WDR45

protein-coding

WD repeat domain 45, the group of WD repeat domain containing|WIPI family

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. 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]

Previous symbols:

WDRX1

MANE transcript

NM_001029896.2

Inheritance

ClinVar variants

P:206U:151B:115

Top phenotype

Neurodegeneration with brain iron accumulation 5

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:49,074,433-49,101,170

External References & Databases

Ensembl (ENSG00000196998)

Transcript & Mutation Effects

hg38 • Region Span ~26.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodegeneration with brain iron accumulation 5STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010476

Submitter: Genomics England PanelApp

neurodegeneration with brain iron accumulation 5MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010476

Submitter: Ambry Genetics

X-linked complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

WDR45 was initially identified in a subset of patients with atypical x-linked neurodegeneration with brain iron accumulation (NBIA) in 2012. The disorder is typically characterized by later (adolescence to adulthood) neurologic deterioration, loss of skills, and progressive impairment. Many individuals were described as presenting in childhood with epilepsy and neurodevelopmental impairment or intellectual disability. The childhood presentation led to the inclusion of this gene on epilepsy panels with resulting earlier identification, broadened phenotypes, and reports of patients at younger ages. The expert panel decided to curate this gene for the X-linked complex neurodevelopmental disorder phenotype which represents a spectrum of neurologic presentations that can include epilepsy, autism, movement disorders, and intellectual disability. It should be noted that a review of the literature identified 34 adolescent and adult cases and 17 pediatric cases. Given the earlier identification, increased reporting, and variable phenotypes, the ultimate course and variability of this disorder may not yet be determined.

neurodegeneration with brain iron accumulation 5DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010476

Submitter: G2P

neurodegeneration with brain iron accumulation 5DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010476

Submitter: Illumina

neurodegeneration with brain iron accumulation 5STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010476

Submitter: PanelApp Australia

neurodegeneration with brain iron accumulation 5STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010476

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Neurodegeneration with brain iron accumulation 5XL

Manifestation: 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: 21920862; 22892189; 23176820; 23435086; 23447832; 23687123

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WDR45 variants in ClinVar

23 Conditions Cataloged

Neurodegeneration with brain iron accumulation 5Total: 474

not providedTotal: 159

Inborn genetic diseasesTotal: 53

not specifiedTotal: 49

WDR45-related disorderTotal: 26

Intellectual disabilityTotal: 6

Oculocutaneous albinism type 7Total: 4

Global developmental delayTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001029896.2. 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	1 clinvar	1 clinvar	5 clinvar	67 clinvar	4 clinvar	78
missense	3 clinvar	30 clinvar	133 clinvar	43 clinvar	1 clinvar	210
nonsense	25 clinvar	4 clinvar	1 clinvar			30
start loss	3 clinvar	2 clinvar				5
frameshift	65 clinvar	21 clinvar	3 clinvar			89
splice donor/acceptor (+/-2bp)	31 clinvar	20 clinvar	9 clinvar			60
Total	128	78	151	110	5	472

Highest pathogenic variant AF is 0.0000063851194

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 186 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001029896.2	RefSeq	NP_001025067.1	10	MANE Select
ENST00000376372.9	Ensembl	ENSP00000365551.3	10	MANE Select
NM_007075.4	RefSeq	NP_009006.2	10	Standard
ENST00000322995.13	Ensembl	ENSP00000365543.5	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Macroautophagy
Cellular responses to external stimuli

Biological Process

autophagosome assembly
autophagy of mitochondrion
protein lipidation
autophagy
cellular response to starvation

Molecular Function

protein binding
protein kinase binding
phosphatidylinositol-3-phosphate binding
phosphatidylinositol-3,5-bisphosphate binding
phosphatidylinositol phosphate binding

Cellular Component

phagophore assembly site
cytosol
extrinsic component of membrane
phagophore assembly site membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356463
Coding exons: 10
Length: 28724
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.02	92	165	0.558	0.0000145	2373
Missense (PolyPhen)		11	32.817	0.33519		529
Synonymous	1.78	47	65.3	0.719	0.00000582	715
Loss of Function	3.50	0	14.3	0.00	0.00000119	205

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	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an important role in the autophagy pathway, which is the major intracellular degradation system by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation. {ECO:0000269|PubMed:23435086}.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.379
RVIS EVS: -0.27
RVIS percentile EVS: 33.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.925

Gene Damage Prediction

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