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| Genetic Epilepsy v0.2148 | PLP1 | Zornitza Stark Marked gene: PLP1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.2148 | PLP1 | Zornitza Stark Gene: plp1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.2148 | PLP1 | Zornitza Stark Classified gene: PLP1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.2148 | PLP1 | Zornitza Stark Gene: plp1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.2147 | PLP1 | Zornitza Stark Classified gene: PLP1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.2147 | PLP1 | Zornitza Stark Gene: plp1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.2144 | PLP1 |
Lisa Norbart 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 Added comment: 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: Literature |
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| Genetic Epilepsy v0.745 | TMEM106B |
Konstantinos Varvagiannis gene: TMEM106B was added gene: TMEM106B was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: TMEM106B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TMEM106B were set to 29186371; 29444210; 32595021 Phenotypes for gene: TMEM106B were set to Leukodystrophy, hypomyelinating, 16 (MIM #617964) Penetrance for gene: TMEM106B were set to Complete Mode of pathogenicity for gene: TMEM106B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: TMEM106B was set to AMBER Added comment: 6 unrelated individuals with Leukodystrophy, hypomyelinating, 16 (MIM #617964) due to a recurrent TMEM106B variant have been reported to date in the literature (Simons et al 2017 - PMID: 29186371, Yan et al 2018 - PMID: 29444210, Ikemoto et al 2020 - PMID: 32595021). While a 3 y.o. female described by Yan et al had DD (eg sitting at 9m, walking at 25m) with normal cognitive functioning, and a 38 y.o. female had borderline intellectual functioning (IQ 76), 4 affected individuals had ID. Among them, a 19 y.o. male with severe ID was also found to harbor a second de novo possibly damaging USP7 variant. Seizures have been reported in 2 unrelated subjects. [Clinical features are also summarized in table 1 - Ikemoto et al]. All harbored NM_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn) which in almost all cases occurred as a de novo event. In a single case this variant was inherited from a mosaic parent with mild DD in infancy but normal cognition (reported by Simons et al). As discussed by Ito et al (2018 - PMID: 30643851) the encoded protein is a structural component of the lysosomal membrane, playing a role on lysosome acidification. Acidity of the lysosome mediates multiple aspects of lysosomal function. Ito et al, using patient-derived fibroblasts assessed mRNA and protein levels. These were unaltered compared with controls. While TMEM106B had been previously shown to affect lysosome number, morphology and acidification, Ito et al demonstrated increased number of lysosomes in patient cells as well as impaired acidification compared to controls. As commented lysosomes are required for generation of myelin. Recurrence of this missense variant, the presence of pLoF TMEM106B variants in gnomAD as well as the phenotypically normal Tmem106b null mice suggest that this variant may have a gain-of-function or dominant negative effect. Genes for other forms of hypomyelinating lipodystrophy (incl. PLP1) have green rating in the ID panel. Overall TMEM106B can be considered for the ID panel with green rating and the epilepsy panel with amber rating. Sources: Literature |
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