The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes

L. Travaglini; C. Aiello; F. Stregapede; A. D’Amico; V. Alesi; A. Ciolfi; A. Bruselles; M. Catteruccia; S. Pizzi; G. Zanni; S. Loddo; S. Barresi; G. Vasco; M. Tartaglia; E. Bertini; F. Nicita

doi:10.1007/s10048-018-0545-9

The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes

L. Travaglini, C. Aiello, F. Stregapede, A. D’Amico, V. Alesi, A. Ciolfi, A. Bruselles, M. Catteruccia, S. Pizzi, G. Zanni, S. Loddo, S. Barresi, G. Vasco, M. Tartaglia, E. Bertini, F. Nicita

Istituto Superiore di Sanita'

Research output: Contribution to journal › Article › peer-review

Abstract

Hereditary spastic paraplegias (HSP) are clinical and genetic heterogeneous diseases with more than 80 disease genes identified thus far. Studies on large cohorts of HSP patients showed that, by means of current technologies, the percentage of genetically solved cases is close to 50%. Notably, the percentage of molecularly confirmed diagnoses decreases significantly in sporadic patients. To describe our diagnostic molecular genetic approach on patients with pediatric-onset pure and complex HSP, 47 subjects with HSP underwent molecular screening of 113 known and candidate disease genes by targeted capture and massively parallel sequencing. Negative cases were successively analyzed by multiplex ligation-dependent probe amplification (MLPA) analysis for the SPAST gene and high-resolution SNP array analysis for genome-wide CNV detection. Diagnosis was molecularly confirmed in 29 out of 47 (62%) patients, most of whom had clinical diagnosis of cHSP. Although SPG11 and SPG4 remain the most frequent cause of, respectively, complex and pure HSP, a large number of pathogenic variants were disclosed in POLR3A, FA2H, DDHD2, ATP2B4, ENTPD1, ERLIN2, CAPN1, ALS2, ADAR1, RNASEH2B, TUBB4A, ATL1, and KIF1A. In a subset of these disease genes, phenotypic expansion and novel genotype-phenotype correlations were recognized. Notably, SNP array analysis did not provide any significant contribution in increasing the diagnostic yield. Our findings document the high diagnostic yield of targeted sequencing for patients with pediatric-onset, complex, and pure HSP. MLPA for SPAST and SNP array should be limited to properly selected cases based on clinical suspicion. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

Original language	English
Pages (from-to)	111-121
Number of pages	11
Journal	Neurogenetics
Volume	19
Issue number	2
DOIs	https://doi.org/10.1007/s10048-018-0545-9
Publication status	Published - 2018

Keywords

Ataxia
CGH array
Hereditary spastic paraplegias
Next-generation sequencing
SNP array
galactosylceramidase
ADAR1 gene
adolescent
adult
ALS2 gene
Article
ataxia
ATL1 gene
ATP2B4 gene
CAPN1 gene
cell expansion
cerebellum atrophy
child
clinical article
clinical feature
cognitive defect
corpus callosum agenesis
DDHD2 gene
diagnostic value
ENTPD1 gene
ERLIN2 gene
FA2H gene
female
gene
gene frequency
gene mutation
gene sequence
genetic association
genetic variability
genotype phenotype correlation
hereditary motor sensory neuropathy
human
infant
KIF1A gene
male
microcephaly
molecular genetics
motor evoked potential
multiplex ligation dependent probe amplification
next generation sequencing
nuclear magnetic resonance imaging
ophthalmoplegia
point mutation
POLR3A gene
priority journal
pyramidal sign
real time polymerase chain reaction
RNASEH2B gene
school child
single nucleotide polymorphism
spastic paraplegia
SPG11 gene
SPG4 gene
TUBB4A gene
walking difficulty
young adult

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Travaglini, L., Aiello, C., Stregapede, F., D’Amico, A., Alesi, V., Ciolfi, A., Bruselles, A., Catteruccia, M., Pizzi, S., Zanni, G., Loddo, S., Barresi, S., Vasco, G., Tartaglia, M., Bertini, E., & Nicita, F. (2018). The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes. Neurogenetics, 19(2), 111-121. https://doi.org/10.1007/s10048-018-0545-9

The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes. / Travaglini, L.; Aiello, C.; Stregapede, F.; D’Amico, A.; Alesi, V.; Ciolfi, A.; Bruselles, A.; Catteruccia, M.; Pizzi, S.; Zanni, G.; Loddo, S.; Barresi, S.; Vasco, G.; Tartaglia, M.; Bertini, E.; Nicita, F.

