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Cited by 90Hereditary Neurological DisordersGenomics and Rare DiseasesGenetic Neurodegenerative Diseases

Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study

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D'Amore, Angelica, Tessa, Alessandra, Casali, Carlo, Dotti, Maria Teresa, Filla, Alessandro, Silvestri, Gabriella, Antenora, Antonella, Astrea, Guja +45 more·2018·Frontiers in Neurology
DOI 10.3389/fneur.2018.00981PMC PMC6289125
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Abstract

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity — there are over 80 potential disease-associated genes — and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning four years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum and genetic landscape of HSP, at least in Italy.

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  • The AMN phenotype is an important differential diagnosis to hereditary spastic paraplegias (HSP).

    “The AMN phenotype is an important differential diagnosis to hereditary spastic paraplegias (HSP)6,7, which are clinically and genetically very heterogeneous (80+ genes are described—see8).”

    From Defining diagnostic cutoffs in neurological patients for serum very long chain fatty acids (VLCFA) in genetically confirmed X-Adrenoleukodystrophy (2020) · cites this paper as [7]

    The Results (Molecular Findings; page unavailable) report ABCD1 variants in two patients with an X-linked HSP diagnosis, providing some evidence of diagnostic overlap. The paper does not identify those patients as having an AMN phenotype or state that AMN is an important differential diagnosis for HSP. (LLM, conf=0.76)

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Authors
D'Amore, A., Tessa, A., Casali, C., Dotti, M. T., Filla, A., Silvestri, G., Antenora, A., Astrea, G., Barghigiani, M., Battini, R., Battisti, C., Bruno, I., Cereda, C., Dato, C., Di Iorio, G., Donadio, V., Felicori, M., Fini, N., Fiorillo, C., Gallone, S., Gemignani, F., Gigli, G. L., Graziano, C., Guerrini, R., Gurrieri, F., Kariminejad, A., Lieto, M., Marques LourenḈo, C., Malandrini, A., Mandich, P., Marcotulli, C., Mari, F., Massacesi, L., Melone, M. A. B., Mignarri, A., Milone, R., Musumeci, O., Pegoraro, E., Perna, A., Petrucci, A., Pini, A., Pochiero, F., Pons, M. R., Ricca, I., Rossi, S., Seri, M., Stanzial, F., Tinelli, F., Toscano, A., Valente, M., Federico, A., Rubegni, A., & Santorelli, F. M.
Affiliations
  • Sapienza University of Rome (IT)
  • University of Siena (IT)
  • University of Naples Federico II (IT)
  • Università Cattolica del Sacro Cuore (IT)
  • IRCCS Materno Infantile Burlo Garofolo (IT)
  • Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT)
  • University of Campania "Luigi Vanvitelli" (IT)
  • Istituto delle Scienze Neurologiche di Bologna (IT)
  • Azienda Ospedaliero-Universitaria di Modena (IT)
  • Istituto Giannina Gaslini (IT)
  • Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
  • University of Pisa (IT)
  • Ospedale Santa Maria della Misericordia di Udine (IT)
  • IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
  • Meyer Children's Hospital (IT)
  • Ospedale Policlinico San Martino (IT)
  • University of Florence (IT)
  • University of Messina (IT)
  • University of Padua (IT)
  • Azienda Ospedaliera San Camillo-Forlanini (IT)
  • National and Kapodistrian University of Athens (GR)
  • Ospedale di Bolzano (IT)
Corresponding author
Santorelli, Filippo Maria
ORCID
Venue
Frontiers in Neurology
Publisher
Frontiers Media SA
Published
2018-12-04
Volume
9
Pages
981-981
ISSN
1664-2295 (ISSN-L)
DOI
10.3389/fneur.2018.00981
PMC
PMC6289125
OpenAlex
W2902650947
Cited by
90
References
1
Citations by year
2026: 10 · 2025: 8 · 2024: 9 · 2023: 13 · 2022: 13 · 2021: 12 · 2020: 11 · 2019: 13 · 2018: 1
FWCI
4.21
Type
journal article
Language
en
Open access
Licence
Locations
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  • Use Siena air (University of Siena) (submittedVersion, cc-by)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
Funders
Ministero della Salute
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
hereditary spastic paraplegia, molecular diagnosis, next-generation sequencing, gene panel, diagnostic yield, variants of uncertain significance, genetic heterogeneity, variant pathogenicity prediction, Italian patients

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