Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia

PLoS One. 2017 Mar 31;12(3):e0174667. doi: 10.1371/journal.pone.0174667. eCollection 2017.


Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease. Pathogenic and likely-pathogenic variants were identified in 20 probands (19%) and variants of uncertain significance in ten probands (10%). Together these accounted for 30 probands (29%) and involved 18 different genes. Among several interesting findings, dominantly inherited KIF1A variants, p.(Val8Met) and p.(Ile27Thr) segregated in two independent families, both presenting with a pure spastic paraplegia phenotype. Two homozygous missense variants, p.(Gly4230Ser) and p.(Leu4221Val) were found in SACS in one consanguineous family, presenting with spastic ataxia and isolated cerebellar atrophy. The average disease duration in probands with pathogenic and likely-pathogenic variants was 31 years, ranging from 4 to 51 years. In conclusion, this study confirmed and expanded the clinical phenotypes associated with known disease genes. The results demonstrate that gene panel sequencing and similar sequencing approaches can serve as efficient diagnostic tools for different heterogeneous disorders. Early use of such strategies may help to reduce both costs and time of the diagnostic process.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • Child, Preschool
  • Female
  • Heat-Shock Proteins / genetics
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Infant
  • Infant, Newborn
  • Kinesins / genetics
  • Magnetic Resonance Spectroscopy
  • Male
  • Middle Aged
  • Muscle Spasticity / genetics
  • Pedigree
  • Spastic Paraplegia, Hereditary / genetics*
  • Spinocerebellar Ataxias / congenital
  • Spinocerebellar Ataxias / genetics
  • Spinocerebellar Degenerations / genetics*
  • Young Adult


  • Heat-Shock Proteins
  • KIF1A protein, human
  • SACS protein, human
  • Kinesins

Supplementary concepts

  • Spastic ataxia Charlevoix-Saguenay type

Grant support

Z.I., I.M.W., and L.P. have been supported by grants from the South-Eastern Norway Regional Health Authority. M.T. and A.H.R. have received funding from the Research Council of Norway. M.T. is also supported by a career fellowship from the South-Eastern Norway Regional Health Authority. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.