In: Neurogenetics, Vol. 19, No. 2, 2018, p. 111-121.

Research output: Contribution to journal › Article › peer-review

Travaglini, L, Aiello, C, Stregapede, F, D’Amico, A, Alesi, V, Ciolfi, A, Bruselles, A, Catteruccia, M, Pizzi, S, Zanni, G, Loddo, S, Barresi, S, Vasco, G, Tartaglia, M, Bertini, E & Nicita, F 2018, 'The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes', Neurogenetics, vol. 19, no. 2, pp. 111-121. https://doi.org/10.1007/s10048-018-0545-9

Travaglini, L. ; Aiello, C. ; Stregapede, F. ; D’Amico, A. ; Alesi, V. ; Ciolfi, A. ; Bruselles, A. ; Catteruccia, M. ; Pizzi, S. ; Zanni, G. ; Loddo, S. ; Barresi, S. ; Vasco, G. ; Tartaglia, M. ; Bertini, E. ; Nicita, F. / The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes. In: Neurogenetics. 2018 ; Vol. 19, No. 2. pp. 111-121.

@article{be729f45c35f47f58ab391fa71143473,

title = "The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes",

abstract = "Hereditary spastic paraplegias (HSP) are clinical and genetic heterogeneous diseases with more than 80 disease genes identified thus far. Studies on large cohorts of HSP patients showed that, by means of current technologies, the percentage of genetically solved cases is close to 50%. Notably, the percentage of molecularly confirmed diagnoses decreases significantly in sporadic patients. To describe our diagnostic molecular genetic approach on patients with pediatric-onset pure and complex HSP, 47 subjects with HSP underwent molecular screening of 113 known and candidate disease genes by targeted capture and massively parallel sequencing. Negative cases were successively analyzed by multiplex ligation-dependent probe amplification (MLPA) analysis for the SPAST gene and high-resolution SNP array analysis for genome-wide CNV detection. Diagnosis was molecularly confirmed in 29 out of 47 (62%) patients, most of whom had clinical diagnosis of cHSP. Although SPG11 and SPG4 remain the most frequent cause of, respectively, complex and pure HSP, a large number of pathogenic variants were disclosed in POLR3A, FA2H, DDHD2, ATP2B4, ENTPD1, ERLIN2, CAPN1, ALS2, ADAR1, RNASEH2B, TUBB4A, ATL1, and KIF1A. In a subset of these disease genes, phenotypic expansion and novel genotype-phenotype correlations were recognized. Notably, SNP array analysis did not provide any significant contribution in increasing the diagnostic yield. Our findings document the high diagnostic yield of targeted sequencing for patients with pediatric-onset, complex, and pure HSP. MLPA for SPAST and SNP array should be limited to properly selected cases based on clinical suspicion. {\textcopyright} 2018, Springer-Verlag GmbH Germany, part of Springer Nature.",

keywords = "Ataxia, CGH array, Hereditary spastic paraplegias, Next-generation sequencing, SNP array, galactosylceramidase, ADAR1 gene, adolescent, adult, ALS2 gene, Article, ataxia, ATL1 gene, ATP2B4 gene, CAPN1 gene, cell expansion, cerebellum atrophy, child, clinical article, clinical feature, cognitive defect, corpus callosum agenesis, DDHD2 gene, diagnostic value, ENTPD1 gene, ERLIN2 gene, FA2H gene, female, gene, gene frequency, gene mutation, gene sequence, genetic association, genetic variability, genotype phenotype correlation, hereditary motor sensory neuropathy, human, infant, KIF1A gene, male, microcephaly, molecular genetics, motor evoked potential, multiplex ligation dependent probe amplification, next generation sequencing, nuclear magnetic resonance imaging, ophthalmoplegia, point mutation, POLR3A gene, priority journal, pyramidal sign, real time polymerase chain reaction, RNASEH2B gene, school child, single nucleotide polymorphism, spastic paraplegia, SPG11 gene, SPG4 gene, TUBB4A gene, walking difficulty, young adult",

