Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA

Am J Hum Genet. 2012 Dec 7;91(6):1144-9. doi: 10.1016/j.ajhg.2012.10.019. Epub 2012 Nov 21.


Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype. The clinical features include early-onset global developmental delay and further neurological deterioration (parkinsonism, dystonia, and dementia developing by early adulthood). Brain MRI revealed evidence of iron deposition in the substantia nigra and globus pallidus. Males and females are phenotypically similar, an observation that might be explained by somatic mosaicism in surviving males and germline or somatic mutations in females, as well as skewing of X chromosome inactivation. This clinically recognizable disorder is among the more common forms of NBIA, and we suggest that it be named accordingly as beta-propeller protein-associated neurodegeneration.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Base Sequence
  • Brain / metabolism*
  • Brain / pathology
  • Carrier Proteins / genetics*
  • Exome*
  • Female
  • Gene Order
  • Genes, X-Linked*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Iron Overload / diagnosis
  • Iron Overload / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Phenotype*


  • Carrier Proteins
  • WDR45 protein, human