
2-19910333-C-T		Cranioectodermal dysplasia 2 • Short-rib thoracic dysplasia 7 with or without polydactyly	Uncertain significance (Jan 13, 2018)
2-19910568-C-A		Cranioectodermal dysplasia 2 • Short-rib thoracic dysplasia 7 with or without polydactyly	Uncertain significance (Jan 13, 2018)
2-19910569-G-A		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Uncertain significance (Jan 12, 2018)
2-19910596-G-A		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Uncertain significance (Jan 13, 2018)
2-19910601-C-T		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Benign (Jan 13, 2018)
2-19910671-A-G		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Uncertain significance (Jan 13, 2018)
2-19910722-G-A		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Benign (Jan 12, 2018)
2-19910761-C-T		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Uncertain significance (Jan 13, 2018)
2-19910810-C-A		Cranioectodermal dysplasia 2 • Short-rib thoracic dysplasia 7 with or without polydactyly	Uncertain significance (Jan 13, 2018)
2-19910832-T-C		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Uncertain significance (Jan 13, 2018)
2-19910833-C-A		Cranioectodermal dysplasia 2 • Short-rib thoracic dysplasia 7 with or without polydactyly	Uncertain significance (Jan 13, 2018)
2-19910929-A-T		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Uncertain significance (Jan 13, 2018)
2-19910935-A-G		Cranioectodermal dysplasia 2 • Short-rib thoracic dysplasia 7 with or without polydactyly	Benign (Jan 12, 2018)
2-19910936-T-C		Cranioectodermal dysplasia 2 • Short-rib thoracic dysplasia 7 with or without polydactyly	Benign (Jan 13, 2018)
2-19910938-C-T		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Uncertain significance (Jan 12, 2018)
2-19910939-G-A		Cranioectodermal dysplasia 2 • Short-rib thoracic dysplasia 7 with or without polydactyly	Uncertain significance (Jan 13, 2018)
2-19910940-C-T		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Uncertain significance (Jan 12, 2018)
2-19910999-T-C		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Uncertain significance (Jan 13, 2018)
2-19911095-G-A		Cranioectodermal dysplasia 2 • Short-rib thoracic dysplasia 7 with or without polydactyly	Benign (Jan 12, 2018)
2-19911150-C-G		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Benign (Jan 12, 2018)
2-19911217-C-G		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Uncertain significance (Jan 13, 2018)
2-19911243-C-G		Short-rib thoracic dysplasia 7 with or without polydactyly • Cranioectodermal dysplasia 2	Likely benign (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
WDR35	protein_coding	protein_coding	ENST00000345530	28	79872

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.05e-22	0.984	125518	0	230	125748	0.000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.599	588	630	0.933	0.0000331	7780
Missense in Polyphen		252	266.98	0.94389		3377
Synonymous	0.239	213	217	0.979	0.0000113	2170
Loss of Function	2.87	47	73.5	0.639	0.00000398	851

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00196	0.00196
Ashkenazi Jewish	0.000992	0.000993
East Asian	0.000544	0.000544
Finnish	0.00127	0.00125
European (Non-Finnish)	0.000975	0.000906
Middle Eastern	0.000544	0.000544
South Asian	0.00111	0.00111
Other	0.000691	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: As a component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport, it is involved in ciliogenesis (PubMed:21473986, PubMed:28400947). May promote CASP3 activation and TNF-stimulated apoptosis. {ECO:0000269|PubMed:20193664, ECO:0000269|PubMed:21473986, ECO:0000269|PubMed:28400947}.
• Disease: DISEASE: 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. {ECO:0000269|PubMed:20817137}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:21473986, ECO:0000269|PubMed:28400947}. Note=The disease is caused by mutations 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 (PubMed:21473986). {ECO:0000269|PubMed:21473986}.; DISEASE: 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. {ECO:0000269|PubMed:27158779}. Note=The disease is caused by mutations 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. {ECO:0000269|PubMed:27158779}.
• Pathway: Signal Transduction;Hedgehog ,off, state;Signaling by Hedgehog;Intraflagellar transport;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.109

Intolerance Scores

• loftool: 0.596
• rvis_EVS: 0.48
• rvis_percentile_EVS: 78.87

Haploinsufficiency Scores

• pHI: 0.144
• hipred: N
• hipred_score: 0.492
• ghis: 0.523

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.763

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	High	Medium	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Wdr35
• Phenotype: limbs/digits/tail phenotype; digestive/alimentary phenotype; skeleton phenotype; respiratory system phenotype; embryo phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: wdr35
• Affected structure: neuromast hair cell
• Phenotype tag: abnormal
• Phenotype quality: absent

Gene ontology

• Biological process: response to toxic substance;negative regulation of gene expression;response to lipopolysaccharide;intraciliary retrograde transport;intraciliary transport involved in cilium assembly;positive regulation of cysteine-type endopeptidase activity involved in apoptotic process;negative regulation of nitric oxide biosynthetic process;cilium assembly;protein localization to cilium;cellular response to glucose stimulus;cellular response to tumor necrosis factor;positive regulation of release of cytochrome c from mitochondria;liver regeneration;negative regulation of blood vessel diameter;cellular response to paclitaxel;cellular response to leukemia inhibitory factor
• Cellular component: centrosome;cilium;axoneme;intraciliary transport particle A;ciliary basal body;ciliary tip
• Molecular function: phosphatidylinositol binding