High-throughput, massively parallel genetic testing, known as next-generation sequencing (NGS), has greatly improved the molecular diagnosis of genetic diseases, particularly neurological disorders.1 For disorders known to be caused by variations in multiple genes, NGS provides an opportunity for clinicians to more quickly and efficiently investigate the genetic cause than is possible using traditional methods like Sanger sequencing. Invitae’s recent expansion of its NGS-based panels provides opportunities to learn more about the genetic basis of neurological disorders, including hereditary spastic paraplegia (HSP).
HSP is a group of neurological disorders that exhibit weakness and spasticity of the legs and hip muscles as its primary symptom. This can sometimes also be accompanied by other neurological and movement-related issues. HSP is particularly difficult to diagnose because of its variety in presentation, age of onset, and inheritance pattern. The disorder shows an enormous degree of genetic diversity, with more than 70 HSP-related genes identified to date. While several of these genes are known to be common causes of autosomal dominant and recessive forms of HSP, the yield from testing each individual additional gene beyond these few has traditionally been low—in addition to being time-consuming and cost prohibitive.2,3 In population-based studies, the number of families without a genetic diagnosis after systematic testing ranged from 45% to 67% for autosomal dominant HSP and from 71% to 82% for autosomal recessive HSP.4
Invitae’s testing results illustrate the impact of multi-gene NGS panels on the genetic understanding of HSP. In a retrospective review, we found that Invitae’s HSP panel identified likely pathogenic or pathogenic variants in 35 patients out of 163 studied (22%). In total, 35 different pathogenic variants were identified in the following genes, covering all inheritance patterns: ATL1, BSCL2, CYP7B1, KIAA0196, KIF5A, PLP1, REEP1, SPAST, SPG11, and SPG7. The variants broadly included four copy number variations (ranging from single exon deletions to deletions of entire coding regions), 13 missense variants, 13 nonsense variants, 4 indels, and 1 splice site variant.
As demonstrated by our review, all types of mutations (including both sequence variants and copy number changes) have been identified in HSP genes. To efficiently provide a molecular diagnosis, genes need to be comprehensively assessed for the spectrum of mutations that have can occur. Historically, this required many types of tests: Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), exon-targeted array-CGH, and so on. This inevitably added to both the cost and time of this analysis, and historically very few studies on the genetic characterization of HSP employed this comprehensive approach. An advantage of Invitae’s HSP panel is that it provides comprehensive sequencing and copy number variation analysis in a single test.
Invitae’s HSP panel provides opportunities to learn more about the many types and causes of HSP. The ultimate goal is to help families by ending a diagnostic odyssey, directing medical treatment and predicting outcomes, preventing unnecessary additional investigations, and providing accurate risk predictions for family members. In the future, as HSP therapies emerge, genetic testing may also become a prerequisite for the selection of personalized treatment.2
1Warman Chardon J, et al., Curr Neurol Neurosci Rep. 2015; 15(9):64
2Hensiek, A, et al., J Neurol. 2015; 262(7):1601-12.
3Tesson, C, et al., Hum Genet. 2015; 134(6):511-38.
4Ruano, L, et al., Neuroepidemiology. 2014; 42(3):174-83.