Exome sequencing in 30 neurodegeneration with brain iron accumulation patients

Aims: The three major clinically distinct forms of neurodegeneration with brain iron accumulation (NBIA), PKAN (PANK2 mutations), MPAN (C19orf12 mutations), and PLAN (PLA2G6 mutations) account for approximately 70% of cases. Few others are explained by the rare minor NBIA forms but a meaningful number remains undiagnosed.

Methods: Next generation sequencing-based approaches are promising tools to identify the underlying gene defects in the unclear cases. However, functional studies or statistic evidence are needed to substantiate the disease-causal role of the postulated disease gene. To identify the molecular basis of the disorder we applied a dual approach of exome sequencing combined with clinical stratification to 30 NBIA cases.

Results: We detected approximately 11,000 nonsynonymous variants in each individual. Exclusion of variants present in controls and public databases left approximately 250 private variants per patient and a focus on recessive-type variants further reduced the number to 10 to 50 candidate genes. One patient harbored mutations in PLA2G6 missed in routine diagnostics. A second in a gene linked to another disorder and a third in VPS13A. However, only joint analysis discovered dominant mutations in a new gene, WDR45, in 14 individuals. WDR45 plays a putative role in autophagy. The remaining cases have no clear candidates or follow-up is ongoing.

Conclusion: We identified another major locus for NBIA, the first to be associated with X-linked dominant inheritance. The associated phenotype is clinically recognizable. Our findings indicate that autophagy might be an important pathway involved in the pathogenesis requiring experimental follow-up also in other forms of NBIA.