WDR19
protein-codingWD repeat domain 19, the group of WD repeat domain containing|IFT-A complex
Gene summary
The protein encoded by this gene is a member of the WD (tryptophan-aspartic acid) repeat family, which is a large family of structurally-related proteins known to participate in a wide range of cellular processes. Each WD repeat typically contains about 40 amino acids that are usually bracketed by glycine-histidine and tryptophan-aspartic acid (WD) dipeptides. This protein contains six WD repeats, three transmembrane domains, and a clathrin heavy-chain repeat. Mutations in this gene have been described in individuals with a wide range of disorders affecting function of the cilium. These disorders are known as ciliopathies, and include Jeune syndrome, Sensenbrenner syndromes, Senior-Loken syndrome, combined or isolated nephronophthisis (NPHP), and retinitis pigmentosa (RP). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~103.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013719
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0017842
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009728
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0018770
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009032
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013717
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: ClinGen
*WDR19* was first reported in relation to autosomal recessive ciliopathies in 2011 (Bedrup et al., PMID: 22019272). Evidence supporting this gene-disease relationship includes case-level data and experimental data. *WDR19* has been noted to be associated with the following disease entities: Cranioectodermal dysplasia 4 (OMIM:614378), Nephronophthisis 13 (OMIM:614377), Senior-Loken syndrome 8 (OMIM:616307), and Short-rib thoracic dysplasia 5 with or without polydactyly (OMIM:614376). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and the phenotypic variability was representative of a syndromic spectrum of ciliopathy disorders caused by *WDR19*. Therefore, the above disease entities have been lumped into one disease entity, ciliopathy (MONDO:0005308). The mechanism of pathogenicity is reported to be loss of function. Variants in this gene have been reported in at least 14 probands in 4 publications (PMIDs: 22019272, 23683095, 23559409, 25726036) and are included in this curation. Additionally, variants in this gene segregated with disease in 3 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by expression studies, functional alteration studies, and animal models. (PMIDs: 33517396, 22228095, 25726036, 22019273). Expression studies demonstrated a reduction in ciliated cells, a lack of WDR19 in cilia, and diffuse cytoplasmic staining in cells from affected patients. Exogenous expression of *WDR19* variants in *WDR19*-knockout cells did not rescue ciliogenesis defects. Finally, ENU-derived mice with a hypomorphic missense mutation (p.Leu750Pro) in *Wdr19* replicate skeletal and craniofacial anomalies seen in human skeletal ciliopathies. In summary, *WDR19* is definitively associated with autosomal recessive ciliopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 5/25/22 (SOP Version 8).
Inheritance Pattern: AR
Disease ID:MONDO:0014579
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013717
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013719
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013718
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Dental; Dermatologic; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Pulmonary; Renal
Intervention: General
Rationale: Genetic knowledge may potentially be beneficial related to manifestations such as renal issues; 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
Comments: Renal transplantation has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to WDR19 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_025132.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 14 | 251 | 265 | |||
| missense | 7 | 30 | 589 | 24 | 3 | 653 |
| nonsense | 18 | 20 | 1 | 39 | ||
| start loss | 1 | 1 | ||||
| frameshift | 22 | 24 | 2 | 48 | ||
| splice donor/acceptor (+/-2bp) | 4 | 47 | 12 | 63 | ||
| Total | 51 | 121 | 619 | 275 | 3 | 1069 |
Highest pathogenic variant AF is 0.000110417175
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_079408.3 | 36 | MANE Select | |
| Ensembl | ENSP00000382717.3 | 36 | MANE Select | |
| RefSeq | NP_001304853.1 | 31 | Standard | |
| Ensembl | ENSP00000423706.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| wdr19 | Danio rerio | Structure: post-vent region Quality: curved ventral abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signal Transduction
- Hedgehog ,off, state
- Signaling by Hedgehog
- Intraflagellar transport
- Cilium Assembly
Biological Process
- cell morphogenesis
- in utero embryonic development
- gonad development
- embryonic limb morphogenesis
- embryonic camera-type eye development
Cellular Component
- photoreceptor outer segment
- nucleoplasm
- cytoplasm
- cytoskeleton
- cilium
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000399820
- Coding exons
- 36
- Length
- 103407
- Individuals with no LoFs
- 124550
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 93
- Defined
- 124643
- p
- 0.000373
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.50 | 573 | 684 | 0.838 | 0.0000347 | 8839 |
| Missense (PolyPhen) | 124 | 173.4 | 0.7151 | 2136 | ||
| Synonymous | 0.316 | 228 | 234 | 0.974 | 0.0000122 | 2413 |
| Loss of Function | 4.68 | 31 | 74.6 | 0.415 | 0.00000392 | 956 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00026 | 0.00026 | rare |
| Latino/Admixed American | 0.00036 | 0.00035 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00047 | 0.00045 | rare |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.00046 | 0.00043 | rare |
| South Asian | 0.00046 | 0.00042 | rare |
| Other | 0.00087 | 0.00083 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport (PubMed:20889716). Involved in cilia function and/or assembly (By similarity). Associates with the BBSome complex to mediate ciliary transport (By similarity). {ECO:0000250|UniProtKB:Q3UGF1, ECO:0000269|PubMed:20889716}.;
- Disease
- DISEASE: Cranioectodermal dysplasia 4 (CED4) [MIM:614378]: A disorder primarily characterized by craniofacial, skeletal and ectodermal abnormalities. Clinical features include craniosynostosis, narrow rib cage, short limbs, brachydactyly, hypoplastic and widely spaced teeth, sparse hair, skin laxity and abnormal nails. Nephronophthisis leading to progressive renal failure, hepatic fibrosis, heart defects, and retinitis pigmentosa have also been described. {ECO:0000269|PubMed:22019273}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Short-rib thoracic dysplasia 5 with or without polydactyly (SRTD5) [MIM:614376]: 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. {ECO:0000269|PubMed:22019273}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Nephronophthisis 13 (NPHP13) [MIM:614377]: An autosomal recessive disorder resulting in end-stage renal disease. It is a progressive tubulo-interstitial kidney disorder histologically characterized by modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts. {ECO:0000269|PubMed:22019273}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Senior-Loken syndrome 8 (SLSN8) [MIM:616307]: A renal- retinal disorder characterized by progressive wasting of the filtering unit of the kidney (nephronophthisis), with or without medullary cystic renal disease, and progressive eye disease. Typically this disorder becomes apparent during the first year of life. {ECO:0000269|PubMed:23559409, ECO:0000269|PubMed:23683095}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.0973
Intolerance Scores
- LoFtool
- 0.548
- RVIS EVS
- 0.56
- RVIS percentile EVS
- 81.71
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.265
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |