Frontiers in Neurology (Dec 2018)
Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study
- Angelica D'Amore,
- Angelica D'Amore,
- Alessandra Tessa,
- Carlo Casali,
- Maria Teresa Dotti,
- Alessandro Filla,
- Gabriella Silvestri,
- Gabriella Silvestri,
- Antonella Antenora,
- Guja Astrea,
- Melissa Barghigiani,
- Roberta Battini,
- Carla Battisti,
- Irene Bruno,
- Cristina Cereda,
- Clemente Dato,
- Giuseppe Di Iorio,
- Vincenzo Donadio,
- Monica Felicori,
- Nicola Fini,
- Chiara Fiorillo,
- Salvatore Gallone,
- Federica Gemignani,
- Gian Luigi Gigli,
- Claudio Graziano,
- Renzo Guerrini,
- Fiorella Gurrieri,
- Ariana Kariminejad,
- Maria Lieto,
- Charles Marques LourenḈo,
- Alessandro Malandrini,
- Paola Mandich,
- Paola Mandich,
- Christian Marcotulli,
- Francesco Mari,
- Luca Massacesi,
- Maria A. B. Melone,
- Andrea Mignarri,
- Roberta Milone,
- Olimpia Musumeci,
- Elena Pegoraro,
- Alessia Perna,
- Alessia Perna,
- Antonio Petrucci,
- Antonella Pini,
- Francesca Pochiero,
- Maria Roser Pons,
- Ivana Ricca,
- Salvatore Rossi,
- Salvatore Rossi,
- Marco Seri,
- Franco Stanzial,
- Francesca Tinelli,
- Antonio Toscano,
- Mariarosaria Valente,
- Antonio Federico,
- Anna Rubegni,
- Filippo Maria Santorelli
Affiliations
- Angelica D'Amore
- Molecular Medicine, Pisa, Italy
- Angelica D'Amore
- Department of Biology, University of Pisa, Pisa, Italy
- Alessandra Tessa
- Molecular Medicine, Pisa, Italy
- Carlo Casali
- Department of Medical and Surgical Sciences and Biotechnologies, University of Rome Sapienza, Latina, Italy
- Maria Teresa Dotti
- Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Siena, Italy
- Alessandro Filla
- Department of Neurosciences, Reproductive and Odontostomatologic Sciences, Federico II University, Naples, Italy
- Gabriella Silvestri
- IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
- Gabriella Silvestri
- Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy
- Antonella Antenora
- Department of Neurosciences, Reproductive and Odontostomatologic Sciences, Federico II University, Naples, Italy
- Guja Astrea
- Molecular Medicine, Pisa, Italy
- Melissa Barghigiani
- Molecular Medicine, Pisa, Italy
- Roberta Battini
- Molecular Medicine, Pisa, Italy
- Carla Battisti
- Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Siena, Italy
- Irene Bruno
- Department of Pediatrics, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy
- Cristina Cereda
- Genomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy
- Clemente Dato
- 0Second Division of Neurology, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Luigi Vanvitelli, Naples, Italy
- Giuseppe Di Iorio
- 0Second Division of Neurology, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Luigi Vanvitelli, Naples, Italy
- Vincenzo Donadio
- 1IRCCS Istituto delle Scienze Neurologiche di Bologna-UOC Clinica Neurologica, Bologna, Italy
- Monica Felicori
- 2Istituto delle Scienze Neurologiche di Bologna-UOC Neuropsichiatria Infantile, Bologna, Italy
- Nicola Fini
- 3Department of Neurosciences, Sant'Agostino-Estense Hospital, Azienda Ospedaliero Universitaria di Modena, Modena, Italy
- Chiara Fiorillo
- 4Pediatric Neurology and Neuromuscular Disorders, University of Genoa and Istituto Giannina Gaslini, Genova, Italy
- Salvatore Gallone
- 5Neurology I, Department of Neuroscience and Mental Health, AOU Città della Salute e della Scienza, Turin, Italy
- Federica Gemignani
- Department of Biology, University of Pisa, Pisa, Italy
- Gian Luigi Gigli
- 6Neurology Clinic, Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine, Italy
- Claudio Graziano
- 7Medical Genetics Unit, Sant'Orsola-Malpighi University Hospital, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Renzo Guerrini
- 8Pediatric Neurology Unit, Children's Hospital A. Meyer, University of Firenze, Florence, Italy
- Fiorella Gurrieri
- 9Institute of Genomic Medicine, Catholic University of the Sacred Heart, Rome, Italy
- Ariana Kariminejad
- 0Clinical Genetics, Kariminejad-Najmabadi Pathology & Genetics Research Center, Tehran, Iran
- Maria Lieto
- Department of Neurosciences, Reproductive and Odontostomatologic Sciences, Federico II University, Naples, Italy
- Charles Marques LourenḈo
- 1Neurogenetics Division, Clinics Hospital of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
- Alessandro Malandrini
- Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Siena, Italy
- Paola Mandich
- 2Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Medical Genetics, University of Genoa, Genoa, Italy
- Paola Mandich
- 3Medical Genetics Unit, Department of Diagnosis, Pathology and Treatments of High Technological Complexity, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Christian Marcotulli
- Department of Medical and Surgical Sciences and Biotechnologies, University of Rome Sapienza, Latina, Italy
- Francesco Mari
- 8Pediatric Neurology Unit, Children's Hospital A. Meyer, University of Firenze, Florence, Italy
- Luca Massacesi
- 4Department of Neurosciences Drugs and Child Health, University of Florence, Florence, Italy
- Maria A. B. Melone
- 0Second Division of Neurology, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Luigi Vanvitelli, Naples, Italy
- Andrea Mignarri
- Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Siena, Italy
- Roberta Milone
- 5Child Neuropsychiatry, ULSS 7 Pedemontana, Vicenza, Italy
- Olimpia Musumeci
- 6Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
- Elena Pegoraro
- 7Department of Neurosciences, University of Padua, Padua, Italy
- Alessia Perna
- IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
- Alessia Perna
- Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy
- Antonio Petrucci
- 8Neurology Department, San Camillo Hospital, Rome, Italy
- Antonella Pini
- 2Istituto delle Scienze Neurologiche di Bologna-UOC Neuropsichiatria Infantile, Bologna, Italy
- Francesca Pochiero
- 9Metabolic and Muscular Unit, Neuroscience Department, Meyer Children's Hospital, Florence, Italy
- Maria Roser Pons
- 0First Department of Pediatrics, Aghia Sophia Children's Hospital, University of Athens, Athens, Greece
- Ivana Ricca
- Molecular Medicine, Pisa, Italy
- Salvatore Rossi
- IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
- Salvatore Rossi
- Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy
- Marco Seri
- 7Medical Genetics Unit, Sant'Orsola-Malpighi University Hospital, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Franco Stanzial
- 1Clinical Genetics Service and South Tyrol Coordination Center for Rare Diseases, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy
- Francesca Tinelli
- Molecular Medicine, Pisa, Italy
- Antonio Toscano
- 6Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
- Mariarosaria Valente
- 6Neurology Clinic, Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine, Italy
- Antonio Federico
- Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Siena, Italy
- Anna Rubegni
- Molecular Medicine, Pisa, Italy
- Filippo Maria Santorelli
- Molecular Medicine, Pisa, Italy
- DOI
- https://doi.org/10.3389/fneur.2018.00981
- Journal volume & issue
-
Vol. 9
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 4 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
- next generation sequencing
- neurogenetics
- diagnostic yield
- variants of unknown significance
