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Whole exome sequencing in Serbian patients with hereditary spastic paraplegia

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Abstract  

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases with a high genetic and clinical heterogeneity. Numerous HSP patients remain genetically undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel variants and genes is needed. Our previous study analyzed 74 adult Serbian HSP patients from 65 families using panel of the 13 most common HSP genes in combination with a copy number variation analysis. Conclusive genetic findings were established in 23 patients from 19 families (29%). In the present study, nine patients from nine families previously negative on the HSP gene panel were selected for the whole exome sequencing (WES). Further, 44 newly diagnosed adult HSP patients from 44 families were sent to WES directly, since many studies showed WES may be used as the first step in HSP diagnosis. WES analysis of cohort 1 revealed a likely genetic cause in five (56%) of nine HSP families, including variants in the ETHE1, ZFYVE26, RNF170, CAPN1, and WASHC5 genes. In cohort 2, possible causative variants were found in seven (16%) of 44 patients (later updated to 27% when other diagnosis were excluded), comprising six different genes: SPAST, SPG11, WASCH5, KIF1A, KIF5A, and ABCD1. These results expand the genetic spectrum of HSP patients in Serbia and the region with implications for molecular genetic diagnosis and future causative therapies. Wide HSP panel can be the first step in diagnosis, alongside with the copy number variation (CNV) analysis, while WES should be performed after.

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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(2):525–551

    Article  PubMed  Google Scholar 

  2. Ruano L, Melo C, Silva MC, Coutinho P (2014) The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology 42(3):174–183

    Article  PubMed  Google Scholar 

  3. Schüle R, Wiethoff S, Martus P et al (2016) Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients. Ann Neurol 79(4):646–658

    Article  PubMed  Google Scholar 

  4. Murala S, Nagarajan E, Bollu PC (2021) Hereditary spastic paraplegia. Neurol Sci 42(3):883–894

    Article  PubMed  Google Scholar 

  5. Darios F, Coarelli G, Durr A (2022) Genetics in hereditary spastic paraplegias: Essential but not enough. Curr Opin Neurobiol 72:8–14

    Article  CAS  PubMed  Google Scholar 

  6. Meyyazhagan A, Kuchi Bhotla H, Pappuswamy M, Orlacchio A (2022) The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment. Int J Mol Sci 23(14):7665 (Published 2022 Jul 11)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Iqbal Z, Rydning SL, Wedding IM et al (2017) Correction: Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia. PLoS One 12(10):e0186571 (Published 2017 Oct 12)

    Article  PubMed  PubMed Central  Google Scholar 

  8. Méreaux JL, Banneau G, Papin M et al (2022) Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia. Brain 145(3):1029–1037

    Article  PubMed  Google Scholar 

  9. Perić S, Marković V, Candayan A et al (2022) Phenotypic and Genetic Heterogeneity of Adult Patients with Hereditary Spastic Paraplegia from Serbia. Cells 11(18):2804 (Published 2022 Sep 8)

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hedera P (2000) Hereditary Spastic Paraplegia Overview. In: Adam MP, Feldman J, Mirzaa GM et al (eds) GeneReviews®. University of Washington, Seattle, Seattle (WA)

    Google Scholar 

  11. Seo GH, Kim T, Choi IH et al (2020) Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE. Clin Genet 98(6):562–570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Karczewski KJ, Francioli LC, Tiao G et al (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 581(7809):434–443 ([published correction appears in Nature. 2021 Feb;590(7846):E53] [published correction appears in Nature. 2021 Sep;597(7874):E3-E4])

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Richards S, Aziz N, Bale S 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(5):405–424

    Article  PubMed  PubMed Central  Google Scholar 

  14. Köhler S, Gargano M, Matentzoglu N et al (2021) The Human Phenotype Ontology in 2021. Nucleic Acids Res 49(D1):D1207–D1217

    Article  PubMed  Google Scholar 

  15. Köhler S, Schulz MH, Krawitz P et al (2009) Clinical diagnostics in human genetics with semantic similarity searches in ontologies. Am J Hum Genet 85(4):457–464

