Recent Advances in the Genetics of Frontotemporal Dementia

  • Daniel W. Sirkis
  • Ethan G. Geier
  • Luke W. Bonham
  • Celeste M. Karch
  • Jennifer S. YokoyamaEmail author
Neurogenetics and Psychiatric Genetics (C Cruchaga and C Karch, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Neurogenetics and Psychiatric Genetics


Purpose of Review

In this review, we highlight recent advances in the human genetics of frontotemporal dementia (FTD). In addition to providing a broad survey of genes implicated in FTD in the last several years, we also discuss variation in genes implicated in both hereditary leukodystrophies and risk for FTD (e.g., TREM2, TMEM106B, CSF1R, AARS2, NOTCH3).

Recent Findings

Over the past 5 years, genetic variation in approximately 50 genes has been confirmed or suggested to cause or influence risk for FTD and FTD-spectrum disorders. We first give background and discuss recent findings related to C9ORF72, GRN, and MAPT, the genes most commonly implicated in FTD. We then provide a broad overview of other FTD-associated genes and go on to discuss new findings in FTD genetics in East Asian populations, including pathogenic variation in CHCHD10, which may represent a frequent cause of disease in Chinese populations. Finally, we consider recent insights gleaned from genome-wide association and genetic pleiotropy studies.


Recent genetic discoveries highlight cellular pathways involving autophagy, the endolysosomal system, and neuroinflammation and reveal an intriguing overlap between genes that confer risk for leukodystrophy and FTD.


Frontotemporal lobar degeneration Leukodystrophy Genetics Autophagy Lysosomes Inflammation 



We thank Lin Yuan (UCSF) for her helpful reading of the manuscript.

Funding information

Primary research support in the Yokoyama lab is provided by the Rainwater Charitable Foundation, the Bluefield Project to Cure FTD, the Association for Frontotemporal Degeneration Susan Marcus Memorial Fund Clinical Research Grant, the Larry L. Hillblom Foundation (2016-A-005-SUP), the National Institute on Aging (K01 AG049152), and the John Douglas French Alzheimer’s Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with Ethical Standards

Conflict of Interest

Daniel W. Sirkis, Ethan G. Geier, Luke W. Bonham, Celeste M. Karch, and Jennifer S. Yokoyama each declare no potential conflicts of interest.