author = "L. Travaglini and C. Aiello and F. Stregapede and A. D{\textquoteright}Amico and V. Alesi and A. Ciolfi and A. Bruselles and M. Catteruccia and S. Pizzi and G. Zanni and S. Loddo and S. Barresi and G. Vasco and M. Tartaglia and E. Bertini and F. Nicita",

note = "Cited By :2 Export Date: 11 April 2019 CODEN: NEROF Correspondence Address: Bertini, E.; Unit of Neuromuscular and Neurodegenerative Disorders, Ospedale Pediatrico Bambino Ges{\`u}, Polo di Ricerca S. Paolo, V.le S. Paolo, 15, Italy; email: enricosilvio.bertini@opbg.net Chemicals/CAS: galactosylceramidase, 9027-89-8 References: Lo Giudice, T., Lombardi, F., Santorelli, F.M., Kawarai, T., Orlacchio, A., Hereditaryspastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms (2014) Exp Neurol, 261, pp. 518-539. , PID: 24954637; Sch{\"u}le, R., Wiethoff, S., Martus, P., Karle, K.N., Otto, S., Klebe, S., Klimpe, S., Sch{\"o}ls, L., Hereditary spastic paraplegia: clinico-genetic lessons from 608 patients (2016) Ann Neurol, 79, pp. 646-658. , PID: 26856398; Kara, E., Tucci, A., Manzoni, C., Lynch, D.S., Elpidorou, M., Bettencourt, C., Chelban, V., Houlden, H., Genetic and phenotypic characterization of complex hereditary spastic paraplegia (2016) Brain, 139, pp. 1904-1918. , PID: 27217339; Povysil, G., Tzika, A., Vogt, J., Haunschmid, V., Messiaen, L., Zschocke, J., Klambauer, G., Wimmer, K., Panelcn.MOPS: copy-number detection in targeted NGS panel data for clinical diagnostics (2017) Hum Mutat, 38, pp. 889-897. , PID: 28449315; Travaglini, L., Bellacchio, E., Aiello, C., Pro, S., Bertini, E., Nicita, F., Expanding the clinical phenotype of CAPN1-associated mutations: a new case with congenital-onset pure spastic paraplegia (2017) J Neurol Sci, 378, pp. 210-212. , PID: 28566166; Crow, Y.J., Zaki, M.S., Abdel-Hamid, M.S., Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia (2014) Neuropediatrics, 45, pp. 386-391. , PID: 25243380; Minnerop, M., Kurzwelly, D., Wagner, H., Soehn, A.S., Reichbauer, J., Tao, F., Rattay, T.W., Sch{\"u}le, R., Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia (2017) Brain, 140, pp. 1561-1578. , PID: 28459997; Wakil, S.M., Bohlega, S., Hagos, S., Baz, B., al Dossari, H., Ramzan, K., al-Hassnan, Z.N., A novel splice site mutation in ERLIN2 causes hereditary spastic paraplegia in a Saudi family (2013) Eur J Med Genet, 56, pp. 43-45. , PID: 23085305; Hehr, U., Bauer, P., Winner, B., Schule, R., Olmez, A., Koehler, W., Uyanik, G., Winkler, J., Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia (2007) Ann Neurol, 62, pp. 656-665. , PID: 18067136; Stromillo, M.L., Malandrini, A., Dotti, M.T., Battaglini, M., Borgogni, F., Tessa, A., Storti, E., de Stefano, N., Structural and metabolic damage in brains of patients with SPG11-related spastic paraplegia as detected by quantitative MRI (2011) J Neurol, 258, pp. 2240-2247. , PID: 21625935; Guidubaldi, A., Piano, C., Santorelli, F.M., Silvestri, G., Petracca, M., Tessa, A., Bentivoglio, A.R., Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early-onset levodopa-responsive parkinsonism (2011) Mov Disord, 26, pp. 553-556. , PID: 21381113; Lee, M.J., Cheng, T.W., Hua, M.S., Mutations of the SPG11 gene in patients with autosomal recessive spastic paraparesis and thin corpus callosum (2008) J Neurol Neurosurg Psychiatry, 79, pp. 607-609. , PID: 18408091; Denora, P.S., Schlesinger, D., Casali, C., Kok, F., Tessa, A., Boukhris, A., Azzedine, H., Santorelli, F.M., Screening of ARHSP-TCC patients expands the spectrum of mutations and includes a large scale gene deletion (2009) Hum Mutat, 30, pp. E500-E519. , PID: 19105190; Smith, B.N., Bevan, S., Vance, C., Renwick, P., Wilkinson, P., Proukakis, C., Squitieri, F., Shaw, C.E., Four novel SPG3A/atlastin mutations identified in autosomal dominant hereditary spastic paraplegia kindreds with intra-familial variability in age of onset and complex phenotype (2009) Clin Genet, 75, pp. 485-489. , PID: 19459885; D{\"u}rr, A., Camuzat, A., Colin, E., Tallaksen, C., Hannequin, D., Coutinho, P., Fontaine, B., Brice, A., Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia (2004) Arch Neurol, 61, pp. 1867-1872. , PID: 15596607; Kancheva, D., Chamova, T., Guergueltcheva, V., Mitev, V., Azmanov, D.N., Kalaydjieva, L., Tournev, I., Jordanova, A., Mosaic