WDR45

Chr XXLD

WD repeat domain 45

Also known as: JM5, NBIA4, NBIA5, WDRX1, WIPI-4, WIPI4

NCBI Gene: 11152ENSG00000196998UniProt: Q9Y484

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. This gene has a pseudogene at chromosome 4q31.3. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity and full-length nature of some variants have not been determined. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Neurodegeneration with brain iron accumulation 5MIM #300894
XLD
273
ClinVar variants
118
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— WDR45
🧬
Gene-Disease Validity (ClinGen)
X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
118 Pathogenic / Likely Pathogenic· 66 VUS of 273 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.21LOEUF
pLI 0.991
Z-score 3.50
OE 0.00 (0.00–0.21)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.02Z-score
OE missense 0.56 (0.47–0.66)
92 obs / 164.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.56 (0.47–0.66)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.72
0≤1.21.6
LoF obs/exp: 0 / 14.3Missense obs/exp: 92 / 164.8Syn Z: 1.78

ClinVar Variant Classifications

273 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic93
Likely Pathogenic25
VUS66
Likely Benign66
Benign12
Conflicting11
93
Pathogenic
25
Likely Pathogenic
66
VUS
66
Likely Benign
12
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
31
2
60
0
93
Likely Pathogenic
12
8
5
0
25
VUS
2
53
9
2
66
Likely Benign
0
10
38
18
66
Benign
0
0
9
3
12
Conflicting
—11
Total457312123273

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

WDR45 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

WDR45-related neurodegeneration with brain iron accumulation

definitive
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodegeneration with brain iron accumulation 5

MIM #300894

Molecular basis of disorder known

X-linked dominant
📖
GeneReview available — WDR45
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Neurodegeneration with brain iron accumulation.
Hayflick SJ et al.·Handb Clin Neurol
2018Review
WDR45, one gene associated with multiple neurodevelopmental disorders.
Cong Y et al.·Autophagy
2021Review
De novo mutations in moderate or severe intellectual disability.
Hamdan FF et al.·PLoS Genet
2014
The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy.
Deneubourg C et al.·Autophagy
2022
WDR45 mutations in Rett (-like) syndrome and developmental delay: Case report and an appraisal of the literature.
Hoffjan S et al.·Mol Cell Probes
2016Review
WDR45 variants as a major cause for a clinically variable intellectual disability syndrome from early infancy in females.
Abe-Hatano C et al.·J Med Genet
2024
Linking autism spectrum disorders and parkinsonism: clinical and genetic association.
Mai AS et al.·Ann Clin Transl Neurol
2023Review
WDR45 deficiency shortens axon length in dopaminergic neurons from patient-derived iPSCs.
Huang N et al.·Hum Mol Genet
2025
AAV-Mediated Gene Transfer of WDR45 Corrects Neurological Deficits in the Mouse Model of Beta-Propeller Protein-Associated Neurodegeneration.
Carisi MC et al.·Hum Gene Ther
2025Functional
Prioritizing de novo potential non-canonical splicing variants in neurodevelopmental disorders.
Li K et al.·EBioMedicine
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Generation of two human iPSC lines from fibroblasts of BPAN patients carrying pathogenic variants in the WDR45 gene.
Gasparini G et al.·Stem Cell Res
2026Cohort
Generation of two induced pluripotent stem cell lines (FDCHi011-A and FDCHi016-A) from different patients with NBIA5 syndrome carrying WDR45 m.700C > T and m.888G > A mutation.
Yin T et al.·Stem Cell Res
2025Cohort
β-propeller protein-associated neurodegeneration protein WDR45 regulates stress granule disassembly via phase separation with Caprin-1.
Li Y et al.·Nat Commun
2025🔓 Open Access
Significant relief of parkinsonism and dystonia with levodopa in beta-propeller protein-associated neurodegeneration: a video case report and insights into the WDR45 c.400C>T mutation.
Li WC et al.·Clin Park Relat Disord
2025🔓 Open AccessCase report
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools