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

Abstract

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.

Figure 1

MRI Features Associated with WDR45 Mutations T2-weighted turbo-spin-echo (TSE) MRI shows (A) a hypointense signal (arrow) in the globus pallidus, which “blooms” on fluid-attenuated inversion-recovery sequence (B, arrow), consistent with iron. A hypointense signal (C, arrow) in the substantia nigra on T2-weighted TSE shows iron, and T1-weighted imaging demonstrates a hyperintense halo (D, arrow) in the substantia nigra.

Figure 2

WDR45 Structure and Conservation of Mutated Residues Exon-intron structure of WDR45 with localization and conservation of amino acid residues harboring substitutions that we predict as the cause of BPAN.

Figure 3

Evidence for Somatic Mutation A sequencing electropherogram from male subject 463 shows two DNA traces of differing peak amplitudes to the right of the arrow.