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| Paraganglioma_phaeochromocytoma v0.32 | MDH2 | Zornitza Stark Marked gene: MDH2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paraganglioma_phaeochromocytoma v0.32 | MDH2 | Zornitza Stark Gene: mdh2 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paraganglioma_phaeochromocytoma v0.32 | MDH2 | Zornitza Stark Publications for gene: MDH2 were set to PMID: 25766404, 30008476 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paraganglioma_phaeochromocytoma v0.28 | MDH2 |
Chirag Patel gene: MDH2 was added gene: MDH2 was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review,Literature Mode of inheritance for gene: MDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MDH2 were set to PMID: 25766404, 30008476 Phenotypes for gene: MDH2 were set to Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Pheochromocytoma/paraganglioma, susceptibility to, no MIM#; Developmental and epileptic encephalopathy 51, MIM#617339 Review for gene: MDH2 was set to RED Added comment: PMID: 25766404 WES of tumour in 1 patient with multiple malignant paragangliomas identified a germline splice variant in MDH2 (c.429+1G>T)(variant confirmed in blood). Sanger sequencing of the 4 available primary tumours from the patient revealed loss of the MDH2 wild-type allele in two tumours, indicating loss of heterozygosity. MDH2 mRNA expression analysis revealed 6-14 fold lower levels of MDH2 expression in the four tumors carrying the variant compared with control patients. Substantially lower levels of MDH2 protein were detected in the MDH2-related tumours compared with control patients. Knockdown (KD) of MDH2 in HeLa cells by shRNA triggered the accumulation of both malate and fumarate, which was reversed by transient introduction of WT MDH2 cDNA. Segregation testing found the variant in 2 out of 5 asymptomatic relatives. MDH2 mRNA and protein expression in blood cells were statistically significantly lower in the two carriers compared with control patients. Subsequent clinical testing detected high levels of normetanephrine for one of the carriers, thus confirming the presence of the disease. PMID: 30008476 Sequencing of MDH2 in 830 patients with PPGLs (negative for the main PPGL driver genes), identified 5 germline variants with potential involvement in pathogenicity (3 x missense, 1 x in-frame deletion, 1 x splice-site). None of the variants was associated with an altered MDH2 localization, or mitochondrial quantity and morphology. LOH was not detected in any of the tumours carrying the missense variants, but was seen in the patient with the inframe deletion. Sources: Expert list, Expert Review, Literature |
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