Spastic Paraplegia 51 via the AP4E1 Gene

Spastic paraplegia-51 (SPG51) is a type of hereditary spastic paraplegia (HSP) and is characterized by neonatal muscular hypotonia of all limbs that gradually progresses to spasticity, hypertonia and severe intellectual disability with absent or poor speech development. Some patients may also manifest short stature, seizures and dysmorphic facial features (Moreno-De-Luca et al. 2011; Abou Jamra et al. 2011).

SPG51 is inherited in an autosomal recessive (AR) manner and is caused by pathogenic variants in the AP4E1 gene. To date, one nonsense pathogenic variant, one frameshift pathogenic variant and one gross deletion have been identified in SPG51 patients (Moreno-De-Luca et al. 2011; Abou Jamra et al. 2011; Kong et al. 2013). AP4E1 encodes the adaptor-related protein complex 4 epsilon 1 subunit, one of the four subunits of the AP-4 complex. This protein complex plays an important role in brain development and function by regulating the transportation of cargo proteins from the trans-Golgi system to the endosomal–lysosomal network (Hirst et al. 1999). Pathogenic variants in the genes encoding the other three subunits of the AP-4 complex have also been reported in patients with autosomal recessive spastic paraplegia (AP4B1/SPG47, AP4M1/SPG50 and AP4S1/SPG52) (Abou Jamra et al. 2011).

SPG51 is allelic with autosomal dominant stuttering. A whole-exome sequencing study identified two missense variants and one nonsense variant in the AP4E1 gene causing persistent stuttering (Raza et al. 2015).

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 AP4E1 gene are detectable by sequencing.

This test provides full coverage of all coding exons of the AP4E1 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).