dominant TUBB4A mutation in an inbred family with complicated hereditary spastic paraplegia (2015) Mov Disord, 30, pp. 854-858. , PID: 25772097; Livingston, J.H., Lin, J.P., Dale, R.C., Gill, D., Brogan, P., Munnich, A., Kurian, M.A., Crow, Y.J., A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1 (2014) J Med Genet, 51, pp. 76-82. , PID: 24262145; Fogli, A., Battini, R., Baldinotti, F., Angela, M., Elena, C.M., Paolo, S., Novel human pathological mutations. Gene symbol: SPG4. Disease: spastic paraplegia, autosomal dominant (2009) Hum Genet, 126, p. 341. , PID: 19694023; Wang, D., Pascual, J.M., Yang, H., Engelstad, K., Jhung, S., Sun, R.P., de Vivo, D.C., Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects (2005) Ann Neurol, 57, pp. 111-118. , PID: 15622525; Fonknechten, N., Mavel, D., Byrne, P., Davoine, C.S., Cruaud, C., B{\"o}nsch, D., Samson, D., Hazan, J., Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia (2000) Hum Mol Genet, 9, pp. 637-644. , PID: 10699187; Nicita, F., Bertini, E., Travaglini, L., Armando, M., Aiello, C., Congenital-onset spastic paraplegia in a patient with TUBB4A mutation and mild hypomyelination (2016) J Neurol Sci, 368, pp. 145-146. , PID: 27538619; Synofzik, M., Sch{\"u}le, R., Overcoming the divide between ataxias and spastic paraplegias: shared phenotypes, genes, and pathways (2017) Mov Disord, 32, pp. 332-345. , PID: 28195350; Kumar, K.R., Wali, G.M., Kamate, M., Wali, G., Minoche, A.E., Puttick, C., Pinese, M., Cowley, M.J., Defining the genetic basis of early onset hereditary spastic paraplegia using whole genome sequencing (2016) Neurogenetics, 17, pp. 265-270. , PID: 27679996; Lynch, D.S., Koutsis, G., Tucci, A., Panas, M., Baklou, M., Breza, M., Karadima, G., Houlden, H., Hereditary spastic paraplegia in Greece: characterisation of a previously unexplored population using next-generation sequencing (2016) Eur J Hum Genet, 24, pp. 857-863. , PID: 26374131; Li, M., Ho, P.W., Pang, S.Y., Tse, Z.H., Kung, M.H., Sham, P.C., Ho, S.L., PMCA4 (ATP2B4) mutation in familial spastic paraplegia (2014) PLoS One, 9. , PID: 25119969; Ho, P.W., Pang, S.Y., Li, M., Tse, Z.H., Kung, M.H., Sham, P.C., Ho, S.L., PMCA4 (ATP2B4) mutation in familial spastic paraplegia causes delay in intracellular calcium extrusion (2015) Brain Behav, 5. , PID: 25798335; Alazami, A.M., Adly, N., Al Dhalaan, H., Alkuraya, F.S., A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18) (2011) Neurogenetics, 12, pp. 333-336. , PID: 21796390; Al-Saif, A., Bohlega, S., Al-Mohanna, F., Loss of ERLIN2 function leads to juvenile primary lateral sclerosis (2012) Ann Neurol, 72, pp. 510-516. , PID: 23109145; Crow, Y.J., Leitch, A., Hayward, B.E., Garner, A., Parmar, R., Griffith, E., Ali, M., Jackson, A.P., Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection (2006) Nature Genet, 38, pp. 910-916. , PID: 16845400; La Piana, R., Cayami, F.K., Tran, L.T., Diffuse hypomyelination is not obligate for POLR3-related disorders (2016) Neurology, 86, pp. 1622-1626. , PID: 27029625; Beetz, C., Nygren, A.O., Schickel, J., Auer-Grumbach, M., B{\"u}rk, K., Heide, G., Kassubek, J., Deufel, T., High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia (2006) Neurology, 67, pp. 1926-1930. , PID: 17035675; Sulek, A., Elert, E., Rajkiewicz, M., Zdzienicka, E., Stepniak, I., Krysa, W., Zaremba, J., Screening for the hereditary spastic paraplaegias SPG4 and SPG3A with the multiplex ligation-dependent probe amplification technique in a large population of affected individuals (2013) Neurol Sci, 34, pp. 239-242. , PID: 22203332; M{\'e}sz{\'a}rosov{\'a}, A.U., Putzov{\'a}, M., {\v C}erm{\'a}kov{\'a}, M., V{\'a}vrov{\'a}, D., Dole{\v z}alov{\'a}, K., Smetanov{\'a}, I., Stejskal, D., Seeman, P., SPAST mutation spectrum and familial occurrence among Czech patients with pure hereditary spastic paraplegia (2016) J Hum Genet, 61, pp. 845-850. , PID: 27334366; Battini, R., Fogli, A., Borghetti, D., Michelucci, A., Perazza, S., Baldinotti, F., Conidi, M.E., Cioni, G., Clinical and genetic findings in a series of Italian children with pure hereditary spastic paraplegia (2011) Eur J Neurol, 18, pp. 150-157. , PID: 20550563",

