Spastic Paraplegia 54 via the DDHD2 Gene

Spastic paraplegia 54 (SPG54) is a type of complex hereditary spastic paraplegia (HSP). Patients with SPG54 have spasticity of the lower limbs, delayed psychomotor development, and mild to moderate intellectual disability. The onset is typically before the age of two years. Brain MRI shows a thin corpus callosum and periventricular white matter lesions (Schuurs-Hoeijmakers et al. 2012, 2013; Doi et al. 2014). An accumulation of lipids in basal ganglia and the thalamus is usually detected with cerebral magnetic resonance spectroscopy (MRS). This can be used as a diagnostic biomarker to distinguish this disease with other types of complex HSP (Schuurs-Hoeijmakers et al. 2012).

SPG54 is inherited in an autosomal recessive manner, and DDHD2 (DDHD-domain-containing 2) is the causative gene (Schuurs-Hoeijmakers et al. 2012; Gonzales et al. 2013). Similar to DDHD1 (the causative gene for SPG28), DDHD2 also belongs to the mammalian intracellular phospholipase A1 family. The DDHD2 gene encodes a phospholipase that hydrolyzes sn-1 ester bonds of phospholipids, producing 2-acyl-lysophospholipids and fatty acids. The DDHD2 protein may determines membrane curvature and regulate membrane and vesicle fusion through membrane phospholipid hydrolysis (Sato et al. 2010; Inoue et al. 2012). Different types of pathogenic variants (nonsense, missense, splice, and deletions/duplications) have been identified in this gene (Human Gene Mutation Database). Most identified pathogenic variants affect the protein’s DDHD domain, which is important for phospholipase activity.

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. Most of the documented pathogenic variants in DDHD2 gene are detectable by sequencing.

To date, only one gross deletion has been identified in DDHD2 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the DDHD2 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).