Human and Animal Rights

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Goldman JS, Farmer JM, Wood EM, Johnson JK, Boxer A, Neuhaus J, et al. Comparison of family histories in FTLD subtypes and related tauopathies. Neurology. Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 2005;65:1817–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Rohrer JD, Guerreiro R, Vandrovcova J, Uphill J, Reiman D, Beck J, et al. The heritability and genetics of frontotemporal lobar degeneration. Neurology. Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 2009;73:1451–6.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Seelaar H, Kamphorst W, Rosso SM, Azmani A, Masdjedi R, de Koning I, et al. Distinct genetic forms of frontotemporal dementia. Neurology. Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 2008;71:1220–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Cacace R, Sleegers K, Van Broeckhoven C. Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement. 2016;12:733–48.PubMedCrossRefGoogle Scholar
  5. 5.
    Mackenzie IRA, Neumann M. Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies. J Neurochem. Wiley/Blackwell (10.1111). 2016;138 Suppl 1:54–70.PubMedCrossRefGoogle Scholar
  6. 6.
    Van Mossevelde S, Engelborghs S, van der Zee J, Van Broeckhoven C. Genotype-phenotype links in frontotemporal lobar degeneration. Nat Rev Neurol Nature Publishing Group. 2018;14:363–78.PubMedCrossRefGoogle Scholar
  7. 7.
    Pottier C, Ravenscroft TA, Sanchez-Contreras M, Rademakers R. Genetics of FTLD: overview and what else we can expect from genetic studies. J Neurochem. Wiley/Blackwell (10.1111). 2016;138 Suppl 1:32–53.PubMedCrossRefGoogle Scholar
  8. 8.
    Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. Wiley-Blackwell. 1998;43:815–25.PubMedCrossRefGoogle Scholar
  9. 9.
    Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, et al. Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc Natl Acad Sci U S A. 1998;95:13103–7.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. Nat Publ Group. 1998;393:702–5.Google Scholar
  11. 11.
    Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A. 1998;95:7737–41.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Rea SL, Majcher V, Searle MS, Layfield R. SQSTM1 mutations—bridging Paget disease of bone and ALS/FTLD. Exp Cell Res. 2014;325:27–37.PubMedCrossRefGoogle Scholar
  13. 13.
    Deleon J, Miller BL. Frontotemporal dementia. Handb Clin Neurol. 2018;148:409–30.PubMedCrossRefGoogle Scholar
  14. 14.
    van der Zee J, Van Langenhove T, Kovacs GG, Dillen L, Deschamps W, Engelborghs S, et al. Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration. Acta Neuropathol. Springer Berlin Heidelberg. 2014;128:397–410.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Dejesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245–56.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Domoto-Reilly K, Davis MY, Keene CD, Bird TD. Unusually long duration and delayed penetrance in a family with FTD and mutation in MAPT (V337M). Tsuang DW, Bird TD, editors. Am J Med Genet B Neuropsychiatr Genet Wiley-Blackwell. 2017;174:70–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Sun L, Chen K, Li X, Xiao S. Rapidly progressive frontotemporal dementia associated with MAPT mutation G389R. J Alzheimers Dis IOS Press. 2017;55:777–85.PubMedCrossRefGoogle Scholar
  18. 18.
    Ygland E, van Westen D, Englund E, Rademakers R, Wszolek ZK, Nilsson K, et al. Slowly progressive dementia caused by MAPT R406W mutations: longitudinal report on a new kindred and systematic review. Alzheimers Res Ther BioMed Central. 2018;10:2.PubMedCrossRefGoogle Scholar
  19. 19.
    Carney RM, Kohli MA, Kunkle BW, Naj AC, Gilbert JR, Zuchner S, et al. Parkinsonism and distinct dementia patterns in a family with the MAPT R406W mutation. Alzheimers Dement. 2014;10:360–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Behnam M, Ghorbani F, Shin J-H, Kim D-S, Jang H, Nouri N, et al. Homozygous MAPT R406W mutation causing FTDP phenotype: a unique instance of a unique mutation. Gene. 2015;570:150–2.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Ng ASL, Sias AC, Pressman PS, Fong JC, Karydas AM, Zanto TP, et al. Young-onset frontotemporal dementia in a homozygous tau R406W mutation carrier. Ann Clin Transl Neurol. Wiley-Blackwell. 2015;2:1124–8.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006;442:920–4.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006;442:916–9.