Skip to main content

Advertisement

Log in

Targeted next-generation sequencing improves diagnosis of hereditary spastic paraplegia in Chinese patients

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurodegenerative diseases characterized by progressive weakness and spasticity of lower limbs. To clarify the genetic spectrum and improve the diagnosis of HSP patients, targeted next-generation sequencing (NGS) was applied to detect the culprit genes in 55 Chinese HSP pedigrees. The classification of novel variants was based on the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Patients remaining negative following targeted NGS were further screened for gross deletions/duplications by multiplex ligation-dependent probe amplification (MLPA). We made a genetic diagnosis in 61.8% (34/55) of families and identified 33 mutations, including 14 known mutations and 19 novel mutations. Of them, one was de novo mutation (NIPA1: c.316G>A). SPAST mutations (22/39, 56.4%) are the most common in Chinese AD-HSP followed by ATL1 (4/39, 10.3%). Moreover, we identified the third BSCL2 mutation (c.1309G>C) related to HSP by further functional studies and first reported the KIF1A mutation (c.304G>A) in China. Our findings broaden the genetic spectrum of HSP and improve the diagnosis of HSP patients. These results demonstrate the efficiency of targeted NGS to make a more rapid and precise diagnosis in patients with clinically suspected HSP.

Key messages

  • We made a genetic diagnosis in 61.8% of families and identified 33 mutations.

  • SPAST mutations are the most common in Chinese AD-HSP followed by ATL1.

  • Our findings broaden the genetic spectrum and improve the diagnosis of HSP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. de Souza PVS, de Rezende Pinto WBV, de Rezende Batistella GN, Bortholin T, Oliveira ASB (2017) Hereditary spastic paraplegia: clinical and genetic hallmarks. Cerebellum 16:525–551

    Article  PubMed  CAS  Google Scholar 

  2. Harding AE (1983) Classification of the hereditary ataxias and paraplegias. Lancet 1:1151–1155

    Article  PubMed  CAS  Google Scholar 

  3. Tesson C, Koht J, Stevanin G (2015) Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology. Hum Genet 134:511–538

    Article  PubMed  PubMed Central  Google Scholar 

  4. Klebe S, Stevanin G, Depienne C (2015) Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting. Rev Neurol 171:505–530

    Article  PubMed  CAS  Google Scholar 

  5. Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS, Martin E, Ouvrard-Hernandez AM, Tessa A, Bouslam N et al (2007) Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet 39:366–372

    Article  PubMed  CAS  Google Scholar 

  6. McDermott CJ, Burness CE, Kirby J, Cox LE, Rao DG, Hewamadduma C, Sharrack B, Hadjivassiliou M, Chinnery PF, Dalton A et al (2006) Clinical features of hereditary spastic paraplegia due to spastin mutation. Neurology 67:45–51

    Article  PubMed  CAS  Google Scholar 

  7. Pensato V, Castellotti B, Gellera C, Pareyson D, Ciano C, Nanetti L, Salsano E, Piscosquito G, Sarto E, Eoli M et al (2014) Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48. Brain 137:1907–1920

    Article  PubMed  Google Scholar 

  8. Lynch DS, Koutsis G, Tucci A, Panas M, Baklou M, Breza M, Karadima G, Houlden H (2016) Hereditary spastic paraplegia in Greece: characterisation of a previously unexplored population using next-generation sequencing. Eur J Hum Genet 24:857–863

    Article  PubMed  Google Scholar 

  9. Kim TH, Lee JH, Park YE, Shin JH, Nam TS, Kim HS, Jang HJ, Semenov A, Kim SJ, Kim DS (2014) Mutation analysis of SPAST, ATL1, and REEP1 in Korean patients with hereditary spastic paraplegia. J Clin Neurol 10:257–261

    Article  PubMed  PubMed Central  Google Scholar 

  10. Liu ZJ, Lin HX, Liu GL, Tai QQ, Ni W, Xiao BG, Wu ZY (2017) The investigation of genetic and clinical features in Chinese patients with juvenile amyotrophic lateral sclerosis. Clin Genet 92:267–273

    Article  PubMed  CAS  Google Scholar 

  11. Nishiyama A, Niihori T, Warita H, Izumi R, Akiyama T, Kato M, Suzuki N, Aoki Y, Aoki M (2017) Comprehensive targeted next-generation sequencing in Japanese familial amyotrophic lateral sclerosis. Neurobiol Aging 53:194 e191–194 e198

  12. Li LX, Liu GL, Liu ZJ, Lu C, Wu ZY (2017) Identification and functional characterization of two missense mutations in NDRG1 associated with Charcot-Marie-Tooth disease type 4D. Hum Mutat 38:1569–1578