    Article  PubMed  PubMed Central  Google Scholar 

  16. Greene D, BioResource NIHR, Richardson S, Turro E (2016) Phenotype Similarity Regression for Identifying the Genetic Determinants of Rare Diseases. Am J Hum Genet 98(3):490–499. https://doi.org/10.1016/j.ajhg.2016.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. D’Amore A, Tessa A, Casali C et al (2018) Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study. Front Neurol 9:981 (Published 2018 Dec 4)

    Article  PubMed  PubMed Central  Google Scholar 

  18. Cui F, Sun L, Qiao J et al (2020) Genetic mutation analysis of hereditary spastic paraplegia: A retrospective study. Medicine (Baltimore) 99(23):e20193

    Article  PubMed  Google Scholar 

  19. Valencia CA, Husami A, Holle J et al (2015) Clinical Impact and Cost-Effectiveness of Whole Exome Sequencing as a Diagnostic Tool: A Pediatric Center’s Experience. Front Pediatr 3:67 (Published 2015 Aug 3)

    Article  PubMed  PubMed Central  Google Scholar 

  20. Zhao M, Chen YJ, Wang MW et al (2019) Genetic and Clinical Profile of Chinese Patients with Autosomal Dominant Spastic Paraplegia. Mol Diagn Ther 23(6):781–789

    Article  CAS  PubMed  Google Scholar 

  21. Schiavoni S, Spagnoli C, Rizzi S et al (2020) Paediatric-onset hereditary spastic paraplegias: a retrospective cohort study. Dev Med Child Neurol 62(9):1068–1074

    Article  PubMed  Google Scholar 

  22. Mandelker D, Schmidt RJ, Ankala A et al (2016) Navigating highly homologous genes in a molecular diagnostic setting: a resource for clinical next-generation sequencing. Genet Med 18(12):1282–1289

    Article  CAS  PubMed  Google Scholar 

  23. Cummings BB, Marshall JL, Tukiainen T et al (2017) Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci Transl Med 9(386):eaal5209

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kremer LS, Bader DM, Mertes C et al (2017) Genetic diagnosis of Mendelian disorders via RNA sequencing. Nat Commun 8:15824

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  25. Frésard L, Smail C, Ferraro NM et al (2019) Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts. Nat Med 25(6):911–919

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lee H, Huang AY, Wang LK et al (2020) Diagnostic utility of transcriptome sequencing for rare Mendelian diseases. Genet Med 22(3):490–499

    Article  CAS  PubMed  Google Scholar 

  27. Logsdon GA, Vollger MR, Eichler EE (2020) Long-read human genome sequencing and its applications. Nat Rev Genet 21(10):597–614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang JO, Yoon JY, Sung DH et al (2021) The emerging genetic diversity of hereditary spastic paraplegia in Korean patients. Genomics 113(6):4136–4148

    Article  CAS  PubMed  Google Scholar 

  29. Fussiger H, Pereira BLDS, Padilha JPD et al (2023) Copy number variations in SPAST and ATL1 are rare among Brazilians. Clin Genet 103(5):580–584

    Article  CAS  PubMed  Google Scholar 

  30. Drousiotou A, DiMeo I, Mineri R, Georgiou T, Stylianidou G, Tiranti V (2011) Ethylmalonic encephalopathy: application of improved biochemical and molecular diagnostic approaches. Clin Genet 79(4):385–390

    Article  CAS  PubMed  Google Scholar 

  31. Kitzler TM, Gupta IR, Osterman B et al (2019) Acute and Chronic Management in an Atypical Case of Ethylmalonic Encephalopathy. JIMD Rep 45:57–63

    Article  PubMed  Google Scholar 

  32. Pigeon N, Campeau PM, Cyr D, Lemieux B, Clarke JT (2009) Clinical heterogeneity in ethylmalonic encephalopathy. J Child Neurol 24(8):991–996

    Article  PubMed  Google Scholar 

  33. Müller vom Hagen J, Karle KN, Schüle R, Krägeloh-Mann I, Schöls L (2014) Leukodystrophies underlying cryptic spastic paraparesis: frequency and phenotype in 76 patients. Eur J Neurol 21(7):983–988

