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

被引：63

作者：

D'Amore, Angelica ^{[1
,2
]}

Tessa, Alessandra ^{[1
]}

Casali, Carlo ^{[3
]}

Dotti, Maria Teresa ^{[4
]}

Filla, Alessandro ^{[5
]}

Silvestri, Gabriella ^{[6
,7
]}

Antenora, Antonella ^{[5
]}

Astrea, Guja ^{[1
]}

Barghigiani, Melissa ^{[1
]}

Battini, Roberta ^{[1
]}

Battisti, Carla ^{[4
]}

Bruno, Irene ^{[8
]}

Cereda, Cristina ^{[9
]}

Dato, Clemente ^{[10
]}

Di Iorio, Giuseppe ^{[10
]}

Donadio, Vincenzo ^{[11
]}

Felicori, Monica ^{[12
]}

Fini, Nicola ^{[13
]}

Fiorillo, Chiara ^{[14
,15
]}

Gallone, Salvatore ^{[16
]}

Gemignani, Federica ^{[2
]}

Gigli, Gian Luigi ^{[17
]}

Graziano, Claudio ^{[18
]}

Guerrini, Renzo ^{[19
]}

Gurrieri, Fiorella ^{[20
]}

Kariminejad, Ariana ^{[21
]}

Lieto, Maria ^{[5
]}

LourenCo, Charles Marques ^{[22
]}

Malandrini, Alessandro ^{[4
]}

Mandich, Paola ^{[23
,24
]}

Marcotulli, Christian ^{[3
]}

Mari, Francesco ^{[19
]}

Massacesi, Luca ^{[25
]}

Melone, Maria A. B. ^{[10
]}

Mignarri, Andrea ^{[4
]}

Milone, Roberta ^{[26
]}

Musumeci, Olimpia ^{[27
]}

Pegoraro, Elena ^{[28
]}

Perna, Alessia ^{[6
,7
]}

Petrucci, Antonio ^{[29
]}

Pini, Antonella ^{[12
]}

Pochiero, Francesca ^{[30
]}

Pons, Maria Roser ^{[31
]}

Ricca, Ivana ^{[1
]}

Rossi, Salvatore ^{[6
,7
]}

Seri, Marco ^{[18
]}

Stanzial, Franco ^{[32
,33
]}

Tinelli, Francesca ^{[1
]}

Toscano, Antonio ^{[27
]}

Valente, Mariarosaria ^{[17
]}

机构：

[1] IRCCS Fdn Stella Maris, Mol Med, Pisa, Italy

[2] Univ Pisa, Dept Biol, Pisa, Italy

[3] Univ Rome Sapienza, Dept Med & Surg Sci & Biotechnol, Latina, Italy

[4] Univ Siena, Med Sch, Dept Med Surg & Neurosci, Siena, Italy

[5] Univ Naples Federico II, Dept Neurosci Reprod & Odontostomatol Sci, Naples, Italy

[6] IRCCS Fdn Policlin Univ A Gemelli, Rome, Italy

[7] Univ Cattolica Sacro Cuore, Inst Neurol, Rome, Italy

[8] IRCCS Burio Garofolo, Dept Pediat, Inst Maternal & Child Hlth, Trieste, Italy

[9] IRCCS Mondino Fdn, Genom & Postgenom Ctr, Pavia, Italy

[10] Univ Luigi Vanvitelli, Dept Med Surg Neurol Metab & Aging Sci, Div Neurol 2, Naples, Italy

[11] IRCCS Ist Sci Neurol Bologna, UOC Clin Neurol, Bologna, Italy

[12] Ist Sci Neurol Bologna, UOC Neuropsichiat Infantile, Bologna, Italy

[13] Azienda Osped Univ Modena, St Agostino Estense Hosp, Dept Neurosci, Modena, Italy

[14] Univ Genoa, Pediat Neurol & Neuromuscular Disorders, Genoa, Italy

[15] Ist Giannina Gaslini, Genoa, Italy

[16] AOU Citta Salute & Sci, Dept Neurosci & Mental Hlth, Neurol 1, Turin, Italy

[17] Azienda Osped Univ Santa Maria Misericordia, Neurol Clin, Udine, Italy

[18] Univ Bologna, St Orsola Malpighi Univ Hosp, Med Genet Unit, Dept Med & Surg Sci, Bologna, Italy

[19] Univ Firenze, Childrens Hosp A Meyer, Pediat Neurol Unit, Florence, Italy

[20] Univ Cattolica Sacro Cuore, Inst Genom Med, Rome, Italy

[21] Kariminejad Najmabadi Pathol & Genet Res Ctr, Clin Genet, Tehran, Iran

[22] Univ Sao Paulo, Clin Hosp Ribeirao Preto, Neurogenet Div, Sao Paulo, Brazil

[23] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, Sect Med Genet, Genoa, Italy

[24] IRCCS Osped Policlin San Martino, Med Genet Unit, Dept Diag Pathol & Treatments High Technol Comple, Genoa, Italy

[25] Univ Florence, Dept Neurosci Drugs & Child Hlth, Florence, Italy

[26] ULSS 7 Pedemontana, Child Neuropsychiat, Vicenza, Italy

[27] Univ Messina, Dept Clin & Expt Med, Messina, Italy

[28] Univ Padua, Dept Neurosci, Padua, Italy

[29] San Camillo Hosp, Neurol Dept, Rome, Italy

[30] Meyer Childrens Hosp, Neurosci Dept, Metab & Muscular Unit, Florence, Italy

[31] Univ Athens, Dept Pediat 1, Aghia Sophia Childrens Hosp, Athens, Greece

[32] Reg Hosp Botzano, Clin Genet Serv, Bolzano, Italy

[33] Reg Hosp Botzano, South Tyrol Coordinat Ctr Rare Dis, Dept Pediat, Bolzano, Italy

来源：

FRONTIERS IN NEUROLOGY | 2018年 / 9卷

关键词：

hereditary spastic paraplegia; next generation sequencing; neurogenetics; diagnostic yield; variants of unknown significance; MUTATIONS; DISEASE; GENE; IDENTIFICATION; ATAXIA; SPG4; PARAPARESIS; ASSOCIATION; POPULATION; PHENOTYPE;

D O I：

10.3389/fneur.2018.00981

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页数：13

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