Neurodegeneration with brain iron accumulation: genes and variants

Genes linked to Neurodegeneration with brain iron accumulation

• WDR45: WD repeat domain phosphoinositide-interacting protein 4

  It participates in early autophagosome formation and cellular recycling pathways, with neurons particularly vulnerable to its dysfunction. De novo or mosaic loss-of-function variants cause beta-propeller protein-associated neurodegeneration, with childhood developmental delay followed by progressive dystonia, parkinsonism, and brain iron accumulation.

  15 disease-causing and 93 uncertain variants in WDR45 are linked to Neurodegeneration with brain iron accumulation.

• ATP13A2: Polyamine-transporting ATPase 13A2

  It supports lysosomal and endolysosomal homeostasis and transports polyamines and other cationic substrates across intracellular membranes. Biallelic pathogenic variants cause Kufor-Rakeb syndrome and related early-onset parkinsonian-neurodegenerative phenotypes.

  1 disease-causing and 0 uncertain variants in ATP13A2 are linked to Neurodegeneration with brain iron accumulation.

Where Neurodegeneration with brain iron accumulation variants cluster

• WDR45 WD 2 (positions 40–84): 4 of 15 disease-causing changes, 2.1× more than its size predicts.
• WDR45 WD 1 (positions 1–34): 3 of 15 disease-causing changes, 2.1× more than its size predicts.
• WDR45 WD 5 (positions 183–222): 3 of 15 disease-causing changes, 1.8× more than its size predicts.

Known disease-causing variants in Neurodegeneration with brain iron accumulation

Uncertain variants in Neurodegeneration with brain iron accumulation that look disease-causing

Which prediction tools work for Neurodegeneration with brain iron accumulation

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• SIFT: 94 out of 100
• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Diseases related to Neurodegeneration with brain iron accumulation

• Optic atrophy, also linked to WDR45
• Developmental disorder, also linked to WDR45
• Kufor-Rakeb syndrome, also linked to ATP13A2
• Autosomal recessive spastic paraplegia type 78, also linked to ATP13A2
• Parkinson disease, also linked to ATP13A2

Frequently asked questions

Which genes are linked to Neurodegeneration with brain iron accumulation?

In CATVariant, Neurodegeneration with brain iron accumulation is linked to 2 analyzed proteins: WDR45 (WD repeat domain phosphoinositide-interacting protein 4) and ATP13A2 (Polyamine-transporting ATPase 13A2).

How many genetic variants are linked to Neurodegeneration with brain iron accumulation?

163 variants: 16 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 93 are of uncertain significance or have conflicting reports.

Which uncertain variants in Neurodegeneration with brain iron accumulation look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example WDR45 R233Q and WDR45 R232C. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Neurodegeneration with brain iron accumulation?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 11 disease-causing and 46 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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