    Article  PubMed  Google Scholar 

  34. Hershkovitz E, Narkis G, Shorer Z et al (2002) Cerebral X-linked adrenoleukodystrophy in a girl with Xq27-Ter deletion. Ann Neurol 52(2):234–237

    Article  PubMed  Google Scholar 

  35. Jung HH, Wimplinger I, Jung S, Landau K, Gal A, Heppner FL (2007) Phenotypes of female adrenoleukodystrophy. Neurology 68(12):960–961

    Article  CAS  PubMed  Google Scholar 

  36. Moser HW (1997) Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain 120(Pt 8):1485–1508

    Article  PubMed  Google Scholar 

  37. Engelen M, van Ballegoij WJC, Mallack EJ et al (2022) International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach. Neurology 99(21):940–951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Olgiati S, Doğu O, Tufekcioglu Z et al (2017) The p.Thr11Met mutation in c19orf12 is frequent among adult Turkish patients with MPAN. Parkinsonism Relat Disord. 39:64–70

    Article  PubMed  Google Scholar 

  39. Fraser S, Koenig M, Farach L, Mancias P, Mowrey K (2021) A De Novo case of autosomal dominant mitochondrial membrane protein-associated neurodegeneration. Mol Genet Genomic Med 9(7):e1706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rickman OJ, Salter CG, Gunning AC et al (2021) Dominant mitochondrial membrane protein-associated neurodegeneration (MPAN) variants cluster within a specific C19orf12 isoform. Parkinsonism Relat Disord 82:84–86

    Article  CAS  PubMed  Google Scholar 

  41. Hartig MB, Iuso A, Haack T et al (2011) Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Am J Hum Genet 89(4):543–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hogarth P, Gregory A, Kruer MC et al (2013) New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. Neurology 80(3):268–275

    Article  PubMed  PubMed Central  Google Scholar 

  43. Schulte EC, Claussen MC, Jochim A et al (2013) Mitochondrial membrane protein associated neurodegenration: a novel variant of neurodegeneration with brain iron accumulation. Mov Disord 28(2):224–227

    Article  CAS  PubMed  Google Scholar 

  44. Selikhova M, Fedotova E, Wiethoff S et al (2017) A 30-year history of MPAN case from Russia. Clin Neurol Neurosurg 159:111–113

    Article  CAS  PubMed  Google Scholar 

  45. Sparber P, Marakhonov A, Filatova A, Sharkova I, Skoblov M (2018) Novel case of neurodegeneration with brain iron accumulation 4 (NBIA4) caused by a pathogenic variant affecting splicing. Neurogenetics 19(4):257–260

    Article  PubMed  Google Scholar 

  46. Gregory A, Lotia M, Jeong SY et al (2019) Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN). Mol Genet Genomic Med 7(7):e00736

    Article  PubMed  PubMed Central  Google Scholar 

  47. Gregory A, Klopstock T, Kmiec T, Hogarth P, Hayflick SJ (2014) Mitochondrial Membrane Protein-Associated Neurodegeneration. In: Adam MP, Feldman J, Mirzaa GM et al (eds) GeneReviews®. University of Washington, Seattle, Seattle (WA)

    Google Scholar 

  48. Sparber P, Krylova T, Repina S et al (2021) Retrospective analysis of 17 patients with mitochondrial membrane protein-associated neurodegeneration diagnosed in Russia. Parkinsonism Relat Disord 84:98–104

    Article  CAS  PubMed  Google Scholar 

  49. Dursun U, Koroglu C, Kocasoy Orhan E, Ugur SA, Tolun A (2009) Autosomal recessive spastic paraplegia (SPG45) with mental retardation maps to 10q24.3–q25.1. Neurogenetics 10(4):325–331

    Article  PubMed  Google Scholar 

  50. Novarino G, Fenstermaker AG, Zaki MS et al (2014) Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343(6170):506–511

