Whole-exome sequencing of Finnish patients with vascular cognitive impairment

European Journal of Human Genetics (2020)Cite this article

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Abstract

Cerebral small vessel disease (CSVD) is the most important cause of vascular cognitive impairment (VCI). Most CSVD cases are sporadic but familial monogenic forms of the disorder have also been described. Despite the variants identified, many CSVD cases remain unexplained genetically. We used whole-exome sequencing in an attempt to identify novel gene variants underlying CSVD. A cohort of 35 Finnish patients with suspected CSVD was analyzed. Patients were screened negative for the most common variants affecting function in NOTCH3 in Finland (p.Arg133Cys and p.Arg182Cys). Whole-exome sequencing was performed to search for a genetic cause of CSVD. Our study resulted in the detection of possibly pathogenic variants or variants of unknown significance in genes known to associate with CSVD in six patients, accounting for 17% of cases. Those genes included NOTCH3, HTRA1, COL4A1, and COL4A2. We also identified variants with predicted pathogenic effect in genes associated with other neurological or stroke-related conditions in seven patients, accounting for 20% of cases. This study supports pathogenic roles of variants in COL4A1, COL4A2, and HTRA1 in CSVD and VCI. Our results also suggest that vascular pathogenic mechanisms are linked to neurodegenerative conditions and provide novel insights into the molecular basis of VCI.

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Fig. 1: Schematic presentation of the study describing the workflow of selection of patients and genetic examinations.

References

  1. 1.

    Dichgans M, Leys D. Vascular cognitive impairment. Circ Res. 2017;120:573–91.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    O’Brien JT, Thomas A. Vascular dementia. Lancet. 2015;386:1698–706.

    Article  PubMed  Google Scholar 

  3. 3.

    Pasi M, Cordonnier C. Clinical relevance of cerebral small vessel diseases. Stroke. 2020;51:47–53.

    Article  PubMed  Google Scholar 

  4. 4.

    Marini S, Anderson CD, Rosand J. Genetics of cerebral small vessel disease. Stroke. 2020;51:12–20.

    Article  PubMed  Google Scholar 

  5. 5.

    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. 1996;383:707–10.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Hara K, Shiga A, Fukutake T, Nozaki H, Miyashita A, Yokoseki A, et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med. 2009;360:1729–39.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Verdura E, Herve D, Scharrer E, Amador Mdel M, Guyant-Marechal L, Philippi A, et al. Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. Brain. 2015;138:2347–58.

    Article  PubMed  Google Scholar 

  8. 8.

    Labelle-Dumais C, Kuo DS, Gould DB. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. hmg. 2012;21:R97–R110.

    Google Scholar 

  9. 9.

    Siitonen M, Borjesson-Hanson A, Poyhonen M, Ora A, Pasanen P, Bras J, et al. Multi-infarct dementia of Swedish type is caused by a 3’UTR mutation of COL4A1. Brain. 2017;140:e29.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Verdura E, Herve D, Bergametti F, Jacquet C, Morvan T, Prieto-Morin C, et al. Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy. Ann Neurol. 2016;80:741–53.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Ilinca A, Samuelsson S, Piccinelli P, Soller M, Kristoffersson U, Lindgren AG. A stroke gene panel for whole-exome sequencing. Eur J Hum Genet. 2019;27:317–24.

    Article  PubMed  Google Scholar 

  12. 12.

    Patel ZH, Kottyan LC, Lazaro S, Williams MS, Ledbetter DH, Tromp H, et al. The struggle to find reliable results in exome sequencing data: filtering out Mendelian errors. Front Genet. 2014;5:16.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Opherk C, Herzog J, Dichgans M, Peters N, Luedtke R. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004;127:2533–9.

    Article  PubMed  Google Scholar 

  15. 15.

    Bianchi S, Di Palma C, Gallus GN, Taglia I, Poggiani A, Rosini F, et al. Two novel HTRA1 mutations in a European CARASIL patient. Neurology. 2014;82:898–900.

    Article  PubMed  Google Scholar 

  16. 16.

    Nozaki H, Kato T, Nihonmatsu M, Saito Y, Mizuta I, Noda T, et al. Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL. Neurology. 2016;86:1964–74.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Guerreiro RJ, Gustafson DR, Hardy J. The genetic architecture of Alzheimer’s disease: beyond APP, PSENs and APOE. Neurobiol Aging. 2012;33:437–56.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Ghani M, Lang AE, Zinman L, Nacmias B, Sorbi S, Bessi V, et al. Mutation analysis of patients with neurodegenerative disorders using NeuroX array. Neurobiol Aging. 2015;36:545.e9–545.14.

    CAS  Article  Google Scholar 

  19. 19.

