Spastic Paraplegia 76 via the CAPN1 Gene

Spastic paraplegia 76 (SPG76) is a type of hereditary spastic paraplegia (HSP) characterized by young-adult onset of progressive spasticity of the lower limbs resulting in walking difficulties. Most SPG76 patients variably presented upper limb involvement, dysarthria, ataxia and sensory axonal neuropathy (Gan-Or et al. 2016. PubMed ID: 27153400; Wang et al. 2016. PubMed ID: 27320912). In a few cases, mild-to moderate cerebellar atrophy has also been shown on brain MRI (Wang et al. 2016. PubMed ID: 27320912). In addition to the adult-onset complicated form of HSP, a congenital-onset pure form of HSP has been reported recently in a SPG76 patient (Travaglini et al. 2017. PubMed ID: 28566166).

SPG76 is inherited in an autosomal recessive (AR) manner. Homozygous or compound heterozygous pathogenic variants in the CAPN1 gene have been reported to cause SPG76 (Gan-Or et al. 2016. PubMed ID: 27153400; Wang et al. 2016. PubMed ID: 27320912; Travaglini et al. 2017. PubMed ID: 28566166). To date, different types of pathogenic variants (missense, nonsense, splicing and small frameshift deletions/duplications) have been identified in SPG76 patients (Human Gene Mutation Database).

CAPN1 encodes for Calpain 1, a type of calcium-dependent non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in signal transduction and cytoskeletal remodeling (Ohno et al. 1990. PubMed ID: 2209092). Previous studies demonstrated that the loss-of-function of CAPN1 is the cause of this disorder (Gan-Or et al. 2016. PubMed ID: 27153400; Wang et al. 2016. PubMed ID: 27320912).

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. Pathogenic variants in CAPN1 gene appear to be a rare cause of spastic paraplegia. All the known pathogenic variants in this gene can be detected by this test.

This test provides full coverage of all coding exons of the CAPN1 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).