Spastic Paraplegia 13 via the HSPD1 Gene

Spastic paraplegia 13 (SPG13) is a type of hereditary spastic paraplegia (HSP). This disorder has been observed in only a limited number of families and the reported patients with the disease manifest babinski sign, hyperreflexia, progressive lower limb spasticity and muscle weakness. Some patients may also have urinary bladder sphincter dysfunction (Fontaine et al. 2000; Hansen et al. 2007). In the single family reported by Fontaine et al. (2000), the onset of SPG13 ranges from 17 to 58 years of age. Incomplete penetrance of the disease has been suggested by one study (Hansen et al. 2007).

SPG13 is caused by pathogenic variants in HSPD1 gene. HSPD1 encodes the heat shock protein 60, which is a molecular chaperone involved in the folding of proteins localized in mitochondria (Bross et al. 2008). To date, only two missense variants have been identified in HSPD1 to cause SPG13 (Human Gene Mutation Database). The transmission mode in the reported families is consistent with autosomal dominant (AD) inheritance (Hansen et al. 2002; Hansen et al. 2007).

A homozygous variant (c.86A>G, p.Asp29Gly) has been observed in HSPD1 to cause hypomyelinating leukodystrophy, which is a different disorder distinguished from SPG13 by its early age of onset, autosomal recessive inheritance, cerebral involvement and lethality (Magen et al. 2008).

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. Pathogenic variants in HSPD1 gene appear to be a rare cause of spastic paraplegia. All the known pathogenic variants in this gene can be detected by sequencing.

This test provides full coverage of all coding exons of the HSPD1 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).