Citations 2
Long-read targeted sequencing uncovers clinicopathological associations forC9orf72-linked diseases
DeJesus‐Hernandez, Mariely, Aleff, Ross A., Jackson, Jazmyne L. , Finch, NiCole A., Murray, Melissa E. , McLaughlin, Ian , Harting, John, Graff‐Radford, Neill R. , Oskarsson, Björn , Josephs, Keith A. , Petersen, Ronald C. , Fryer, John Denis , Petrucelli, Leonard , Rademakers, Rosa , Wieben, Eric D. , Blitterswijk, Marka van , Baker, Matthew C, Gendron, Tania F. , Oskarsson, Björn , Josephs, Keith A , Dickson, Dennis W , Rademakers, Rosa , van Blitterswijk, Marka , Murray, Melissa E , Baker, Matthew , Knopman, David S. , Boeve, Bradley F. , Dickson, Dennis W. , Ebbert, Mark
Brain | January 15, 2021 | Volume: 144 | Issue: 4 | Pages: 1082-1088
AbstractTo examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P = 5.0 × 10−4). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P = 0.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P = 0.003), poly(GP) proteins (P = 1.3 × 10− 5), and poly(GA) proteins (P = 0.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases.
Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases
Ramos, Eliana Marisa , Dokuru, Deepika , Berlo, Victoria Van, Wojta, Kevin , Huang, Alden , Deverasetty, Sandeep, Qin, Yue , Blitterswijk, Marka van , Jackson, Jazmyne L. , Bordelon, Yvette , Brannelly, Patrick , Brushaber, Danielle , Dickinson, Susan, Domoto‐Reilly, Kimiko , Faber, Kelley , Fields, Julie A. , Forsberg, Leah K. , Gavrilova, Ralitza H. , Ghoshal, Nupur , Graff‐Radford, Jonathan , Graff‐Radford, Neill R. , Grant, Ian , Heuer, Hilary W. , Hsiung, Ging‐Yuek Robin , Huey, Edward D. , Irwin, David J. , Kantarci, Kejal , Karydas, Anna, Kaufer, Daniel , Kornak, John , Kramer, Joel H. , Kremers, Walter K. , Kukull, Walter A. , Ljubenkov, Peter A. , Lungu, Codrin , Mackenzie, Ian R. , Mendez, Mario F. , Miller, Bruce L. , Onyike, Chiadi U. , Pantelyat, Alexander , Pearlman, Rodney , Petrucelli, Len, Potter, Madeline, Rankin, Katherine P. , Rascovsky, Katya, Roberson, Erik D. , Rogalskı, Emily , Shaw, Leslie M. , Syrjanen, Jeremy A. , Tartaglia, Maria Carmela , Tatton, Nadine , Taylor, Joanne, Trojanowski, John Q. , Weıntraub, Sandra , Wong, Bonnie , Rademakers, Rosa , Rosen, Howard J. , Boxer, Adam L. , Coppola, Giovanni, Jackson, Jazmyne, Brushaber, Danielle E, Boeve, Brad F, van Blitterswijk, Marka , Irwin, David J , Hsiung, Gink-Yuek , Roberson, Erik , Miller, Bruce L , Kantarci, Kejal , Pantelyat, Alex , Tartaglia, Maria Carmela , Kremers, Walter K , Domoto-Reilly, Kimiko , Wang, Qing , Appleby, Brian S. , Dickerson, Bradford Clark , Fong, Jamie , Foroud, Tatiana , Goldman, Jill , Grossman, Murray , Kerwin, Diana , Knopman, David S. , Litvan, Irene , Toga, Arthur W. , Wszołek, Zbigniew K. , Boeve, Bradley F. , Coppola, Giovanni
Alzheimer's & Dementia | January 16, 2020 | Volume: 16 | Issue: 1 | Pages: 118-130
AbstractIntroductionThe Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes.MethodsWe screened the major dementia‐associated genes in 302 sporadic and 390 familial (symptomatic or at‐risk) participants enrolled in these studies.ResultsAmong the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule‐associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes.DiscussionOur study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.