WDR26

protein-coding

WD repeat domain 26, the group of MicroRNA protein coding host genes|WD repeat domain containing

Gene summary

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. Two transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001379403.1

Inheritance

ClinVar variants

P:76U:188B:48

Top phenotype

Skraban-Deardorff syndrome

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr1:224,385,146-224,437,033

External References & Databases

Ensembl (ENSG00000162923)

Transcript & Mutation Effects

hg38 • Region Span ~51.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Skraban-Deardorff syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054636

Submitter: PanelApp Australia

Skraban-Deardorff syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054636

Submitter: Illumina

Skraban-Deardorff syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0054636

Submitter: G2P

Skraban-Deardorff syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0054636

Submitter: ClinGen

*WDR26* was first reported in relation to autosomal dominant Skraban-Deardoff syndrome in 2017 (Skraban et al., PMID: 28686853). Skraban-Deardoff syndrome is characterized by global developmental delay, intellectual disability, seizures, craniofacial dysmorphisms, and abnormal gait. Twenty-eight variants that have been reported in 28 probands in 8 publications (PMIDs: 28686853, 32030560, 33506510, 33675273, 34055682, 34775451, 35627197, 36269129) are included in this curation. The reported variants include 23 truncating variants (frameshift, nonsense, and splice), and 5 missense variants. All identified variants occurred *de novo*. The mechanism of pathogenicity is known to be loss of function. Currently, there is no experimental evidence to support this gene-disease relationship. *WDR26* encodes a scaffolding protein that regulates MAPK, Wnt, and PI3K signaling pathways and is involved in ubiquitination, but little is known about its role in the brain. In summary, there is definitive evidence to support the relationship between *WDR26* and autosomal dominant Skraban-Deardoff syndrome. 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 Intellectual Disability and Autism Gene Curation Expert Panel on July 19, 2023 (SOP Version 9).

Skraban-Deardorff syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054636

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Skraban-Deardorff syndromeAD

Manifestation: Craniofacial; Dental; Musculoskeletal; Neurologic

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

Refs: 28686853

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WDR26 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 151

Skraban-Deardorff syndromeTotal: 77

Inborn genetic diseasesTotal: 77

not specifiedTotal: 49

WDR26-related disorderTotal: 25

Long QT syndromeTotal: 2

Intellectual disabilityTotal: 2

Neurofibromatosis, type 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001379403.1. 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			2 clinvar	33 clinvar	2 clinvar	37
missense	2 clinvar	17 clinvar	178 clinvar	13 clinvar		210
nonsense	10 clinvar	4 clinvar	1 clinvar			15
start loss						0
frameshift	28 clinvar	7 clinvar	1 clinvar			36
splice donor/acceptor (+/-2bp)	5 clinvar	3 clinvar	6 clinvar			14
Total	45	31	188	46	2	312

Highest pathogenic variant AF is 0.000002478321

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001379403.1	RefSeq	NP_001366332.1	14	MANE Select
ENST00000414423.9	Ensembl	ENSP00000408108.4	14	MANE Select
NM_001115113.3	RefSeq	NP_001108585.2	14	Standard
NM_025160.7	RefSeq	NP_079436.4	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Molecular Function

protein binding

Cellular Component

ubiquitin ligase complex
nucleus
nucleoplasm
cytoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000414423
Coding exons: 14
Length: 51891
Individuals with no LoFs: 125568
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125578
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.58	169	361	0.469	0.0000193	4291
Missense (PolyPhen)		17	90.64	0.18755		1027
Synonymous	1.38	117	138	0.850	0.00000713	1313
Loss of Function	5.48	0	35.0	0.00	0.00000183	412

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0.00033	0.00033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: G-beta-like protein involved in cell signal transduction (PubMed:15378603, PubMed:19446606, PubMed:22065575, PubMed:23625927, PubMed:27098453, PubMed:26895380). Acts as a negative regulator in MAPK signaling pathway (PubMed:15378603). Functions as a scaffolding protein to promote G beta:gamma- mediated PLCB2 plasma membrane translocation and subsequent activation in leukocytes (PubMed:22065575, PubMed:23625927). Core component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1 (PubMed:29911972). Acts as a negative regulator of the canonical Wnt signaling pathway through preventing ubiquitination of beta-catenin CTNNB1 by the beta- catenin destruction complex, thus negatively regulating CTNNB1 degradation (PubMed:27098453). Serves as a scaffold to coordinate PI3K/AKT pathway-driven cell growth and migration (PubMed:26895380). Protects cells from oxidative stress-induced apoptosis via the down-regulation of AP-1 transcriptional activity as well as by inhibiting cytochrome c release from mitochondria (PubMed:19446606). Protects also cells by promoting hypoxia- mediated autophagy and mitophagy (By similarity). {ECO:0000250|UniProtKB:F1LTR1, ECO:0000269|PubMed:15378603, ECO:0000269|PubMed:19446606, ECO:0000269|PubMed:23625927, ECO:0000269|PubMed:26895380, ECO:0000269|PubMed:27098453, ECO:0000269|PubMed:29911972}.;
Disease: DISEASE: Skraban-Deardorff syndrome (SKDEAS) [MIM:617616]: An autosomal dominant syndrome characterized by psychomotor developmental delay, intellectual disability with delayed speech, febrile and non-febrile seizures, abnormal gait, and facial dysmorphism. Facial features include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. {ECO:0000269|PubMed:28686853}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.156

Intolerance Scores

RVIS EVS: -0.47
RVIS percentile EVS: 23.04

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.662

Gene Damage Prediction

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