Abstract
| Original language | English |
|---|---|
| Journal | Neuron |
| DOIs | |
| Publication status | E-pub ahead of print - Nov 26 2020 |
Keywords
- amyotrophic lateral sclerosis
- frontotemporal dementia
- huntingtin
- repeat expansions
- whole-genome sequencing
Fingerprint
Dive into the research topics of 'Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. / International FTD-Genomics Consortium (IFGC) (BENUSSI L, BINETTI G, GHIDONI R sono autori IRCCS).
In: Neuron, 26.11.2020.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
AU - International FTD-Genomics Consortium (IFGC) (BENUSSI L, BINETTI G, GHIDONI R sono autori IRCCS)
AU - Dewan, R.
AU - Chia, R.
AU - Ding, J.
AU - Hickman, R.A.
AU - Stein, T.D.
AU - Abramzon, Y.
AU - Ahmed, S.
AU - Sabir, M.S.
AU - Portley, M.K.
AU - Tucci, A.
AU - Ibáñez, K.
AU - Shankaracharya, F.N.U.
AU - Keagle, P.
AU - Rossi, G.
AU - Caroppo, P.
AU - Tagliavini, F.
AU - Ticozzi, N.
AU - Tiloca, C.
AU - Colombrita, C.
AU - Pensato, V.
AU - Castellotti, B.
AU - Comi, G.P.
AU - Del Bo, R.
AU - Ceroni, M.
AU - Gagliardi, S.
AU - Lauria, G.
AU - Duga, S.
AU - Corti, S.
AU - Cereda, C.
AU - Taroni, F.
AU - Gellera, C.
AU - Ratti, A.
AU - Landi, F.
AU - Mora, G.
AU - Albani, D.
AU - Borroni, B.
AU - Galimberti, D.
AU - Scarpini, E.
AU - Serpente, M.
AU - Nacmias, B.
AU - Sorbi, S.
AU - Novelli, V.
AU - Puca, A.A.
AU - Rossi, M.
AU - Lopez, G.
AU - Benussi, L.
AU - Binetti, G.
AU - Ghidoni, R.
AU - Silani, V.
AU - Ferrari, R.
N1 - Export Date: 23 February 2021 CODEN: NERNE Correspondence Address: Traynor, B.J.; Neuromuscular Diseases Research Section, United States; email: traynorb@mail.nih.gov Funding details: P30 AG066462-01 Funding details: National Institutes of Health, NIH Funding details: National Institute on Aging, NIA Funding details: National Heart, Lung, and Blood Institute, NHLBI, IAA-A-HL-007.001 Funding details: National Human Genome Research Institute, NHGRI Funding details: National Institute of Neurological Disorders and Stroke, NINDS, 1ZIAAG000935, 1ZIANS0030033, 1ZIANS003034, 1ZIANS003154, R01NS073873 Funding details: Amyotrophic Lateral Sclerosis Association, ALSA, 19-SI-459 Funding details: Hereditary Disease Foundation, HDF Funding details: Wellcome Trust, WT, 103838 Funding details: Tow Foundation Funding details: Lewy Body Dementia Association, LBDA Funding details: NIHR Cambridge Biomedical Research Centre Funding text 1: We thank contributors who collected samples used in this initiative and the patients and families, whose help and participation made this work possible. This research was supported by the Intramural Research Program of the National Institutes of Health (National Institute on Aging, National Institute of Neurological Disorders and Stroke, project numbers 1ZIAAG000935 [Principal Investigator (PI) Bryan J. Traynor], 1ZIANS003154 [PI Sonja W. Scholz], and 1ZIANS0030033 and 1ZIANS003034 [David S. Goldstein]). Drs. Sidransky, Grisel Lopez, and Tayebi were supported by the Intramural Research Program of the National Human Genome Research Institute. This research was supported by the Italian Ministry of Health (Ricerca Corrente). R.A.H. is a Columbia University Irving Medical Center ADRC Research Education Component trainee (P30 AG066462-01, PI Scott Small) and is supported by grants from the Hereditary Disease Foundation and Huntington Disease Society of America. J.B.R. is supported by the Wellcome Trust (103838) and National Institute for Health Research Cambridge Biomedical Research Centre. J.E.L. was supported by the National Institutes of Health/National Institute of Neurological Disorders (R01NS073873). The American Genome Center is supported by NHLBI grant IAA-A-HL-007.001. The sequencing activities at NYGC were supported by the ALS Association (grant 19-SI-459) and the Tow Foundation. