Gene Validity Classification Summary

Gene/Disease Pair:

PLP1 : Pelizaeus-Merzbacher disease

MONDO:0010714 | ORPHA:280219 | OMIM:3120808
Mode of Inheritance: X-linked inheritance (HP:0001427)
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
1.00
1
Hoffman-Zacharska D et al. 2013 Oct-Dec (PMID:24519770);
Proband with predicted or proven null variant 1.5 0-2 10 7.00 7
Martínez-Montero P et al. 2013 Dec (PMID:23347225); Hoffman-Zacharska D et al. 2013 Oct-Dec (PMID:24519770); Laššuthová P et al. 2014 Jul (PMID:23771846);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
3.25
3.25
Gencic S et al. 1989 Sep (PMID:2773936); Cailloux F et al. 2000 Nov (PMID:11093273); Hoffman-Zacharska D et al. 2013 Oct-Dec (PMID:24519770); Martínez-Montero P et al. 2013 Dec (PMID:23347225); Lyahyai J et al. 2018 Feb 27 (PMID:29486744); Lu Y et al. 2017 (PMID:28101371);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
0.00
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
0.00
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
3.00
3  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
Laššuthová P et al. 2014 Jul (PMID:23771846); Lyahyai J et al. 2018 Feb 27 (PMID:29486744); Hoffman-Zacharska D et al. 2013 Oct-Dec (PMID:24519770);
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
0.00
Aggregate Variant Analysis 0-6
0.00
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
0.00
Protein Interaction 0.5 0 - 2 0.00
Expression 0.5 0 - 2 0.00
Functional Alteration Patient cells 1 0 - 2 2
0.00
Non-patient cells 0.5 0 - 1 0.00
Models Non-human model organism 2 0 - 4 4 4.00 4
Nave KA et al. 1986 Dec (PMID:3466187); Nadon NL et al. 1990 Oct (PMID:1723945);
Cell culture model 1 0 - 2 0.00
Rescue Rescue in human 2 0 - 4
0.00
Rescue in non-human model organism 2 0 - 4
0.00
Rescue in cell culture model 1 0 - 2 0.00
Rescue in patient cells 1 0 - 2 0.00
Total Experimental Evidence Points (Maximum 6) 4

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 4 16 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
DEFINITIVE
03/09/2018
EXPERT CURATION (DATE)
DEFINITIVE
03/07/2018
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.