year = "2018",

doi = "10.1007/s10048-018-0545-9",

language = "English",

volume = "19",

pages = "111--121",

journal = "Neurogenetics",

issn = "1364-6745",

publisher = "Springer Verlag",

number = "2",

}

TY - JOUR

T1 - The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes

AU - Travaglini, L.

AU - Aiello, C.

AU - Stregapede, F.

AU - D’Amico, A.

AU - Alesi, V.

AU - Ciolfi, A.

AU - Bruselles, A.

AU - Catteruccia, M.

AU - Pizzi, S.

AU - Zanni, G.

AU - Loddo, S.

AU - Barresi, S.

AU - Vasco, G.

AU - Tartaglia, M.

AU - Bertini, E.

AU - Nicita, F.

N1 - Cited By :2 Export Date: 11 April 2019 CODEN: NEROF Correspondence Address: Bertini, E.; Unit of Neuromuscular and Neurodegenerative Disorders, Ospedale Pediatrico Bambino Gesù, Polo di Ricerca S. Paolo, V.le S. Paolo, 15, Italy; email: enricosilvio.bertini@opbg.net Chemicals/CAS: galactosylceramidase, 9027-89-8 References: Lo Giudice, T., Lombardi, F., Santorelli, F.M., Kawarai, T., Orlacchio, A., Hereditaryspastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms (2014) Exp Neurol, 261, pp. 518-539. , PID: 24954637; Schüle, R., Wiethoff, S., Martus, P., Karle, K.N., Otto, S., Klebe, S., Klimpe, S., Schöls, L., Hereditary spastic paraplegia: clinico-genetic lessons from 608 patients (2016) Ann Neurol, 79, pp. 646-658. , PID: 26856398; Kara, E., Tucci, A., Manzoni, C., Lynch, D.S., Elpidorou, M., Bettencourt, C., Chelban, V., Houlden, H., Genetic and phenotypic characterization of complex hereditary spastic paraplegia (2016) Brain, 139, pp. 1904-1918. , PID: 27217339; Povysil, G., Tzika, A., Vogt, J., Haunschmid, V., Messiaen, L., Zschocke, J., Klambauer, G., Wimmer, K., Panelcn.MOPS: copy-number detection in targeted NGS panel data for clinical diagnostics (2017) Hum Mutat, 38, pp. 889-897. , PID: 28449315; Travaglini, L., Bellacchio, E., Aiello, C., Pro, S., Bertini, E., Nicita, F., Expanding the clinical phenotype of CAPN1-associated mutations: a new case with congenital-onset pure spastic paraplegia (2017) J Neurol Sci, 378, pp. 210-212. , PID: 28566166; Crow, Y.J., Zaki, M.S., Abdel-Hamid, M.S., Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia (2014) Neuropediatrics, 45, pp. 386-391. , PID: 25243380; Minnerop, M., Kurzwelly, D., Wagner, H., Soehn, A.S., Reichbauer, J., Tao, F., Rattay, T.W., Schüle, R., Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia (2017) Brain, 140, pp. 1561-1578. , PID: 28459997; Wakil, S.M., Bohlega, S., Hagos, S., Baz, B., al Dossari, H., Ramzan, K., al-Hassnan, Z.N., A novel splice site mutation in ERLIN2 