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (https://hpc.nih.gov). L.B. G.B. C.B.B. P.C. A.C. R.F. L.F. R.G. J.D.G. J.A.H. M.B.H. R.A.H. K.I. E.J. P.M.J. N.K. J.E.L. H.R.M. C.F.N. S.P.-B. S.M.R. O.A.R. G.R. J.B.R. M.R. S.W.S. V.S. A.B.S. T.D.S. F.T. T.T. A. Torkamani, B.J.T. V.V. J.P.V. and M.L.W. collected and prepared the samples and performed the clinical evaluations. Y.A. S.A. R.C. A.C. C.L.D. R.D. J.D. R.F. J.G. M.B.H. R.A.H. P.K. J.E.L. H.R.M. M.K.P. M.S.S. T.D.S. A. Tucci, V.V. C.V. J.P.V. and S. conducted the experiments and the data analysis. R.D. S.W.S. and B.J.T. wrote the manuscript. A.C. R.F. L.F. J.G. J.A.H. M.B.H. J.E.L. H.R.M. A.B.S. S.W.S. and B.J.T. designed and supervised the experiments. S.P.-B. A.B.S. J.A.H. H.R.M. and B.J.T. hold US, EU, and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9 or f72. S.W.S. serves on the scientific advisory council of the Lewy Body Dementia Association and is an editorial board member for the Journal of Parkinson's Disease. B.J.T. is an editorial board member for JAMA Neurology, JNNP, and Neurobiology of Aging. V.S. is on the journal editorial boards of Amyotrophic Lateral Sclerosis, European Neurology, American Journal of Neurodegenerative Diseases, and Frontiers in Neurology. He has also received compensation for consulting services and speaking activities from AveXis, Cytokinetics, Italfarmaco, and Zambon. J.B.R. is an editor for Brain and has received compensation for consulting services from Asceneuron, Biogen, UCB, Astex, and SV Health. J.E.L. is a member of the scientific advisory board for Cerevel Therapeutics and a consultant and provides expert testimony for Perkins Coie. Funding text 2: We thank contributors who collected samples used in this initiative and the patients and families, whose help and participation made this work possible. This research was supported by the Intramural Research Program of the National Institutes of Health ( National Institute on Aging , National Institute of Neurological Disorders and Stroke , project numbers 1ZIAAG000935 [Principal Investigator (PI) Bryan J. Traynor], 1ZIANS003154 [PI Sonja W. Scholz], and 1ZIANS0030033 and 1ZIANS003034 [David S. Goldstein]). Drs. Sidransky, Grisel Lopez, and Tayebi were supported by the Intramural Research Program of the National Human Genome Research Institute . This research was supported by the Italian Ministry of Health (Ricerca Corrente). R.A.H. is a Columbia University Irving Medical Center ADRC Research Education Component trainee ( P30 AG066462-01 , PI Scott Small) and is supported by grants from the Hereditary Disease Foundation and Huntington Disease Society of America . J.B.R. is supported by the Wellcome Trust ( 103838 ) and National Institute for Health Research Cambridge Biomedical Research Centre . J.E.L. was supported by the National Institutes of Health /National Institute of Neurological Disorders (R01NS073873). The American Genome Center is supported by NHLBI grant IAA-A-HL-007.001 . The sequencing activities at NYGC were supported by the ALS Association (grant 19-SI-459 ) and the Tow Foundation . This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health , Bethesda, MD ( https://hpc.nih.gov ). References: Altshuler, D.M., Gibbs, R.A., Peltonen, L., Altshuler, D.M., Gibbs, R.A., Peltonen, L., Dermitzakis, E., Peltonen, L., Integrating common and rare genetic variation in diverse human populations (2010) Nature, 467, pp. 52-58; Arthur, K.C., Calvo, A., Price, T.R., Geiger, J.T., Chiò, A., Traynor, B.J., Projected increase in amyotrophic lateral sclerosis from 2015 to 2040 (2016) Nat. Commun., 7, p. 12408; Bean, L., Bayrak-Toydemir, P., American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, 2014 edition: technical standards and guidelines for Huntington disease (2014) Genet. Med., 