WDR45

Chr XXLD

WD repeat domain 45

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

NCBI Gene: 11152 ENSG00000196998 OMIM: 300526

The encoded protein binds phosphatidylinositol 3-phosphate and controls autophagosome assembly and size regulation, working downstream of WIPI2 and promoting ATG2-mediated lipid transfer in the autophagy pathway. Loss-of-function mutations cause neurodegeneration with brain iron accumulation 5 (NBIA5), which follows X-linked dominant inheritance and predominantly affects females due to male lethality. The gene is highly constrained against loss-of-function variants, consistent with pathogenicity through haploinsufficiency.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismXLDLOEUF 0.211 OMIM phenotype

Clinical Summary— WDR45

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Gene-Disease Validity (ClinGen)

X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

92 unique Pathogenic / Likely Pathogenic· 75 VUS of 287 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — WDR45

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.00 (0.00–0.21)

0≤0.351.4

Missense OE?0.56 (0.47–0.66)

0≤0.61.4

Synonymous OE?0.72

0≤1.21.6

LoF obs/exp: 0 / 14.3Missense obs/exp: 92 / 164.8Syn Z: 1.78

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveWDR45-related neurodegeneration with brain iron accumulationLOFmonoallelic_X_heterozygous

This gene — mechanism propensity

0.3097th %ile

GOF

0.3292th %ile

LOF

0.77top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 79% of P/LP variants are LoF · LOEUF 0.21 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

287 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic61

Likely Pathogenic31

VUS75

Likely Benign75

Benign9

Conflicting10

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	59	0	2	0	61
Likely Pathogenic	14	15	2	0	31
VUS	2	57	13	3	75
Likely Benign	0	11	33	31	75
Benign	0	1	6	2	9
Conflicting	—				10
Total	75	84	56	36	261

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap WDR45 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →