Genetic Epilepsy
Gene: PLP1 Green List (high evidence)Green List (high evidence)
PMID: 7512350 (1994) - Mouse study demonstrating that seizures and convulsions are a result of a 2-fold increased PLP gene dosage. (Cited in OMIM)
PMID: 11071483 (2000) - One family with 2x brothers affected with PMD, both developing seizures in late teens. Other symptoms in both brothers include hypotonia at birth, nystagmus, and slowly progressive spastic paraplegia. (Cited in OMIM)
PMID: 21679407 (2011) - Male cohort, 43 individuals from 38 unrelated families with a PLP1-related disorder diagnosis. Seizures present in 2/43 males (both PLP1 duplication mutations). Additional symptoms include 3/43 stridor, 4/43 developmental delay, and 18/43 muscular hypotonia.
PMID: 28133555 (2017) - Case report on 9 year old male affected with classic PMD. Presented with a history of seizures since age 4. Also presents with developmental delay, nystagmus, microcephaly, spastic quadriplegia. Maternally inherited gain of 436Kb on Xq22.2 encompassing TCEAL1,MORF4L2, PLP1, and RAB9B, of which only PLP1 is associated with a disease.
PMID: 29486744 (2018) - Case report on family diagnosed with connatal PMD (previously diagnosed as X-linked epileptic seizures). The PLP1 missense mutation p.Ala84Asp was found to segregate in the family. 1x proband presenting with daily generalised seizures, onset at 8 months and no treatment response. 2x cousins and 2x maternal uncles also presented with epilepsy, all onset around 6 months and all died in childhood. Additional symptoms include 5/5 hypotonia and 5/5 psycho-motor delay. Consanguinity reported in the family.
PMID: 35346287 (2022) - Chinese cohort of 141 patients, 111 whom were followed up with. Seizures present in 4/28 individuals with connatal PMD, including 1 patient who died due to epileptic seizures at age 7, and 4/56 individuals with transitional PMD. Additional symptoms include 111/111 development delay, 110/111 nystagmus, 93/111 hypotonia, 35/111 stridor, and 4/111 respiratory difficulty.
PMID: 37637647 (2023) - Case report on 1x newborn individual diagnosed with failure to thrive and later PMD. Presented with episodes of rapid eye and side-to-side head movement episodes of 5-10 seconds, onset one month after birth. Diagnosis of seizure disorder considered before further testing. Individual hemizygous for PLP1: c.67G>A (p.Gly23Arg), maternally inherited.
GeneReviews: Seizures may develop in infants affected by 'severe connatal PMD'.
Sources: LiteratureCreated: 4 Jan 2024, 6:53 a.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
Pelizaeus-Merzbacher Disease, MIM#312080
Publications
Gene: plp1 has been classified as Green List (High Evidence).
Gene: plp1 has been classified as Green List (High Evidence).
Gene: plp1 has been classified as Green List (High Evidence).
gene: PLP1 was added gene: PLP1 was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: PLP1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: PLP1 were set to 7512350; 11071483; 21679407; 28133555; 29486744; 35346287; 37637647 Phenotypes for gene: PLP1 were set to Pelizaeus-Merzbacher Disease, MIM#312080 Review for gene: PLP1 was set to GREEN
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.