Spastic Paraplegia 58 via the KIF1C Gene

Spastic paraplegia 58 (SPG58) is a type of hereditary spastic paraplegia (HSP) and is characterized by spasticity in the lower limbs, dysarthria, cervical dystonia and cerebellar ataxia. It has been noted that in some cases the spasticity may affect all four limbs late in life. Some patients with SPG58 may also manifest mild mental retardation and developmental delay. These symptoms typically begin to appear in childhood (Bouslam et al. 2007; Caballero Oteyza et al. 2014; Dor et al. 2014; Novarino et al. 2014).

Studies from families with SPG58 suggest a dual inheritance pattern: mostly autosomal recessive (AR), but autosomal dominant (AD) inheritance has also been observed. Compound heterozygous and homozygous pathogenic variants have been found in the KIF1C gene to cause SPG58 (Caballero Oteyza et al. 2014; Dor et al. 2014; Novarino et al. 2014). Some individuals with the same variants in a heterozygous state may show a less severe or subclinical phenotype (Caballero Oteyza et al. 2014). The KIF1C (Kinesin family member 1C) gene encodes KIF1C protein, which is a member of the kinesin-like motor protein family. The exact function of KIF1C is not clear, but it is considered to be involved in the retrograde vesicular transport of Golgi to endoplasmic reticulum (Dorner et al. 1998).

SPG58 is allelic with autosomal recessive spastic ataxia 2 (SPAX2). The gene KIF1C was shown to be within the SPAX2 locus and it has been confirmed that KIF1C is the SPAX2 gene based on the study done in the original SPAX2 family (Bouslam et al. 2007; Novarino et al. 2014).

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. Almost all the pathogenic variants reported to date in KIF1C gene are detectable by sequencing.

This test provides full coverage of all coding exons of the KIF1C gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).