Comprehensive genetic and mutation analysis of familial dementia with Lewy bodies linked to 2q35-q36.

The second most frequent form of neurodegenerative dementia after Alzheimer's disease is dementia with Lewy bodies (DLB). Since informative DLB families are scarce, little is presently known about the molecular genetic etiology of DLB. We recently mapped the first locus for DLB on chromosome 2q35-q36 in a multiplex Belgian family, DR246, with autopsy-proven DLB pathology in a region of 9.2 Mb. Here, we describe the ascertainment of additional DR246 family members and significant finemapping of the DLB locus to 3.3 Mb based on informative meiotic recombinants. Extensive sequencing of the 42 positional candidate genes within the DLB region did not identify a simple pathogenic mutation that co-segregated with disease in family DR246. Also high resolution analysis of copy number variations in the DLB locus did not provide evidence for a complex mutation. In conclusion, we confirmed the DLB locus at 2q35-q36 as a genetic entity but candidate gene-based sequencing and copy number variation analysis did not identify the pathogenic mutation in family DR246. Other detection strategies will be needed to reveal the underlying mutation explaining the linkage of DLB to 2q35-q26. Possibly the disease mutation in this family acts through a more complex mechanism than generally envisaged for monogenic disorders. Nevertheless, identifying the first familial DLB gene is likely to contribute an entry point into the pathogenic cascades underlying DLB pathology.