Next generation gene testing

Helps identify non-SPG4 HSP


Associate Prof. and Director of Neurogenetics at Sydney’s Royal North Shore Hospital, Carolyn Sue, headed up this research study. Dr Sue has been involved with the stem cell research funded by this Foundation for several years.


Next Generation Sequencing (NGS) was used to successfully identify the HSP mutation in one quarter of HSPers in a study who were known not to have SPG4 HSP. Targeted NGS may be a useful method to screen for the multiple genes associated with HSP.


Molecular characterization is important for an accurate diagnosis in hereditary spastic paraplegia (HSP). Mutations in the gene SPAST (SPG4) are the most common cause of autosomal dominant forms. We performed targeted next generation sequencing (NGS) in a SPAST-negative HSP sample.

Forty-four consecutive HSP patients were recruited from an adult neurogenetics clinic in Sydney, Australia. SPAST mutations were confirmed in 17 subjects, and therefore 27 SPAST-negative patients were entered into this study. Patients were screened according to mode of inheritance using a PCR-based library and NGS (Roche Junior 454 sequencing platform). The screening panel included ten autosomal dominant (AD) and nine autosomal recessive (AR) HSP-causing genes.

A genetic cause for HSP was identified in 25.9 % (7/27) of patients, including 1/12 classified as AD and 6/15 as AR or sporadic inheritance. Several forms of HSP were identified, including one patient with SPG31, four with SPG7 (with one novel SPG7 mutation) and two with SPG5 (including two novel CYP7B1 frameshift mutations). Additional clinical features were noted, including optic atrophy and ataxia for patients with SPG5 and ataxia and a chronic progressive external ophthalmoplegia-like phenotype for SPG7.

This protocol enabled the identification of a genetic cause in approximately 25 % of patients in whom one of the most common genetic forms of HSP (SPG4) was excluded. Targeted NGS may be a useful method to screen for mutations in multiple genes associated with HSP. More studies are warranted to determine the optimal approach to achieve a genetic diagnosis in this condition.


SOURCE:  J Neurol. 2013 Jun 28. [Epub ahead of print]  PMID: 23812641 [PubMed – as supplied by publisher]

Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia.

Kumar KR, Blair NF, Vandebona H, Liang C, Ng K, Sharpe DM, Grünewald A, Gölnitz U, Saviouk V, Rolfs A, Klein C, Sue CM.

Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and The University of Sydney, Pacific Hwy, St Leonards, Sydney, NSW, 2065, Australia.

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