16, p. e2; Brooks, B.R., El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical limits of amyotrophic lateral sclerosis” workshop contributors (1994) J. Neurol. Sci., 124, pp. 96-107; Chang, C.C., Chow, C.C., Tellier, L.C., Vattikuti, S., Purcell, S.M., Lee, J.J., Second-generation PLINK: rising to the challenge of larger and richer datasets (2015) Gigascience, 4, p. 7; Chao, M.J., Gillis, T., Atwal, R.S., Mysore, J.S., Arjomand, J., Harold, D., Holmans, P., Myers, R.H., Haplotype-based stratification of Huntington's disease (2017) Eur. J. Hum. Genet., 25, pp. 1202-1209; Chhetri, S.K., Dayanandan, R., Bindman, D., Craufurd, D., Majeed, T., Amyotrophic lateral sclerosis and Huntington's disease: neurodegenerative link or coincidence? (2014) Amyotroph. Lateral Scler. Frontotemporal Degener., 15, pp. 145-147; Chia, R., Chiò, A., Traynor, B.J., Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications (2018) Lancet Neurol., 17, pp. 94-102; Chiò, A., Logroscino, G., Traynor, B.J., Collins, J., Simeone, J.C., Goldstein, L.A., White, L.A., Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature (2013) Neuroepidemiology, 41, pp. 118-130; Ciosi, M., Maxwell, A., Cumming, S.A., Hensman Moss, D.J., Alshammari, A.M., Flower, M.D., Durr, A., Holmans, P., A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes (2019) EBioMedicine, 48, pp. 568-580; Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W.Y., Humphrey, J., Polke, J., Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia (2019) Nat. Genet., 51, pp. 649-658; Dabrowska, M., Juzwa, W., Krzyzosiak, W.J., Olejniczak, M., Precise excision of the CAG tract from the Huntingtin gene by Cas9 nickases (2018) Front. Neurosci., 12, p. 75; De Rooij, K.E., De Koning Gans, P.A., Roos, R.A., Van Ommen, G.J., Den Dunnen, J.T., Somatic expansion of the (CAG)n repeat in Huntington disease brains (1995) Hum. Genet., 95, pp. 270-274; DePristo, M.A., Banks, E., Poplin, R., Garimella, K.V., Maguire, J.R., Hartl, C., Philippakis, A.A., Hanna, M., A framework for variation discovery and genotyping using next-generation DNA sequencing data (2011) Nat. Genet., 43, pp. 491-498; Dolzhenko, E., van Vugt, J.J.F.A., Shaw, R.J., Bekritsky, M.A., van Blitterswijk, M., Narzisi, G., Ajay, S.S., Johnson, N.H., Detection of long repeat expansions from PCR-free whole-genome sequence data (2017) Genome Res., 27, pp. 1895-1903; Dolzhenko, E., Deshpande, V., Schlesinger, F., Krusche, P., Petrovski, R., Chen, S., Emig-Agius, D., Bowman, B., ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions (2019) Bioinformatics, 35, pp. 4754-4756; Emre, M., Aarsland, D., Brown, R., Burn, D.J., Duyckaerts, C., Mizuno, Y., Broe, G.A., Gauthier, S., Clinical diagnostic criteria for dementia associated with Parkinson's disease (2007) Mov. Disord., 22, pp. 1689-1707. , quiz 1837; Faber, R., Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria (1999) Neurology, 53, p. 1159; Ferrari, R., Manzoni, C., Hardy, J., Genetics and molecular mechanisms of frontotemporal lobar degeneration: an update and future avenues (2019) Neurobiol. Aging, 78, pp. 98-110; Gardiner, S.L., Boogaard, M.W., Trompet, S., de Mutsert, R., Rosendaal, F.R., Gussekloo, J., Jukema, J.W., Aziz, N.A., Prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among large population-based cohorts (2019) JAMA Neurol., 76, pp. 650-656; Höglinger, G.U., Respondek, G., Stamelou, M., Kurz, C., Josephs, K.A., Lang, A.E., Mollenhauer, B., Whitwell, J.L., Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria (2017) Mov. Disord., 32, pp. 853-864; Jama, M., Millson, A., Miller, C.E., Lyon, E., Triplet repeat primed PCR simplifies testing for Huntington disease (2013) J. Mol. Diagn., 15, pp. 255-262; Jun, G., Flickinger, M., Hetrick, K.N., Romm, J.M., Doheny, K.F., Abecasis, G.R., Boehnke, M., Kang, H.M., Detecting