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Wauters E, Van Mossevelde S, van der Zee J, Cruts M, Van Broeckhoven C. Modifiers of GRN-associated frontotemporal lobar degeneration. Trends Mol Med. 2017;23:962–79.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Cruchaga C, Graff C, Chiang H-H, Wang J, Hinrichs AL, Spiegel N, et al. Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Arch Neurol American Medical Association. 2011;68:581–6.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Mukherjee O, Pastor P, Cairns NJ, Chakraverty S, Kauwe JSK, Shears S, et al. HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol Wiley-Blackwell. 2006;60:314–22.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M, et al. Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am J Hum Genet. 2012;90:1102–7.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    • van der Zee J, Mariën P, Crols R, Van Mossevelde S, Dillen L, Perrone F, et al. Mutated CTSF in adult-onset neuronal ceroid lipofuscinosis and FTD. Neurol Genet. 2016;2:e102 Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. Provides evidence that additional genes involved in neuronal ceroid lipofuscinosis may confer risk for FTD. Google Scholar
  29. 29.
    Bras J, Djaldetti R, Alves AM, Mead S, Darwent L, Lleo A, et al. Exome sequencing in a consanguineous family clinically diagnosed with early-onset Alzheimer’s disease identifies a homozygous CTSF mutation. Neurobiol Aging. 2016;46:236.e1–6.CrossRefGoogle Scholar
  30. 30.
    • Geier EG, Bourdenx M, Storm NJ, Cochran JN, Sirkis DW, Hwang J-H, et al. Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia. Acta Neuropathol. 2018;526, 1–18 Springer Berlin Heidelberg; Provides evidence that additional genes involved in neuronal ceroid lipofuscinosis may confer risk for FTD. Google Scholar
  31. 31.
    Watts GDJ, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat genet. Nat Publ Group. 2004;36:377–81.Google Scholar
  32. 32.
    Skibinski G, Parkinson NJ, Brown JM, Chakrabarti L, Lloyd SL, Hummerich H, et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet. 2005;37:806–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Benajiba L, Le Ber I, Camuzat A, Lacoste M, Thomas-Anterion C, Couratier P, et al. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol. Wiley-Blackwell. 2009;65:470–3.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Van Langenhove T, van der Zee J, Sleegers K, Engelborghs S, Vandenberghe R, Gijselinck I, et al. Genetic contribution of FUS to frontotemporal lobar degeneration. Neurology. Wolters Kluwer Health, Inc on behalf of the American Academy of Neurology. 2010;74:366–71.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Deng H-X, Chen W, Hong S-T, Boycott KM, Gorrie GH, Siddique N, et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011;477:211–5.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72:257–68.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Harms M, Benitez BA, Cairns N, Cooper B, Cooper P, Mayo K, et al. C9orf72 hexanucleotide repeat expansions in clinical Alzheimer disease. JAMA Neurol American Medical Association. 2013;70:736–41.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Gao F-B, Almeida S, Lopez-Gonzalez R. Dysregulated molecular pathways in amyotrophic lateral sclerosis-frontotemporal dementia spectrum disorder. EMBO J EMBO Press. 2017;36:2931–50.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Rubino E, Rainero I, Chiò A, Rogaeva E, Galimberti D, Fenoglio P, et al. SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology. Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 2012;79:1556–62.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Haack TB, Ignatius E, Calvo-Garrido J, Iuso A, Isohanni P, Maffezzini C, et al. Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset neurodegeneration with Ataxia, dystonia, and gaze palsy. Am J Hum Genet. 2016;99:735–43.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Ito H, Nakamura M, Komure O, Ayaki T, Wate R, Maruyama H, et al. Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation. Acta Neuropathol. Springer-Verlag. 2011;122:223–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Czell D, Andersen PM, Neuwirth C, Morita M, Weber M. Progressive aphasia as the presenting symptom in a patient with amyotrophic lateral sclerosis with a novel mutation in the OPTN gene. Amyotroph Lateral Scler Frontotemporal Degener. 2013;14:138–40.PubMedCrossRefGoogle Scholar
