Submission Details

PLP1 has been reported in relation to both X-linked Pelizaeus-Merzbacher disease (PMD) and hereditary spastic paraplegia (SPG). Evidence suggests that these disorders are at different ends of the same clinical spectrum; the curation presented here is specifically for the more severe Pelizaeus-Merzbacher presentation. The PLP1 gene encodes two major alternatively spliced transcripts: a full-length transcript that encodes PLP, and a transcript lacking the PLP specific domain in exon 3, known as DM20. Differing molecular mechanisms are known to cause these disorders, including overexpression of PLP/DM20 (commonly caused by large, multi-gene duplications including PLP1 and resulting in "classic" PMD); missense variants resulting in misfolding of both PLP and DM20 (resulting in the more severe, "connatal" PMD); null variants (resulting in milder presentations of PMD or "complicated" SPG); and milder misfolding variants (often associated with the SPG phenotype). Note that though duplications are the most common mechanism of PMD, none are curated here, as most involve more genes than just PLP1. Though extensive functional evidence (including additional animal models) is available to support the link between PLP1 and PMD, only a subset is presented here.

In summary, there is definitive evidence supporting the relationship between PLP1 and X-linked Pelizaeus-Merzbacher disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on March 7, 2018 (SOP Version 5).

Variation in PLP1 has been associated with both Pelizaeus-Merzbacher disease (PMD) and hereditary spastic paraplegia (SPG). Evidence suggests that these disorders are at different ends of the same clinical spectrum; the curation presented here is specifically for the more severe Pelizaeus Merzbacher presentation. The PLP1 gene encodes for 2 major alternatively spliced transcripts: a full length transcript that encodes PLP, and a transcript lacking the PLP specific domain in exon 3, known as DM20. Differing molecular mechanisms are known to cause these disorders, including overexpression of PLP/DM20 (commonly caused by large, multi-gene duplications including PLP1 and resulting in "classic" PMD); missense variants resulting in misfolding of both PLP and DM20 (resulting in the more severe, "connatal" PMD); null variants (resulting in milder presentations of PMD or "complicated" SPG); and milder misfolding variants (often associated with the SPG phenotype). Note that though duplications are the most common mechanism of PMD, none are curated here (as most involve more genes than just PLP1). Though extensive functional evidence (including additional animal models) is available to support the link between PLP1 and PMD, only a subset is presented here.