and estimating contamination of human DNA samples in sequencing and array-based genotype data (2012) Am. J. Hum. Genet., 91, pp. 839-848; Kanai, K., Kuwabara, S., Sawai, S., Nakata, M., Misawa, S., Isose, S., Hirano, S., Hattori, T., Genetically confirmed Huntington's disease masquerading as motor neuron disease (2008) Mov. Disord., 23, pp. 748-751; Kennedy, L., Evans, E., Chen, C.M., Craven, L., Detloff, P.J., Ennis, M., Shelbourne, P.F., Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis (2003) Hum. Mol. Genet., 12, pp. 3359-3367; La Spada, A.R., Wilson, E.M., Lubahn, D.B., Harding, A.E., Fischbeck, K.H., Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy (1991) Nature, 352, pp. 77-79; Langbehn, D.R., Hayden, M.R., Paulsen, J.S., CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical approaches (2010) Am. J. Med. Genet. B. Neuropsychiatr. Genet., 153B, pp. 397-408; Li, H., Durbin, R., Fast and accurate short read alignment with Burrows-Wheeler transform (2009) Bioinformatics, 25, pp. 1754-1760; Lillo, P., Hodges, J.R., Frontotemporal dementia and motor neurone disease: overlapping clinic-pathological disorders (2009) J. Clin. Neurosci., 16, pp. 1131-1135; Loh, P.R., Palamara, P.F., Price, A.L., Fast and accurate long-range phasing in a UK Biobank cohort (2016) Nat. Genet., 48, pp. 811-816; MacDonald, M.E., Ambrose, C.M., Duyao, M.P., Myers, R.H., Lin, C., Srinidhi, L., Barnes, G., Groot, N., A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes (1993) Cell, 72, pp. 971-983; Majounie, E., Renton, A.E., Mok, K., Dopper, E.G., Waite, A., Rollinson, S., Chiò, A., Simon-Sanchez, J., Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study (2012) Lancet Neurol., 11, pp. 323-330; McKeith, I.G., Dickson, D.W., Lowe, J., Emre, M., O'Brien, J.T., Feldman, H., Cummings, J., Perry, E.K., Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium (2005) Neurology, 65, pp. 1863-1872; Mouro Pinto, R., Arning, L., Giordano, J.V., Razghandi, P., Andrew, M.A., Gillis, T., Correia, K., Parwez, C.R., Patterns of CAG repeat instability in the central nervous system and periphery in Huntington's disease and in spinocerebellar ataxia type 1 (2020) Hum. Mol. Genet., 29, pp. 2551-2567; Neary, D., Snowden, J., Mann, D., Frontotemporal dementia (2005) Lancet Neurol., 4, pp. 771-780; Nielsen, T.R., Bruhn, P., Nielsen, J.E., Hjermind, L.E., Behavioral variant of frontotemporal dementia mimicking Huntington's disease (2010) Int. Psychogeriatr., 22, pp. 674-677; Onyike, C.U., Diehl-Schmid, J., The epidemiology of frontotemporal dementia (2013) Int. Rev. Psychiatry, 25, pp. 130-137; Papageorgiou, S.G., Antelli, A., Bonakis, A., Vassos, E., Zalonis, I., Kalfakis, N., Panas, M., Association of genetically proven Huntington's disease and sporadic amyotrophic lateral sclerosis in a 72-year-old woman (2006) J. Neurol., 253, pp. 1649-1650; Peplow, M., The 100,000 Genomes Project (2016) BMJ, 353, p. i1757; Phukan, J., Ali, E., Pender, N.P., Molloy, F., Hennessy, M., Walsh, R.J., Hardiman, O., Huntington's disease presenting as amyotrophic lateral sclerosis (2010) Amyotroph. Lateral Scler., 11, pp. 405-407; Poplin, R., Ruano-Rubio, V., DePristo, M.A., Fennell, T.J., Carneiro, M.O., Van der Auwera, G.A., Kling, D.E., Roazen, D., Scaling accurate genetic variant discovery to tens of thousands of samples (2018) bioRxiv; Pringsheim, T., Wiltshire, K., Day, L., Dykeman, J., Steeves, T., Jette, N., The incidence and prevalence of Huntington's disease: a systematic review and meta-analysis (2012) Mov. Disord., 27, pp. 1083-1091; Regier, A.A., Farjoun, Y., Larson, D.E., Krasheninina, O., Kang, H.M., Howrigan, D.P., Chen, B.J., Ames, D.C., Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects (2018) Nat. Commun., 9, p. 4038; Renton, A.E., Chiò, A., Traynor, B.J., State of play in amyotrophic