causes hereditary spastic paraplegia in a Saudi family (2013) Eur J Med Genet, 56, pp. 43-45. , PID: 23085305; Hehr, U., Bauer, P., Winner, B., Schule, R., Olmez, A., Koehler, W., Uyanik, G., Winkler, J., Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia (2007) Ann Neurol, 62, pp. 656-665. , PID: 18067136; Stromillo, M.L., Malandrini, A., Dotti, M.T., Battaglini, M., Borgogni, F., Tessa, A., Storti, E., de Stefano, N., Structural and metabolic damage in brains of patients with SPG11-related spastic paraplegia as detected by quantitative MRI (2011) J Neurol, 258, pp. 2240-2247. , PID: 21625935; Guidubaldi, A., Piano, C., Santorelli, F.M., Silvestri, G., Petracca, M., Tessa, A., Bentivoglio, A.R., Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early-onset levodopa-responsive parkinsonism (2011) Mov Disord, 26, pp. 553-556. , PID: 21381113; Lee, M.J., Cheng, T.W., Hua, M.S., Mutations of the SPG11 gene in patients with autosomal recessive spastic paraparesis and thin corpus callosum (2008) J Neurol Neurosurg Psychiatry, 79, pp. 607-609. , PID: 18408091; Denora, P.S., Schlesinger, D., Casali, C., Kok, F., Tessa, A., Boukhris, A., Azzedine, H., Santorelli, F.M., Screening of ARHSP-TCC patients expands the spectrum of mutations and includes a large scale gene deletion (2009) Hum Mutat, 30, pp. E500-E519. , PID: 19105190; Smith, B.N., Bevan, S., Vance, C., Renwick, P., Wilkinson, P., Proukakis, C., Squitieri, F., Shaw, C.E., Four novel SPG3A/atlastin mutations identified in autosomal dominant hereditary spastic paraplegia kindreds with intra-familial variability in age of onset and complex phenotype (2009) Clin Genet, 75, pp. 485-489. , PID: 19459885; Dürr, A., Camuzat, A., Colin, E., Tallaksen, C., Hannequin, D., Coutinho, P., Fontaine, B., Brice, A., Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia (2004) Arch Neurol, 61, pp. 1867-1872. , PID: 15596607; Kancheva, D., Chamova, T., Guergueltcheva, V., Mitev, V., Azmanov, D.N., Kalaydjieva, L., Tournev, I., Jordanova, A., Mosaic dominant TUBB4A mutation in an inbred family with complicated hereditary spastic paraplegia (2015) Mov Disord, 30, pp. 854-858. , PID: 25772097; Livingston, J.H., Lin, J.P., Dale, R.C., Gill, D., Brogan, P., Munnich, A., Kurian, M.A., Crow, Y.J., A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1 (2014) J Med Genet, 51, pp. 76-82. , PID: 24262145; Fogli, A., Battini, R., Baldinotti, F., Angela, M., Elena, C.M., Paolo, S., Novel human pathological mutations. Gene symbol: SPG4. 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PY - 2018

