Clinical and molecular characterization of hereditary spastic paraplegias: A next-generation sequencing panel approach

Burguêz, Daniela; Polese-Bonatto, Márcia; Scudeiro, Laís Alves Jacinto; Björkhem, Ingemar; Schöls, Lüdger; Jardim, Laura Bannach; Matte, Úrsula; Saraiva-Pereira, Maria Luiza; Siebert, Marina; Saute, Jonas Alex Morales

doi:10.1016/j.jns.2017.10.010

Cited by 41 publications

(45 citation statements)

References 37 publications

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“…Six out of seven cases studied by Verrips et al did not have tendon xanthomas [35]. Patients with CYP27A1 variants affected with pure and complicated HSP but without xanthomas were also described by Burguez et al and Nicholls et al [15, 36]. These findings suggest that patients with CYP27A1 variants may present the broader clinical spectrum including HSP phenotype, nonetheless the lack of the typical symptoms of CTX, especially xantomas, should not exclude the investigation of CYP27A1 gene mutations.…”

Section: Discussionmentioning

confidence: 97%

Next-generation sequencing study reveals the broader variant spectrum of hereditary spastic paraplegia and related phenotypes

et al. 2019

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Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders. Numerous genes linked to HSPs, overlapping phenotypes between HSP subtypes and other neurodegenerative disorders and the HSPs’ dual mode of inheritance (both dominant and recessive) make the genetic diagnosis of HSPs complex and difficult. Out of the original HSP cohort comprising 306 index cases (familial and isolated) who had been tested according to “traditional workflow/guidelines” by Multiplex Ligation-dependent Probe Amplification (MLPA) and Sanger sequencing, 30 unrelated patients (all familial cases) with unsolved genetic diagnoses were tested using next-generation sequencing (NGS). One hundred thirty-two genes associated with spastic paraplegias, hereditary ataxias and related movement disorders were analysed using the Illumina TruSight™ One Sequencing Panel. The targeted NGS data showed pathogenic variants, likely pathogenic variants and those of uncertain significance (VUS) in the following genes: SPAST (spastin, SPG4), ATL1 (atlastin 1, SPG3), WASHC5 (SPG8), KIF5A (SPG10), KIF1A (SPG30), SPG11 (spatacsin), CYP27A1, SETX and ITPR1. Out of the nine genes mentioned above, three have not been directly associated with the HSP phenotype to date. Considering the phenotypic overlap and joint cellular pathways of the HSP, spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis (ALS) genes, our findings provide further evidence that common genetic testing may improve the diagnostics of movement disorders with a spectrum of ataxia-spasticity signs.Electronic supplementary materialThe online version of this article (10.1007/s10048-019-00565-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 97%

Next-generation sequencing study reveals the broader variant spectrum of hereditary spastic paraplegia and related phenotypes

et al. 2019

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“…Several different approaches to genetic testing for HSP may be employed. 16,43 Next generation sequencing-based gene panels for HSP are increasingly cost-efficient and now widely available. They are most commonly used to screen the exons of a large number of genes associated with HSP but have their limitations; they will generally not identify copy number variants (i.e.…”

Section: Genetic Testingmentioning

confidence: 99%

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Shribman

Reid

Crosby

et al. 2019

The Lancet Neurology

215

207

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Hereditary spastic paraplegia (HSP) describes a heterogeneous group of genetic neurodegenerative diseases characterised by progressive spasticity of the lower limbs. The pathogenic mechanism, associated clinical features and imaging abnormalities vary significantly according to the affected gene. Here, we describe the clinical and imaging characteristics of the more common forms of HSP. We discuss how to approach the diagnosis and management of a suspected case of HSP in the era of next generation sequencing, before discussing treatment and the potential of emerging therapeutic options for specific causes of HSP based on their underlying molecular mechanism.

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“…7,8 Owing to CMT's clinical and genetic heterogeneity, it is expensive and time-consuming to screen all the possible causative genes using conventional Sanger sequencing. However, highthroughput targeted next-generation sequencing (NGS) has been employed successfully in CMT 9,10 and other neurogenetic diseases such as amyotrophic lateral sclerosis (ALS), [11][12][13] hereditary spastic paraplegia (HSP), 14,15 and hereditary ataxia (HA). 16,17 Consequently, nearly 90 genes associated with CMT and other inherited peripheral neuropathies have been assembled in a gene panel, and parallel sequencing can be performed to interrogate these genes.…”

mentioning

confidence: 99%

Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot‐Marie‐Tooth disease

et al. 2019

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Charcot‐Marie‐Tooth (CMT) disease is a heterogeneous group of inherited sensorimotor neuropathies. To clarify the genetic spectrum and clinical profiles in Chinese CMT patients, we enrolled 150 unrelated CMT patients from southeast China. We performed multiplex ligation‐dependent probe amplification (MLPA) testing in all patients and next‐generation sequencing (NGS) among those patients without PMP22 rearrangements. We identified PMP22 duplications in 40 patients and deletions in 12 patients. In addition, we found 19 novel variants and 36 known mutations in 57 patients. Among these 55 variants, 45 pathogenic or likely pathogenic variants were identified in 48 cases, and 10 variants with uncertain significance were identified in 9 cases. Therefore, we obtained a genetic diagnosis in 63.8% (88/138) of CMT patients and 66.7% (100/150) of all included patients. PMP22, GJB1, and MFN2 are the most common causative genes in CMT1 (demyelinated form), intermediate CMT, and CMT2 (axonal form), respectively. In this study, we identified a higher proportion of intermediate CMT, a relatively high frequency of NDRG1 mutations and clinical features of later onset age in CMT1A patients. Our results broaden the genetic and clinical spectrum of CMT patients, which can help optimize the genetic and clinical diagnosis.

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Clinical and molecular characterization of hereditary spastic paraplegias: A next-generation sequencing panel approach

Cited by 41 publications

References 37 publications

Next-generation sequencing study reveals the broader variant spectrum of hereditary spastic paraplegia and related phenotypes

Next-generation sequencing study reveals the broader variant spectrum of hereditary spastic paraplegia and related phenotypes

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot‐Marie‐Tooth disease

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