lateral sclerosis genetics (2014) Nat. Neurosci., 17, pp. 17-23; Rowland, L.P., Shneider, N.A., Amyotrophic lateral sclerosis (2001) N. Engl. J. Med., 344, pp. 1688-1700; Rubio, A., Steinberg, K., Figlewicz, D.A., MacDonald, M.E., Greenamyre, T., Hamill, R., Shoulson, I., Powers, J.M., Coexistence of Huntington's disease and familial amyotrophic lateral sclerosis: case presentation (1996) Acta Neuropathol., 92, pp. 421-427; Sadeghian, H., O'Suilleabhain, P.E., Battiste, J., Elliott, J.L., Trivedi, J.R., Huntington chorea presenting with motor neuron disease (2011) Arch. Neurol., 68, pp. 650-652; Sedlazeck, F.J., Rescheneder, P., Smolka, M., Fang, H., Nattestad, M., von Haeseler, A., Schatz, M.C., Accurate detection of complex structural variations using single-molecule sequencing (2018) Nat. Methods, 15, pp. 461-468; Simon-Sanchez, J., Hanson, M., Singleton, A., Hernandez, D., McInerney, A., Nussbaum, R., Werner, J., Gwinn-Hardy, K., Analysis of SCA-2 and SCA-3 repeats in Parkinsonism: evidence of SCA-2 expansion in a family with autosomal dominant Parkinson's disease (2005) Neurosci. Lett., 382, pp. 191-194; Swami, M., Hendricks, A.E., Gillis, T., Massood, T., Mysore, J., Myers, R.H., Wheeler, V.C., Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset (2009) Hum. Mol. Genet., 18, pp. 3039-3047; Tabrizi, S.J., Leavitt, B.R., Landwehrmeyer, G.B., Wild, E.J., Saft, C., Barker, R.A., Blair, N.F., Rickards, H., Targeting Huntingtin Expression in Patients with Huntington's Disease (2019) N. Engl. J. Med., 380, pp. 2307-2316; Tada, M., Coon, E.A., Osmand, A.P., Kirby, P.A., Martin, W., Wieler, M., Shiga, A., Makifuchi, T., Coexistence of Huntington's disease and amyotrophic lateral sclerosis: a clinicopathologic study (2012) Acta Neuropathol., 124, pp. 749-760; Telenius, H., Kremer, B., Goldberg, Y.P., Theilmann, J., Andrew, S.E., Zeisler, J., Adam, S., Clarke, L.A., Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm (1994) Nat. Genet., 6, pp. 409-414; van Swieten, J., Rosso, S., Heutink, P., MAPT-Related Disorders (2000) GeneReviews, , M. Adam H.H. Ardinger R.A. Pagon et al. (eds.) University of Washington, Seattle Seattle, WA; Vonsattel, J.P., Myers, R.H., Stevens, T.J., Ferrante, R.J., Bird, E.D., Richardson, E.P., Jr., Neuropathological classification of Huntington's disease (1985) J. Neuropathol. Exp. Neurol., 44, pp. 559-577; Wang, K., Li, M., Hakonarson, H., ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data (2010) Nucleic Acids Res., 38, p. e164
PY - 2020/11/26
Y1 - 2020/11/26
N2 - We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40–64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. © 2020 Using large-scale whole-genome sequencing, Dewan et al. identify pathogenic HTT repeat expansions in patients diagnosed with FTD/ALS neurodegenerative disorders. Autopsies confirm the TDP-43 pathology expected in FTD/ALS and show polyglutamine inclusions within the frontal cortices but no striatal degeneration. These data broaden the phenotype resulting from HTT repeat expansions. © 2020
AB - We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40–64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. © 2020 Using large-scale whole-genome sequencing, Dewan et al. identify pathogenic HTT repeat expansions in patients diagnosed with FTD/ALS neurodegenerative disorders. Autopsies confirm the TDP-43 pathology expected in FTD/ALS and show polyglutamine inclusions within the frontal cortices but no striatal degeneration. These data broaden the phenotype resulting from HTT repeat expansions. © 2020
KW - amyotrophic lateral sclerosis
KW - frontotemporal dementia
KW - huntingtin
KW - repeat expansions
KW - whole-genome sequencing
U2 - 10.1016/j.neuron.2020.11.005
DO - 10.1016/j.neuron.2020.11.005
M3 - Article
JO - Neuron
JF - Neuron
SN - 0896-6273
ER -