Y1 - 2018

N2 - Hereditary spastic paraplegias (HSP) are clinical and genetic heterogeneous diseases with more than 80 disease genes identified thus far. Studies on large cohorts of HSP patients showed that, by means of current technologies, the percentage of genetically solved cases is close to 50%. Notably, the percentage of molecularly confirmed diagnoses decreases significantly in sporadic patients. To describe our diagnostic molecular genetic approach on patients with pediatric-onset pure and complex HSP, 47 subjects with HSP underwent molecular screening of 113 known and candidate disease genes by targeted capture and massively parallel sequencing. Negative cases were successively analyzed by multiplex ligation-dependent probe amplification (MLPA) analysis for the SPAST gene and high-resolution SNP array analysis for genome-wide CNV detection. Diagnosis was molecularly confirmed in 29 out of 47 (62%) patients, most of whom had clinical diagnosis of cHSP. Although SPG11 and SPG4 remain the most frequent cause of, respectively, complex and pure HSP, a large number of pathogenic variants were disclosed in POLR3A, FA2H, DDHD2, ATP2B4, ENTPD1, ERLIN2, CAPN1, ALS2, ADAR1, RNASEH2B, TUBB4A, ATL1, and KIF1A. In a subset of these disease genes, phenotypic expansion and novel genotype-phenotype correlations were recognized. Notably, SNP array analysis did not provide any significant contribution in increasing the diagnostic yield. Our findings document the high diagnostic yield of targeted sequencing for patients with pediatric-onset, complex, and pure HSP. MLPA for SPAST and SNP array should be limited to properly selected cases based on clinical suspicion. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

AB - Hereditary spastic paraplegias (HSP) are clinical and genetic heterogeneous diseases with more than 80 disease genes identified thus far. Studies on large cohorts of HSP patients showed that, by means of current technologies, the percentage of genetically solved cases is close to 50%. Notably, the percentage of molecularly confirmed diagnoses decreases significantly in sporadic patients. To describe our diagnostic molecular genetic approach on patients with pediatric-onset pure and complex HSP, 47 subjects with HSP underwent molecular screening of 113 known and candidate disease genes by targeted capture and massively parallel sequencing. Negative cases were successively analyzed by multiplex ligation-dependent probe amplification (MLPA) analysis for the SPAST gene and high-resolution SNP array analysis for genome-wide CNV detection. Diagnosis was molecularly confirmed in 29 out of 47 (62%) patients, most of whom had clinical diagnosis of cHSP. Although SPG11 and SPG4 remain the most frequent cause of, respectively, complex and pure HSP, a large number of pathogenic variants were disclosed in POLR3A, FA2H, DDHD2, ATP2B4, ENTPD1, ERLIN2, CAPN1, ALS2, ADAR1, RNASEH2B, TUBB4A, ATL1, and KIF1A. In a subset of these disease genes, phenotypic expansion and novel genotype-phenotype correlations were recognized. Notably, SNP array analysis did not provide any significant contribution in increasing the diagnostic yield. Our findings document the high diagnostic yield of targeted sequencing for patients with pediatric-onset, complex, and pure HSP. MLPA for SPAST and SNP array should be limited to properly selected cases based on clinical suspicion. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

KW - Ataxia

KW - CGH array

KW - Hereditary spastic paraplegias

KW - Next-generation sequencing

KW - SNP array

KW - galactosylceramidase

KW - ADAR1 gene

KW - adolescent

KW - adult

KW - ALS2 gene

KW - Article

KW - ataxia

KW - ATL1 gene

KW - ATP2B4 gene

KW - CAPN1 gene

KW - cell expansion

KW - cerebellum atrophy

KW - child

KW - clinical article

KW - clinical feature

KW - cognitive defect

KW - corpus callosum agenesis

KW - DDHD2 gene

KW - diagnostic value

KW - ENTPD1 gene

KW - ERLIN2 gene

KW - FA2H gene

KW - female

KW - gene

KW - gene frequency

KW - gene mutation

KW - gene sequence

KW - genetic association

KW - genetic variability

KW - genotype phenotype correlation

KW - hereditary motor sensory neuropathy

KW - human

KW - infant

KW - KIF1A gene

KW - male

KW - microcephaly

KW - molecular genetics

KW - motor evoked potential

KW - multiplex ligation dependent probe amplification

KW - next generation sequencing

KW - nuclear magnetic resonance imaging

KW - ophthalmoplegia

KW - point mutation

KW - POLR3A gene

KW - priority journal

KW - pyramidal sign

KW - real time polymerase chain reaction

KW - RNASEH2B gene

KW - school child

KW - single nucleotide polymorphism

KW - spastic paraplegia

KW - SPG11 gene

KW - SPG4 gene

KW - TUBB4A gene

KW - walking difficulty

KW - young adult

U2 - 10.1007/s10048-018-0545-9

DO - 10.1007/s10048-018-0545-9

M3 - Article

VL - 19

SP - 111

EP - 121

JO - Neurogenetics

JF - Neurogenetics

SN - 1364-6745

IS - 2

ER -