    Article  PubMed  CAS  Google Scholar 

  13. Lu C, Zheng YC, Dong Y, Li HF (2016) Identification of novel senataxin mutations in Chinese patients with autosomal recessive cerebellar ataxias by targeted next-generation sequencing. BMC Neurol 16:179

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E et al (2015) 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 17:405–424

    Article  PubMed  PubMed Central  Google Scholar 

  15. Beetz C, Nygren AO, Schickel J, Auer-Grumbach M, Burk K, Heide G, Kassubek J, Klimpe S, Klopstock T, Kreuz F et al (2006) High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia. Neurology 67:1926–1930

    Article  PubMed  CAS  Google Scholar 

  16. Sulek A, Elert E, Rajkiewicz M, Zdzienicka E, Stepniak I, Krysa W, Zaremba J (2013) Screening for the hereditary spastic paraplaegias SPG4 and SPG3A with the multiplex ligation-dependent probe amplification technique in a large population of affected individuals. Neurol Sci 34:239–242

    Article  PubMed  Google Scholar 

  17. Goizet C, Depienne C, Benard G, Boukhris A, Mundwiller E, Sole G, Coupry I, Pilliod J, Martin-Negrier ML, Fedirko E et al (2011) REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction. Hum Mutat 32:1118–1127

    Article  PubMed  CAS  Google Scholar 

  18. Guillen-Navarro E, Sanchez-Iglesias S, Domingo-Jimenez R, Victoria B, Ruiz-Riquelme A, Rabano A, Loidi L, Beiras A, Gonzalez-Mendez B, Ramos A et al (2013) A new seipin-associated neurodegenerative syndrome. J Med Genet 50:401–409

    Article  PubMed  CAS  Google Scholar 

  19. Ito D, Suzuki N (2007) Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. Ann Neurol 61:237–250

    Article  PubMed  CAS  Google Scholar 

  20. Ito D, Fujisawa T, Iida H, Suzuki N (2008) Characterization of seipin/BSCL2, a protein associated with spastic paraplegia 17. Neurobiol Dis 31:266–277

    Article  PubMed  CAS  Google Scholar 

  21. Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Horl G, Malli R, Reed JA, Dierick I, Verpoorten N et al (2004) Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet 36:271–276

    Article  PubMed  CAS  Google Scholar 

  22. Stevanin G, Azzedine H, Denora P, Boukhris A, Tazir M, Lossos A, Rosa AL, Lerer I, Hamri A, Alegria P et al (2008) Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. Brain 131:772–784

    Article  PubMed  Google Scholar 

  23. Lan MY, Yeh TH, Chang YY, Kuo HC, Sun HS, Lai SC, Lu CS (2015) Clinical and genetic analysis of Taiwanese patients with hereditary spastic paraplegia type 5. Eur J Neurol 22:211–214

    Article  PubMed  Google Scholar 

  24. Citterio A, Arnoldi A, Panzeri E, Merlini L, D’Angelo MG, Musumeci O, Toscano A, Bondi A, Martinuzzi A, Bresolin N et al (2015) Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis. J Neurol 262:2684–2690

    Article  PubMed  CAS  Google Scholar 

  25. Liu YT, Laura M, Hersheson J, Horga A, Jaunmuktane Z, Brandner S, Pittman A, Hughes D, Polke JM, Sweeney MG et al (2014) Extended phenotypic spectrum of KIF5A mutations: from spastic paraplegia to axonal neuropathy. Neurology 83:612–619

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Luo Y, Chen C, Zhan Z, Wang Y, Du J, Hu Z, Liao X, Zhao G, Wang J, Yan X et al (2014) Mutation and clinical characteristics of autosomal-dominant hereditary spastic paraplegias in China. Neurodegener Dis 14:176–183

    Article  PubMed  Google Scholar 

  27. Proukakis C, Moore D, Labrum R, Wood NW, Houlden H (2011) Detection of novel mutations and review of published data suggests that hereditary spastic paraplegia caused by spastin (SPAST) mutations is found more often in males. J Neurol Sci 306:62–65

    Article  PubMed  CAS  Google Scholar 

  28. Orlacchio A, Kawarai T, Gaudiello F, Totaro A, Schillaci O, Stefani A, Floris R, St George-Hyslop PH, Sorbi S, Bernardi G (2005) Clinical and genetic study of a large SPG4 Italian family. Movement Disord 20:1055–1059

    Article  PubMed  Google Scholar 

  29. Hu R, Sun H, Zhang Q, Chen J, Wu N, Meng H, Cui G, Hu S, Li F, Lin J et al (2012) G-protein coupled estrogen receptor 1 mediated estrogenic neuroprotection against spinal cord injury. Crit Care Med 40:3230–3237

