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neurogenetics

, Volume 19, Issue 2, pp 111–121 | Cite as

The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes

  • Lorena Travaglini
  • Chiara Aiello
  • Fabrizia Stregapede
  • Adele D’Amico
  • Viola Alesi
  • Andrea Ciolfi
  • Alessandro Bruselles
  • Michela Catteruccia
  • Simone Pizzi
  • Ginevra Zanni
  • Sara Loddo
  • Sabina Barresi
  • Gessica Vasco
  • Marco Tartaglia
  • Enrico Bertini
  • Francesco Nicita
Original Article
  • 359 Downloads

Abstract

Hereditary spastic paraplegias (HSP) are clinical and genetic heterogeneous diseases with more than 80 disease genes identified thus far. Studies on large cohorts of HSP patients showed that, by means of current technologies, the percentage of genetically solved cases is close to 50%. Notably, the percentage of molecularly confirmed diagnoses decreases significantly in sporadic patients. To describe our diagnostic molecular genetic approach on patients with pediatric-onset pure and complex HSP, 47 subjects with HSP underwent molecular screening of 113 known and candidate disease genes by targeted capture and massively parallel sequencing. Negative cases were successively analyzed by multiplex ligation-dependent probe amplification (MLPA) analysis for the SPAST gene and high-resolution SNP array analysis for genome-wide CNV detection. Diagnosis was molecularly confirmed in 29 out of 47 (62%) patients, most of whom had clinical diagnosis of cHSP. Although SPG11 and SPG4 remain the most frequent cause of, respectively, complex and pure HSP, a large number of pathogenic variants were disclosed in POLR3A, FA2H, DDHD2, ATP2B4, ENTPD1, ERLIN2, CAPN1, ALS2, ADAR1, RNASEH2B, TUBB4A, ATL1, and KIF1A. In a subset of these disease genes, phenotypic expansion and novel genotype-phenotype correlations were recognized. Notably, SNP array analysis did not provide any significant contribution in increasing the diagnostic yield. Our findings document the high diagnostic yield of targeted sequencing for patients with pediatric-onset, complex, and pure HSP. MLPA for SPAST and SNP array should be limited to properly selected cases based on clinical suspicion.

Keywords

Hereditary spastic paraplegias Ataxia Next-generation sequencing SNP array CGH array 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Integrity of research and reporting

The authors declare that all human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All the parents of individuals enrolled in the study gave their informed consent prior to their inclusion in the study. Details that might disclose the identity of the subjects under study were omitted.

Supplementary material

10048_2018_545_MOESM1_ESM.docx (326 kb)
ESM 1 (DOCX 326 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Lorena Travaglini
    • 1
    • 2
  • Chiara Aiello
    • 1
    • 2
  • Fabrizia Stregapede
    • 1
    • 3
  • Adele D’Amico
    • 1
    • 2
  • Viola Alesi
    • 4
  • Andrea Ciolfi
    • 2
  • Alessandro Bruselles
    • 5
  • Michela Catteruccia
    • 1
    • 2
  • Simone Pizzi
    • 2
  • Ginevra Zanni
    • 1
    • 2
  • Sara Loddo
    • 4
  • Sabina Barresi
    • 2
  • Gessica Vasco
    • 6
  • Marco Tartaglia
    • 2
  • Enrico Bertini
    • 1
    • 2
  • Francesco Nicita
    • 1
    • 2
  1. 1.Unit of Neuromuscular and Neurodegenerative DisordersOspedale Pediatrico Bambino GesùRomeItaly
  2. 2.Genetics and Rare Diseases Research DivisionOspedale Pediatrico Bambino GesùRomeItaly
  3. 3.Department of SciencesRoma Tre UniversityRomeItaly
  4. 4.Clinical Genetics, Genetics and Rare Diseases Research DivisionOspedale Pediatrico Bambino GesùRomeItaly
  5. 5.Department of Oncology and Molecular MedicineIstituto Superiore di SanitàRomeItaly
  6. 6.Movement Analysis and Robotics Laboratory (MARLab), Neurorehabilitation UnitOspedale Pediatrico Bambino GesùRomeItaly

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