  43. 43.
    Pottier C, Bieniek KF, Finch N, van de Vorst M, Baker M, Perkersen R, et al. Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. Acta Neuropathol. Springer Berlin Heidelberg. 2015;130:77–92.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Müller K, et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci Nat Publ Group. 2015;18:631–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Gijselinck I, Van Mossevelde S, van der Zee J, Sieben A, Philtjens S, Heeman B, et al. Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort. Neurology. Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 2015;85:2116–25.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    • Xu D, Jin T, Zhu H, Chen H, Ofengeim D, Zou C, et al. TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging. Cell. 2018;174:1477–1491.e19 Provides evidence that a regulator of autophagy influences the inflammatory response.Google Scholar
  47. 47.
    • Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD, et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature. 2018;561:258–62 Nature Publishing Group. Provides evidence that regulators of mitophagy influence the inflammatory response.Google Scholar
  48. 48.
    Zimmermann M, Wilke C, Schulte C, Hoffmann J, Klopfer J, Reimold M, et al. Biallelic Parkin (PARK2) mutations can cause a bvFTD phenotype without clinically relevant parkinsonism. Parkinsonism Relat Disord. 2018;55:145–147.Google Scholar
  49. 49.
    Mackenzie IR, Nicholson AM, Sarkar M, Messing J, Purice MD, Pottier C, et al. TIA1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia promote phase separation and Alter stress granule dynamics. Neuron. 2017;95:808–9.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    van der Spek RA, van Rheenen W, Pulit SL, Kenna KP, Ticozzi N, Kooyman M, et al. Reconsidering the causality of TIA1 mutations in ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2018;19:1–3.PubMedCrossRefGoogle Scholar
  51. 51.
    Baradaran-Heravi Y, Dillen L, Nguyen HP, Van Mossevelde S, Baets J, De Jonghe P, et al. No supportive evidence for TIA1 gene mutations in a European cohort of ALS-FTD spectrum patients. Neurobiol Aging. 2018;69:293.e9–293.e11.CrossRefGoogle Scholar
  52. 52.
    Heck MV, Azizov M, Stehning T, Walter M, Kedersha N, Auburger G. Dysregulated expression of lipid storage and membrane dynamics factors in Tia1 knockout mouse nervous tissue. Neurogenetics. Springer Berlin Heidelberg. 2014;15:135–44.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Williams KL, Topp S, Yang S, Smith B, Fifita JA, Warraich ST, et al. CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nat Commun Nat Publ Group. 2016;7:11253.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron. 2016;89:37–53.PubMedCrossRefGoogle Scholar
  55. 55.
    Chen-Plotkin AS, Geser F, Plotkin JB, Clark CM, Kwong LK, Yuan W, et al. Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration. Hum Mol Genet. 2008;17:1349–62.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Greene CS, Krishnan A, Wong AK, Ricciotti E, Zelaya RA, Himmelstein DS, et al. Understanding multicellular function and disease with human tissue-specific networks. Nat Genet Nat Publ Group. 2015;47:569–76.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Paloneva J, Kestilä M, Wu J, Salminen A, Böhling T, Ruotsalainen V, et al. Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet. 2000;25:357–61.PubMedCrossRefGoogle Scholar
  58. 58.
    Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet. 2002;71:656–62.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Chouery E, Delague V, Bergougnoux A, Koussa S, Serre J-L, Mégarbané A. Mutations in TREM2 lead to pure early-onset dementia without bone cysts. Hum Mutat. 2008;29:E194–204.PubMedCrossRefGoogle Scholar
  60. 60.
    Guerreiro R, Bilgic B, Guven G, Bras J, Rohrer J, Lohmann E, et al. Novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family. Neurobiol Aging. 2013;34:2890.e1–5.CrossRefGoogle Scholar
  61. 61.
    Guerreiro RJ, Lohmann E, Brás JM, Gibbs JR, Rohrer JD, Gurunlian N, et al. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 2013;70:78–84.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Le Ber I, De Septenville A, Guerreiro R, Bras J, Camuzat A, Caroppo P, et al. Homozygous TREM2 mutation in a family with atypical frontotemporal dementia. Neurobiol Aging. 2014;35:2419.e23–5.CrossRefGoogle Scholar