    Article  PubMed  CAS  Google Scholar 

  30. Namekawa M, Ribai P, Nelson I, Forlani S, Fellmann F, Goizet C, Depienne C, Stevanin G, Ruberg M, Durr A et al (2006) SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years. Neurology 66:112–114

    Article  PubMed  CAS  Google Scholar 

  31. Klebe S, Lacour A, Durr A, Stojkovic T, Depienne C, Forlani S, Poea-Guyon S, Vuillaume I, Sablonniere B, Vermersch P et al (2007) NIPA1 (SPG6) mutations are a rare cause of autosomal dominant spastic paraplegia in Europe. Neurogenetics 8:155–157

    Article  PubMed  Google Scholar 

  32. Hsiao CT, Tsai PC, Lin CC, Liu YT, Huang YH, Liao YC, Huang HW, Lin KP, Soong BW, Lee YC (2016) Clinical and molecular characterization of BSCL2 mutations in a Taiwanese cohort with hereditary neuropathy. PLoS One 11:e0147677

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Patel H, Hart PE, Warner TT, Houlston RS, Patton MA, Jeffery S, Crosby AH (2001) The Silver syndrome variant of hereditary spastic paraplegia maps to chromosome 11q12-q14, with evidence for genetic heterogeneity within this subtype. Am J Hum Genet 69:209–215

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Irobi J, Van den Bergh P, Merlini L, Verellen C, Van Maldergem L, Dierick I, Verpoorten N, Jordanova A, Windpassinger C, De Vriendt E et al (2004) The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V. Brain 127:2124–2130

    Article  PubMed  Google Scholar 

  35. Choi BO, Park MH, Chung KW, Woo HM, Koo H, Chung HK, Choi KG, Park KD, Lee HJ, Hyun YS (2013) Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2. Neurogenetics 14:35–42

    Article  PubMed  Google Scholar 

  36. Lee JR, Srour M, Kim D, Hamdan FF, Lim SH, Brunel-Guitton C, Decarie JC, Rossignol E, Mitchell GA, Schreiber A et al (2015) De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy. Hum Mutat 36:69–78

    Article  PubMed  CAS  Google Scholar 

  37. Ylikallio E, Kim D, Isohanni P, Auranen M, Kim E, Lonnqvist T, Tyynismaa H (2015) Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia. Eur J Hum Genet 23:1427–1430

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Denora PS, Schlesinger D, Casali C, Kok F, Tessa A, Boukhris A, Azzedine H, Dotti MT, Bruno C, Truchetto J et al (2009) Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion. Hum Mutat 30:E500–E519

    Article  PubMed  Google Scholar 

  39. Pippucci T, Panza E, Pompilii E, Donadio V, Borreca A, Babalini C, Patrono C, Zuntini R, Kawarai T, Bernardi G et al (2009) Autosomal recessive hereditary spastic paraplegia with thin corpus callosum: a novel mutation in the SPG11 gene and further evidence for genetic heterogeneity. Eur J Neurol 16:121–126

    Article  PubMed  CAS  Google Scholar 

  40. Stevanin G, Montagna G, Azzedine H, Valente EM, Durr A, Scarano V, Bouslam N, Cassandrini D, Denora PS, Criscuolo C et al (2006) Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity. Neurogenetics 7:149–156

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors sincerely thank the participants for their help and willingness to participate in this study.

Funding

This study was supported by a grant from the National Natural Science Foundation of China to Zhi-Ying Wu (81125009) and the research foundation for distinguished scholar of Zhejiang University to Zhi-Ying Wu (188020-193810101/089).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zhi-Ying Wu.

Ethics declarations

All the participants or their legal guardians provided written informed consents for the study. The study was approved by Ethics Committees of Second Affiliated Hospital affiliated to Zhejiang University School of Medicine and Huashan Hospital affiliated to Fudan University.

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary Fig 1

Chromatograms of 8 unlinked SNP markers in the family of case 55. In each frame, the upper chromatogram shows the father’s sequence, the middle one depicts the mother’s sequence, and the lower one indicates the patient’s sequence. (GIF 130 kb)

High Resolution (TIF 7693 kb)

Supplementary Table 1

(DOCX 39 kb)

Supplementary Table 2

(DOCX 30 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lu, C., Li, LX., Dong, HL. et al. Targeted next-generation sequencing improves diagnosis of hereditary spastic paraplegia in Chinese patients. J Mol Med 96, 701–712 (2018). https://doi.org/10.1007/s00109-018-1655-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-018-1655-4

Keywords

Navigation