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Front Neurol. 2018 Dec 4;9:981. doi: 10.3389/fneur.2018.00981. eCollection 2018.

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

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Molecular Medicine, Pisa, Italy.
Department of Biology, University of Pisa, Pisa, Italy.
Department of Medical and Surgical Sciences and Biotechnologies, University of Rome Sapienza, Latina, Italy.
Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Siena, Italy.
Department of Neurosciences, Reproductive and Odontostomatologic Sciences, Federico II University, Naples, Italy.
IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy.
Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy.
Department of Pediatrics, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy.
Genomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy.
Second Division of Neurology, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Luigi Vanvitelli, Naples, Italy.
IRCCS Istituto delle Scienze Neurologiche di Bologna-UOC Clinica Neurologica, Bologna, Italy.
Istituto delle Scienze Neurologiche di Bologna-UOC Neuropsichiatria Infantile, Bologna, Italy.
Department of Neurosciences, Sant'Agostino-Estense Hospital, Azienda Ospedaliero Universitaria di Modena, Modena, Italy.
Pediatric Neurology and Neuromuscular Disorders, University of Genoa and Istituto Giannina Gaslini, Genova, Italy.
Neurology I, Department of Neuroscience and Mental Health, AOU Città della Salute e della Scienza, Turin, Italy.
Neurology Clinic, Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine, Italy.
Medical Genetics Unit, Sant'Orsola-Malpighi University Hospital, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
Pediatric Neurology Unit, Children's Hospital A. Meyer, University of Firenze, Florence, Italy.
Institute of Genomic Medicine, Catholic University of the Sacred Heart, Rome, Italy.
Clinical Genetics, Kariminejad-Najmabadi Pathology & Genetics Research Center, Tehran, Iran.
Neurogenetics Division, Clinics Hospital of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Medical Genetics, University of Genoa, Genoa, Italy.
Medical Genetics Unit, Department of Diagnosis, Pathology and Treatments of High Technological Complexity, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Department of Neurosciences Drugs and Child Health, University of Florence, Florence, Italy.
Child Neuropsychiatry, ULSS 7 Pedemontana, Vicenza, Italy.
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
Department of Neurosciences, University of Padua, Padua, Italy.
Neurology Department, San Camillo Hospital, Rome, Italy.
Metabolic and Muscular Unit, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.
First Department of Pediatrics, Aghia Sophia Children's Hospital, University of Athens, Athens, Greece.
Clinical Genetics Service and South Tyrol Coordination Center for Rare Diseases, Department of Pediatrics, Regional Hospital of Bolzano, 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 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.


diagnostic yield; hereditary spastic paraplegia; neurogenetics; next generation sequencing; variants of unknown significance

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