PLP1-Related Disorders via the PLP1 Gene

PLP1-related disorders are neurodegenerative disorders of dysmyelination of the central nervous system. PLP1-related disorders represent a clinical spectrum from the severe form of Pelizaeus-Merzbacher disease (PMD; OMIM 312080) to spastic paraplegia 2 (SPG2; OMIM 312920). The severe PMD form usually manifests during the neonatal period with almost complete absence of white matter and severe quadriparesis and rapid progression. Classic PMD manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment and is followed by severe spasticity and ataxia later in life. Mild PMD is distinguished by absence of nystagmus and presence of mild spasticity of the lower extremities, ataxia, and mild demyelinating peripheral neuropathy (Raskind et al. Am J Hum Genet 49:1355-1360, 1991, Gencic et al. Am J Hum Genet 45:435-442, 1989; Hudson et al. Proc Nat Acad Sci 86:8128-8131, 1989; Inoue et al. Am J Hum Genet 59:32-39, 1996). SPG2 manifests as spastic paraparesis with or without central nervous system involvement, such as cerebellar ataxia, sensory loss, nystagmus, optic atrophy, and cognitive impairments (Saugier-Veber et al. Nat Genet 6:257-262, 1994).

PLP1-related disorders are inherited in an X-linked recessive manner; however, female carriers may manifest symptoms of the disease (Marble et al. Am J Med Genet 143A:1442-1447, 2007). Variants in the PLP1 gene cause PLP1-related disorders including Pelizaeus-Merzbacher disease and spastic paraplegia 2 (Gencic et al. Am J Hum Genet 45:435-442, 1989; Hudson et al. Proc Natl Acad Sci USA 86:8128-8131, 1989; Saugier-Veber et al. Nat Genet 6:257-262, 1994). The PLP1 gene encodes two alternatively-spliced myelin membrane proteins (PLP and DM20) of the central nervous system (Nave et al. Proc Nat Acad Sci 84:5665-5669, 1987). The PLP protein, the longer isoform, is predicted to have a role in myelin sheath formation and compaction and in axon stability (Yool et al. Hum Molec Genet 9:987-992, 2000; Hobson et al. Ann Neurol 52:477-488, 2002). A mix of missense, nonsense, splicing, and frameshift variants as well as duplications, deletions, and chromosomal rearrangements within the PLP1 gene have been reported (Gencic et al. 1989; Hudson 1989; Saugier-Veber et al. 1994; Inoue et al. Am J Hum Genet 59:32-39, 1996; Raskind et al. Am J Hum Genet 49:1355-1360, 1991).

PLP1 is the only gene associated PLP1-related disorders. Approximately 50-60% of the reported variants are deletions and duplications, while approximately 15-20% of the reported variants can be detected by DNA sequencing (Sistermans et al. Neurology 50:1749-1754, 1998; Wang et al. J Cell Biochem 97:999-1016, 2006).

This test provides full coverage of all coding exons of the PLP1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.