A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD
van der Zee, Julie Rademakers, Rosa Engelborghs, Sebastiaan Gijselinck, Ilse Bogaerts, Veerle Vandenberghe, Rik Santens, Patrick Caekebeke, Jo De Pooter, Tim Peeters, Karin Lübke, Ursula Van den Broeck, Marleen Martin, Jean-Jacques Cruts, Marc De Deyn, Peter P Van Broeckhoven, Christine × Dermaut, Bart #
Brain vol:129 issue:Pt 4 pages:841-852
Among patients with frontotemporal lobar degeneration (FTLD), the respective frequencies of dominant 17q21-linked tau-negative FTLD (with unidentified molecular defect) and 17q21-linked tau-positive FTLD (due to MAPT mutations) remain unknown. Here, in a series of 98 genealogically unrelated Belgian FTLD patients, we identified an ancestral 8 cM MAPT containing haplotype in two patients belonging to multiplex families DR2 and DR8, without demonstrable MAPT mutations, in which FTLD was conclusively linked to 17q21 [maximum summed log of the odds (LOD) score of 5.28 at D17S931]. Interestingly, the same DR2-DR8 ancestral haplotype was observed in five additional familial FTLD patients, indicative of a founder effect. In the FTLD series, the DR2-DR8 ancestral haplotype explained 7% (7 out of 98) of FTLD and 17% (7 out of 42) of familial FTLD and was seven times more frequent than MAPT mutations (1 out of 98 or 1%). Clinically, DR2-DR8 haplotype carriers presented with FTLD often characterized by language impairment, and in one carrier the neuropathological diagnosis was FTLD with rare tau-negative ubiquitin-positive inclusions. Together, these results strongly suggest that the DR2-DR8 founder haplotype at 17q21 harbours a tau-negative FTLD causing mutation that is a much more frequent cause of FTLD in Belgium than MAPT mutations.