  63. 63.
    Ng ASL, Tan YJ, Yi Z, Tandiono M, Chew E, Dominguez J, et al. Targeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement. Neurobiol Aging. 2018;68:160.e15–9.CrossRefGoogle Scholar
  64. 64.
    Peplonska B, Berdynski M, Mandecka M, Barczak A, Kuzma-Kozakiewicz M, Barcikowska M, et al. TREM2 variants in neurodegenerative disorders in the polish population. Homozygosity and compound heterozygosity in FTD patients. Amyotroph Lateral Scler Frontotemporal Degener. 2018;19:407–12.PubMedCrossRefGoogle Scholar
  65. 65.
    Redaelli V, Salsano E, Colleoni L, Corbetta P, Tringali G, Del Sole A, et al. Frontotemporal dementia and chorea associated with a compound heterozygous TREM2 mutation. J Alzheimers Dis. IOS Press. 2018;63:195–201.PubMedCrossRefGoogle Scholar
  66. 66.
    Su W-H, Shi Z-H, Liu S-L, Wang X-D, Liu S, Ji Y. The rs75932628 and rs2234253 polymorphisms of the TREM2 gene were associated with susceptibility to frontotemporal lobar degeneration in Caucasian populations. Ann Hum Genet. Wiley/Blackwell (10.1111). 2018;82:177–85.PubMedCrossRefGoogle Scholar
  67. 67.
    Carmona S, Zahs K, Wu E, Dakin K, Bras J, Guerreiro R. The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders. Lancet Neurol. 2018;17:721–30.PubMedCrossRefGoogle Scholar
  68. 68.
    Benitez BA, Cruchaga C, United States–Spain Parkinson’s Disease Research Group. TREM2 and neurodegenerative disease. N Engl J Med. 2013;369:1567–8.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet Nat Publ Group. 2011;44:200–5.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Gore E, Manley A, Dees D, Appleby BS, Lerner AJ. A young-onset frontal dementia with dramatic calcifications due to a novel CSF1R mutation. Neurocase. 2016;22:257–62.PubMedCrossRefGoogle Scholar
  71. 71.
    Kawakami I, Iseki E, Kasanuki K, Minegishi M, Sato K, Hino H, et al. A family with hereditary diffuse leukoencephalopathy with spheroids caused by a novel c.2442+2T>C mutation in the CSF1R gene. J Neurol Sci. 2016;367:349–55.PubMedCrossRefGoogle Scholar
  72. 72.
    Kim E-J, Kim Y-E, Jang J-H, Cho E-H, Na DL, Seo SW, et al. Analysis of frontotemporal dementia, amyotrophic lateral sclerosis, and other dementia-related genes in 107 Korean patients with frontotemporal dementia. Neurobiol. Aging. 2018;72:186.e1–186.e7.Google Scholar
  73. 73.
    Van Deerlin VM, Sleiman PMA, Martinez-Lage M, Chen-Plotkin A, Wang L-S, Graff-Radford NR, et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet Nat Publ Group. 2010;42:234–9.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Finch N, Carrasquillo MM, Baker M, Rutherford NJ, Coppola G, Dejesus-Hernandez M, et al. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology. Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 2011;76:467–74.PubMedCrossRefGoogle Scholar
  75. 75.
    van Blitterswijk M, Mullen B, Nicholson AM, Bieniek KF, Heckman MG, Baker MC, et al. TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathol. 2014;127(3):397–406.Google Scholar
  76. 76.
    • Simons C, Dyment D, Bent SJ, Crawford J, D'Hooghe M, Kohlschütter A, et al. A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy. Brain. 2017;140:3105–11 An important FTD risk modifier is implicated in leukodystrophy. PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    • Yan H, Kubisiak T, Ji H, Xiao J, Wang J, Burmeister M. The recurrent mutation in TMEM106B also causes hypomyelinating leukodystrophy in China and is a CpG hotspot. Brain. 2018;141:e36 An important FTD risk modifier is implicated in leukodystrophy. PubMedCrossRefGoogle Scholar
  78. 78.
    Zhou X, Sun L, Bastos de Oliveira F, Qi X, Brown WJ, Smolka MB, et al. Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin. J Cell Biol. Rockefeller University Press. 2015;210:991–1002.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Nicholson AM, Finch NA, Almeida M, Perkerson RB, van Blitterswijk M, Wojtas A, et al. Prosaposin is a regulator of progranulin levels and oligomerization. Nat Commun Nat Publ Group. 2016;7:11992.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Motta M, Tatti M, Furlan F, Celato A, Di Fruscio G, Polo G, et al. Clinical, biochemical and molecular characterization of prosaposin deficiency. Clin Genet. 8 ed. Wiley/Blackwell (10.1111). 2016;90:220–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Carrasquillo MM, Nicholson AM, Finch N, Gibbs JR, Baker M, Rutherford NJ, et al. Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma. Am J Hum Genet. 2010;87:890–7.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Hu F, Padukkavidana T, Vægter CB, Brady OA, Zheng Y, Mackenzie IR, et al. Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron. 2010;68:654–67.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Philtjens S, Van Mossevelde S, van der Zee J, Wauters E, Dillen L, Vandenbulcke M, et al. Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia. Neurobiol Aging. 2018;66:181.e3–181.e10.CrossRefGoogle Scholar
