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Front. Neurol. | doi: 10.3389/fneur.2018.00981

Next generation molecular diagnosis of Hereditary Spastic Paraplegias: an Italian cross-sectional study

Angelica D'Amore1, Alessandra Tessa1, Carlo Casali2, Maria Teresa Dotti3,  Alessandro Filla4,  Gabriella Silvestri5,  Antonella Antenora4, Guja Astrea1, Melissa Barghigiani1, Roberta Battini1, Carla Battisti3, Irene Bruno6,  Cristina Cereda7,  Clemente Dato8, Giuseppe Di Iorio8,  VIncenzo Donadio9, Monica Felicori10,  Nicola Fini11,  Chiara Fiorillo12,  Salvatore Gallone13, Federica Gemignani14, Gian Luigi Gigli15,  Claudio Graziano9, Renzo Guerrini16, Fiorella Gurrieri5, Ariana Karaminejan17, Maria Lieto4,  CHARLES MARQUES LOURECO18, Alessandro Malandrini3, Paola Mandich12, Christian Marcotulli2, Francesco Mari19,  Luca Massacesi16, Marina Melone8, Andrea Mignarri3, Roberta Milone1, Olimpia Musumeci20, Elena Pegoraro21, Alessia Perna5,  Antonio Petrucci22, Antonella Pini23, Francesca Pochiero19, Maria Roser Pons24, Ivana Ricca1, Salvatore Rossi5, Marco Seri9, Franco Stanzial25, Francesca Tinelli1,  Antonio Toscano20, Mariarosaria Valente15,  Antonio Federico3, Anna Rubegni1 and  Filippo M. Santorelli1*
  • 1Fondazione Stella Maris (IRCCS), Italy
  • 2La Sapienza University of Rome, Italy
  • 3Università degli Studi di Siena, Italy
  • 4Azienda Ospedaliera Universitaria Federico II, Italy
  • 5Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore, Italy
  • 6IRCCS Materno Infantile Burlo Garofolo (IRCCS), Italy
  • 7Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IRCCS), Italy
  • 8Azienda Ospedaliera Universitaria, Seconda Università Degli Studi Di Napoli, Italy
  • 9Università degli Studi di Bologna, Italy
  • 10Azienda USL di Bologna, Italy
  • 11Azienda Unità Sanitaria Locale di Modena, Italy
  • 12Università di Genova, Italy
  • 13Università degli Studi di Torino, Italy
  • 14Università degli Studi di Pisa, Italy
  • 15Università degli Studi di Udine, Italy
  • 16Università degli Studi di Firenze, Italy
  • 17Iran University of Medical Sciences, Iran
  • 18University of Ribeirão Preto, Brazil
  • 19Azienda Ospedaliero Universitaria Meyer, Italy
  • 20Università degli Studi di Messina, Italy
  • 21Università degli Studi di Padova, Italy
  • 22Azienda Ospedaliera San Camillo-Forlanini, Italy
  • 23IRCCS Istituto delle Scienze Neurologiche di Bologna (ISNB), Italy
  • 24First Pediatric Clinic, University of Athens, Greece
  • 25Ospedale di Bolzano, Italy

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.

Keywords: hereditary spastic paraplegia, diagnostic yield, next generation sequencing, Neurogenetics, Variants of unknown significance

Received: 24 Sep 2018; Accepted: 30 Oct 2018.

Edited by:

Antonio Orlacchio, Fondazione Santa Lucia (IRCCS), Italy

Reviewed by:

Nicolas Dupre, Laval University, Canada
Pabulo Henrique Rampelotto, Universidade Federal do Rio Grande do Sul (UFRGS), Brazil  

Copyright: © 2018 D'Amore, Tessa, Casali, Dotti, Filla, Silvestri, Antenora, Astrea, Barghigiani, Battini, Battisti, Bruno, Cereda, Dato, Di Iorio, Donadio, Felicori, Fini, Fiorillo, Gallone, Gemignani, Gigli, Graziano, Guerrini, Gurrieri, Karaminejan, Lieto, MARQUES LOURECO, Malandrini, Mandich, Marcotulli, Mari, Massacesi, Melone, Mignarri, Milone, Musumeci, Pegoraro, Perna, Petrucci, Pini, Pochiero, Pons, Ricca, Rossi, Seri, Stanzial, Tinelli, Toscano, Valente, Federico, Rubegni and Santorelli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Filippo M. Santorelli, Fondazione Stella Maris (IRCCS), Tirrenia, Italy,