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  51. Elsaid MF, Ibrahim K, Chalhoub N, Elsotouhy A, El Mudehki N, Abdel Aleem A (2017) NT5C2 novel splicing variant expands the phenotypic spectrum of Spastic Paraplegia (SPG45): case report of a new member of thin corpus callosum SPG-Subgroup. BMC Med Genet 18(1):33 (Published 2017 Mar 21)

    Article  PubMed  PubMed Central  Google Scholar 

  52. Shenoy VS, Sampath R (2023) Syringomyelia. In: statpearls. Treasure island (FL): statpearls publishing. https://www.ncbi.nlm.nih.gov/books/NBK537110/. Accessed 10 Apr 2023

  53. Arnoldi A, Crimella C, Tenderini E et al (2012) Clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations. Clin Genet 81(2):150–157

    Article  CAS  PubMed  Google Scholar 

  54. Theuriet J, Pegat A, Leblanc P et al (2021) Phenoconversion from Spastic Paraplegia to ALS/FTD Associated with CYP7B1 Compound Heterozygous Mutations. Genes (Basel) 12(12):1876 (Published 2021 Nov 25)

    Article  CAS  PubMed  Google Scholar 

  55. Goizet C, Boukhris A, Durr A et al (2009) CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. Brain 132(Pt 6):1589–1600

    Article  PubMed  Google Scholar 

  56. Schlipf NA, Schüle R, Klimpe S et al (2011) Amplicon-based high-throughput pooled sequencing identifies mutations in CYP7B1 and SPG7 in sporadic spastic paraplegia patients. Clin Genet 80(2):148–160

    Article  CAS  PubMed  Google Scholar 

  57. Kumar KR, Blair NF, Vandebona H et al (2013) Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia. J Neurol 260(10):2516–2522

    Article  PubMed  Google Scholar 

  58. Roos P, Svenstrup K, Danielsen ER, Thomsen C, Nielsen JE (2014) CYP7B1: novel mutations and magnetic resonance spectroscopy abnormalities in hereditary spastic paraplegia type 5A. Acta Neurol Scand 129(5):330–334

    Article  CAS  PubMed  Google Scholar 

  59. Goizet C, Boukhris A, Maltete D et al (2009) SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum. Neurology 73(14):1111–1119

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Whole exome sequencing, analysis and variant interpretation were performed at the 3billion, Inc, Seoul, Republic of Korea as a part of 3billion's research funding program granted to DSP, VRS and SP.

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Authors and Affiliations

  1. Faculty of Medicine, University of Belgrade, Dr Subotica 6, Belgrade, Serbia

    Marija Brankovic, Vukan Ivanovic, Ivana Basta, Zorica Stevic, Vladana Markovic, Ivo Bozovic, Marina Svetel, Ana Marjanovic, Nikola Veselinovic, Sarlota Mesaros, Ivana Novakovic & Stojan Peric

  2. Neurology Clinic, University Clinical Center of Serbia, Belgrade, Serbia

    Ivana Basta, Zorica Stevic, Vladana Markovic, Marina Svetel, Nikola Veselinovic, Sarlota Mesaros, Milena Jankovic & Stojan Peric

  3. 3Billion, Inc., Seoul, South Korea

    Rin Khang, Eugene Lee, GoHun Seo & Hane Lee

  4. Clinical-Hospital Center Zvezdara, Belgrade, Serbia

    Branislav Ralic

  5. Institute for Oncology and Radiology of Serbia, Belgrade, Serbia

    Radoje Tubic

  6. Center for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia

    Dusanka Savic-Pavicevic

  7. Neurology Clinic, University Clinical Center of Vojvodina, Novi Sad, Serbia

    Zita Jovin

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  1. Marija Brankovic
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  2. Vukan Ivanovic
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Correspondence to Marija Brankovic.

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The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethical Board of the University Clinical Center of Serbia.

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Brankovic, M., Ivanovic, V., Basta, I. et al. Whole exome sequencing in Serbian patients with hereditary spastic paraplegia. Neurogenetics (2024). https://doi.org/10.1007/s10048-024-00755-x

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