Beta-propeller protein-associated neurodegeneration (BPAN) is an X-linked rare dominant disorder of autophagy. The role of WDR45 has been implicated in BPAN almost exclusively in females possibly due to male lethality. Characterization of distinctive clinical manifestations and potentially the complex genetic determinants in rare male patients remain crucial for deciphering BPAN and other X-linked dominant diseases. We performed whole exome sequencing (WES) followed by segregation analysis and identified a novel nonsense and mosaic variant in WDR45, namely NM_007075.3:c.873C>G; p.(Tyr291*) in an affected male at the age of 34. His biphasic medical history was compatible with BPAN, which was characterized by delayed psychomotor development, intellectual disability, and progression into dystonia parkinsonism in his twenties. The variant had an apparently mosaic pattern both in whole exome and Sanger sequencing findings. In order to figure out if mosaicism was restricted to this variant or related to a chromosomal level mosaicism, we used our in-house WES data from 129 unrelated individuals to calculate the threshold values of male and female X chromosome heterozygosity (XcHet) in WES data for our pipeline. A background level of heterozygous variants on X chromosome excluding the pseudoautosomal loci is an observed phenomenon in WES analysis and this level has been used as a quality measure. Herein, we suggest utilization of this measure for detection of digital anomalies of the X chromosome in males by potentially observing a higher XcHet value than the threshold value. This approach has revealed a variant level mosaicism in the affected male, which was further supported with cytogenetic analyses.
Keywords: BPAN; Mosaicism; WDR45; Whole exome sequencing; X chromosome heterozygosity.