Spastic Paraplegia 72 via the REEP2 Gene

Spastic paraplegia 72 (SPG72) is a type of hereditary spastic paraplegia (HSP) that has been described recently in two large families (Esteves et al. 2014). SPG72 has onset of walking difficulty and stiff legs in early childhood. It is relatively "pure", i.e., the symptoms are limited in the lower limbs. Some patients may manifest sphincter disturbances and/or pes cavus. SPG72 is slowly progressive, and some affected individuals may need assistance in walking in their later life (Esteves et al. 2014).

SPG72 is caused by pathogenic variants in REEP2, and it can be inherited as an autosomal dominant (AD) or autosomal recessive (AR) disorder. Esteves et al identified a missense pathogenic variant (c.107T>A) that segregated in the heterozygous state in a French family with AD inheritance, and two pathogenic variants (c.215T>A and c.105+3G>T) that segregated in trans in a Portuguese family with AR transmission (Esteves et al. 2014). Similar to REEP1, REEP2 also encodes a protein of the Reep/DP1/Yop1p family, which is highly expressed in the brain and spinal cord (Hurt et al. 2014). The REEP2 (receptor expression-enhancing protein 2) protein contains two highly conserved hydrophobic N-terminal domains, which can form hairpins that insert into the endoplasmic reticulum (ER) membrane and modulate its curvature (Björk et al. 2013). The two missense variants in REEP2 reported in the Esteves et al study and almost all the missense variants identified so far in REEP1 are located in the N-terminal domains (Esteves et al. 2014; Goizet et al. 2011; Beetz et al. 2008; Human Gene Mutation Database).

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. The few reported pathogenic variants are detectable by sequencing.

This test provides full coverage of all coding exons of the REEP2 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).