    Schulte EC, Fukumori A, Mollenhauer B, Hor H, Arzberger T, Perneczky R, et al. Rare variants in beta-Amyloid precursor protein (APP) and Parkinson’s disease. Eur J Hum Genet. 2015;23:1328–33.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Geiger JT, Ding J, Crain B, Pletnikova O, Letson C, Dawson TM, et al. Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies. Neurobiol Dis. 2016;94:55–62.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Vidal R, Frangione B, Rostagno A, Mead S, Revesz T, Plant G, et al. A stop-codon mutation in the BRI gene associated with familial British dementia. Nature. 1999;399:776–81.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Vidal R, Révész T, Rostagno A, Kim E, Holton JL, Bek T, et al. A decamer duplication in the 3′ region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. Proc Natl Acad Sci USA. 2000;97:4920–5.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Audo I, Bujakowska K, Orhan E, El Shamieh S, Sennlaub F, Guillonneau X, et al. The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family. Hum Mol Genet. 2014;23:491–501.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Notelet L, Chapon F, Khoury S, Vahedi K, Chodkiewicz JP, Courtheoux P, et al. Familial cavernous malformations in a large French kindred: mapping of the gene to the CCM1 locus on chromosome 7q. J Neurol Neurosurg Psychiatry. 1997;63:40–45.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Craig HD, Gunel M, Cepeda O, Johnson EW, Ptacek L, Steinberg GK, et al. Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Hum Mol Genet. 1998;7:1851–8.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Liquori CL, Berg MJ, Siegel AM, Huang E, Zawistowski JS, Stoffer T, et al. Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet. 2003;73:1459–64.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Rajakulendran S, Kaski D, Hanna MG. Neuronal P/Q-type calcium channel dysfunction in inherited disorders of the CNS. Nat Rev Neurol. 2012;8:86–96.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR, et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet. 2010;42:234–9.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Simons C, Dyment D, Bent SJ, Crawford J, D’Hooghe M, Kohlschutter A, et al. A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy. Brain. 2017;140:3105–11.

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Kapferer-Seebacher I, Pepin M, Werner R, Aitman TJ, Nordgren A, Stoiber H, et al. Periodontal Ehlers-Danlos syndrome is caused by mutations in C1R and C1S, which encode subcomponents C1r and C1s of complement. Am J Hum Genet. 2016;99:1005–14.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Cikla U, Sadighi A, Bauer A, Baskaya MK. Fatal ruptured blood blister-like aneurysm of middle cerebral artery associated with Ehlers-Danlos syndrome type VIII (Periodontitis Type). J Neurol Surg Rep. 2014;75:210.

    Article  Google Scholar 

  32. 32.

    Hodgson-Zingman DM, Karst ML, Zingman LV, Heublein DM, Darbar D, Herron KJ, et al. Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. N Engl J Med. 2008;359:158–65.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Abraham RL, Yang T, Blair M, Roden DM, Darbar D. Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation. J Mol Cell Cardiol. 2010;48:181–90.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Ilinca A, Martinez-Majander N, Samuelsson S, Piccinelli P, Truve K, Cole J, et al. Whole-Exome Sequencing in 22 Young Ischemic Stroke Patients With Familial Clustering of Stroke. Stroke 2020;51:1056–63.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Cai Z, Wang C, He W, Tu H, Tang Z, Xiao M, et al. Cerebral small vessel disease and Alzheimer’s disease. Clin Interv Aging. 2015;10:1695–704.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Boyle PA, Yu L, Wilson RS, Leurgans SE, Schneider JA, Bennett DA. Person-specific contribution of neuropathologies to cognitive loss in old age. Ann Neurol. 2018;83:74–83.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Liu Y, Braidy N, Poljak A, Chan DKY, Sachdev P. Cerebral small vessel disease and the risk of Alzheimer’s disease: A systematic review. Ageing Res Rev. 2018;47:41–48.

    Article  PubMed  Google Scholar 

  38. 38.

    Thal DR, von Arnim CA, Griffin WS, Mrak RE, Walker L, Attems J, et al. Frontotemporal lobar degeneration FTLD-tau: preclinical lesions, vascular, and Alzheimer-related co-pathologies. J Neural Transm (Vienna). 2015;122:1007–18.

    CAS  Article  Google Scholar 

  39. 39.

    Dichgans M, Zietemann V. Prevention of vascular cognitive impairment. Stroke. 2012;43:3137–46.

    Article  PubMed  Google Scholar 

  40. 40.

    Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47:D886–D894.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank Prof. (emeritus) Hannu Kalimo and the CADASIL group for discussions when planning this study.

Funding

This study was supported by Academy of Finland (294817), Helsinki University Hospital Competetive Fund, and The Finnish Medical Society Duodecim.

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Author notes

  1. These authors contributed equally: Rita Guerreiro, Liisa Myllykangas

Affiliations

  1. Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland

    Saana Mönkäre, Liina Kuuluvainen & Minna Pöyhönen

  2. Turku University Hospital, Laboratory Division, Genomics, Department of Medical Genetics, Turku, Finland

    Saana Mönkäre & Johanna Schleutker

  3. Department of Clinical Genetics, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland

    Liina Kuuluvainen & Minna Pöyhönen

  4. Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA

    Celia Kun-Rodrigues, Susana Carmona, Jose Bras & Rita Guerreiro

  5. Institute of Biomedicine, University of Turku, Turku, Finland

    Johanna Schleutker

  6. Division of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI, USA

    Jose Bras & Rita Guerreiro

  7. Department of Pathology, University of Helsinki, Helsinki, Finland

    Liisa Myllykangas

  8. HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland

    Liisa Myllykangas

Authors
  1. Saana Mönkäre
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  2. Liina Kuuluvainen
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  6. Jose Bras
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  7. Minna Pöyhönen
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  8. Rita Guerreiro
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  9. Liisa Myllykangas
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Correspondence to Liisa Myllykangas.

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Mönkäre, S., Kuuluvainen, L., Kun-Rodrigues, C. et al. Whole-exome sequencing of Finnish patients with vascular cognitive impairment. Eur J Hum Genet (2020). https://doi.org/10.1038/s41431-020-00775-9

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