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

Ewelina Elert-Dobkowska,Wioletta Krysa,Iwona Stepniak,Jacek Pilch,Dorota Antczak-Marach,Anna Sobanska,Karolina Ziora-Jakutowicz,Maria Rakowicz,Anna Sulek,Jacek Zaremba

doi:10.1007/s10048-019-00565-6

Abstract

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.

Highlights

Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Hereditary spastic paraplegias (HSPs) comprise a group of genetic disorders resulting from neurodegeneration of the corticospinal tracts
We identified 18 pathogenic and likely pathogenic variants in 16 spastic paraplegia probands, as well as six variants of uncertain significance (Table 2; Table 3)
In 11 out of 22 individuals, in whom SPAST, ATL1 and REEP1 gene single nucleotide variants (SNV) were previously excluded by Sanger sequencing, we identified three HSP subtypes with AD transmission: WASHC5 (SPG8), KIF5A (SPG10) and KIF1A (SPG30) and SPG11 (SPG11) as the only ARHSPs

Summary

Introduction

The HSPs’ main clinical feature is a progressive spasticity and weakness of the lower limbs. HSP is classified as a pure form when symptoms are limited to: progressive spasticity and weakness of the lower limbs, bladder dysfunction and mild somatosensory deficits. In case of any additional neurological symptoms, a complicated HSP form is recognised. Over 70 different SPG loci have been identified, and over 60 corresponding genes have been investigated [1,2,3]. All modes of HSP inheritance have already been described: autosomal dominant (ADHSP), autosomal recessive (ARHSP), X-linked (XLHSP) and less frequently, mitochondrial. Among 20 different ADHSP subtypes, SPG4 is the most common one, accounting for approximately 40% of the cases. The main ARHSPs identified to date are SPG5, SPG7, SPG11 and SPG15 [4]

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