  84. 84.
    Dallabona C, Diodato D, Kevelam SH, Haack TB, Wong L-J, Salomons GS, et al. Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology. Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 2014;82:2063–71.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Lynch DS, Zhang WJ, Lakshmanan R, Kinsella JA, Uzun GA, Karbay M, et al. Analysis of mutations in AARS2 in a series of CSF1R-negative patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. JAMA Neurol. American Medical Association. 2016;73:1433–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Lee J-M, Yang H-J, Kwon J-H, Kim W-J, Kim S-Y, Lee E-M, et al. Two Korean siblings with recently described ovarioleukodystrophy related to AARS2 mutations. Eur J Neurol. Wiley/Blackwell (10.1111). 2017;24:e21–2.PubMedCrossRefGoogle Scholar
  87. 87.
    Hamatani M, Jingami N, Tsurusaki Y, Shimada S, Shimojima K, Asada-Utsugi M, et al. The first Japanese case of leukodystrophy with ovarian failure arising from novel compound heterozygous AARS2 mutations. J Hum Genet Nature Publishing Group. 2016;61:899–902.PubMedCrossRefGoogle Scholar
  88. 88.
    Taglia I, Di Donato I, Bianchi S, Cerase A, Monti L, Marconi R, et al. AARS2-related ovarioleukodystrophy: Clinical and neuroimaging features of three new cases. Acta Neurol Scand Wiley/Blackwell (10.1111). 2018;42:S27.Google Scholar
  89. 89.
    Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. Nat Publ Group. 1996;383:707–10.PubMedCrossRefGoogle Scholar
  90. 90.
    Alexander SK, Brown JM, Graham A, Nestor PJ. CADASIL presenting with a behavioural variant frontotemporal dementia phenotype. J Clin Neurosci. 2014;21:165–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Kim H-J, Kim HY, Paek WK, Park A, Young Park M, Ki CS, et al. Amyotrophic lateral sclerosis and frontotemporal lobar degeneration in association with CADASIL. Neurologist. 2012;18:92–5.PubMedCrossRefGoogle Scholar
  92. 92.
    Guerreiro RJ, Lohmann E, Kinsella E, Brás JM, Luu N, Gurunlian N, et al. Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer’s disease. Neurobiol Aging. 2012;33:1008.e17–23.CrossRefGoogle Scholar
  93. 93.
    Che X-Q, Zhao Q-H, Huang Y, Li X, Ren R-J, Chen S-D, et al. Genetic features of MAPT, GRN, C9orf72 and CHCHD10 gene mutations in Chinese patients with frontotemporal dementia. Curr Alzheimer Res. 2017;14:1102–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Shi Z, Liu S, Xiang L, Wang Y, Liu M, Liu S, et al. Frontotemporal dementia-related gene mutations in clinical dementia patients from a Chinese population. J Hum Genet. Nature Publishing Group. 2016;61:1003–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Tang M, Gu X, Wei J, Jiao B, Zhou L, Zhou Y, et al. Analyses MAPT, GRN, and C9orf72 mutations in Chinese patients with frontotemporal dementia. Neurobiol Aging. 2016;46:235.e11–5.CrossRefGoogle Scholar
  96. 96.
    Jiao B, Tang B, Liu X, Yan X, Zhou L, Yang Y, et al. Identification of C9orf72 repeat expansions in patients with amyotrophic lateral sclerosis and frontotemporal dementia in mainland China. Neurobiol Aging. 2014;35:936.e19–22.CrossRefGoogle Scholar
  97. 97.
    Liu F, Liu Q, Lu CX, Cui B, Guo XN, Wang RR, et al. Identification of a novel loss-of-function C9orf72 splice site mutation in a patient with amyotrophic lateral sclerosis. Neurobiol Aging. 2016;47:219.e1–5.CrossRefGoogle Scholar
  98. 98.
    Chen Y, Lin Z, Chen X, Cao B, Wei Q, Ou R, et al. Large C9orf72 repeat expansions are seen in Chinese patients with sporadic amyotrophic lateral sclerosis. Neurobiol Aging. 2016;38:217.e15–22.CrossRefGoogle Scholar
  99. 99.
    Mok K, Traynor BJ, Schymick J, Tienari PJ, Laaksovirta H, Peuralinna T, et al. Chromosome 9 ALS and FTD locus is probably derived from a single founder. Neurobiol Aging. 2012;33:209.e3–8.CrossRefGoogle Scholar
  100. 100.
    Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain. 2014;137:2329–45.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    • Jiao B, Xiao T, Hou L, Gu X, Zhou Y, Zhou L, et al. High prevalence of CHCHD10 mutation in patients with frontotemporal dementia from China. Brain. 2016;139:e21 Indicates that pathogenic CHCHD10 mutations may be a common cause of FTD in Chinese populations. PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Tsai P-C, Liu Y-C, Lin K-P, Liu Y-T, Liao Y-C, Hsiao C-T, et al. Mutational analysis of TBK1 in Taiwanese patients with amyotrophic lateral sclerosis. Neurobiol Aging. 2016;40:191.e11–6.CrossRefGoogle Scholar
  103. 103.
    Smith BN, Topp SD, Fallini C, Shibata H, Chen H-J, Troakes C, et al. Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis. Sci Transl Med. American Association for the Advancement of Science. 2017;9:eaad9157.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Zhang K, Liu Q, Liu K, Shen D, Tai H, Shu S, et al. ANXA11 mutations prevail in Chinese ALS patients with and without cognitive dementia. Neurol Genet. Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 2018;e237:4.Google Scholar
  105. 105.
    Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, et al. Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurol. 2014;13:686–99.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Mishra A, Ferrari R, Heutink P, Hardy J, Pijnenburg Y, Posthuma D, et al. Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia. Brain. 2017;140:1437–46.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Höglinger GU, Melhem NM, Dickson DW, Sleiman PMA, Wang L-S, Klei L, et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet. Nat Publ Group. 2011;43:699–705.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Chen JA, Chen Z, Won H, Huang AY, Lowe JK, Wojta K, et al. Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases. Mol Neurodegener. BioMed Central. 2018;13:41.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Sanchez-Contreras MY, Kouri N, Cook CN, Serie DJ, Heckman MG, Finch NA, et al. Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci. Mol Neurodegener. BioMed Central. 2018;13:37.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Kouri N, Ross OA, Dombroski B, Younkin CS, Serie DJ, Soto-Ortolaza A, et al. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nat Commun Nat Publ Group. 2015;6:7247.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Pottier C, Zhou X, Perkerson RB, Baker M, Jenkins GD, Serie DJ, et al. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Lancet Neurol. 2018;17:548–58.PubMedCrossRefGoogle Scholar
  112. 112.
    Zhang M, Ferrari R, Tartaglia MC, Keith J, Surace EI, Wolf U, et al. A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers. Brain. 2018;141:2895–907.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Ferrari R, Wang Y, Vandrovcova J, Guelfi S, Witeolar A, Karch CM, et al. Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer’s and Parkinson’s diseases. J Neurol Neurosurg Psychiatr. 2016;88(2):152–164.Google Scholar
  114. 114.
    Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature Nat Publ Group. 2017;549:523–7.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Yokoyama JS, Karch CM, Fan CC, Bonham LW, Kouri N, Ross OA, et al. Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia. Acta Neuropathol. Springer Berlin Heidelberg. 2017;133:825–37.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Bonham LW, Karch CM, Fan CC, Tan C, Geier EG, Wang Y, et al. CXCR4 involvement in neurodegenerative diseases. Transl Psychiatry. Nat Publ Group. 2018;8:73.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Karch CM, Wen N, Fan CC, Yokoyama JS, Kouri N, Ross OA, et al. Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum. JAMA Neurol. 2018;75(7):860–875.Google Scholar
  118. 118.
    Broce I, Karch CM, Wen N, Fan CC, Wang Y, Hong Tan C, et al. Immune-related genetic enrichment in frontotemporal dementia: an analysis of genome-wide association studies. PLoS Med Public Libr Sci. 2018;e1002487:15.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Daniel W. Sirkis
    • 1
  • Ethan G. Geier
    • 1
  • Luke W. Bonham
    • 1
  • Celeste M. Karch
    • 2
  • Jennifer S. Yokoyama
    • 1
    Email author
  1. 1.Memory and Aging Center, Department of NeurologyUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.Hope Center for Neurological Disorders, Department of PsychiatryWashington University School of MedicineSt. LouisUSA

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