Genetic Screening and Diagnosis in Epilepsy?
Genetic Screening and Diagnosis in Epilepsy?
Much of the preceding considers what might be done by a practicing neurologist seeing a patient in whom a genetic diagnosis is suspected. Can there be an epilepsy in which there is no genetic contribution? Is it simply a matter of time and numbers before every brain-expressed or mutation-intolerant gene is implicated in some epilepsy? The pace of gene discovery in epilepsy over the recent past has certainly been breath-taking. Careful quality control and use of next-generation sequencing data have been critical in ensuring discoveries can be considered robust. Discoveries have been too numerous to list each individually. Progress has been most dramatic for the epileptic encephalopathies. Though individually rare, the encephalopathies account for an important part of the burden of the epilepsies and often seem to be caused by variants of large effect, making them tractable. A set of genes and related pathways responsible for a number of epileptic encephalopathies was reported using trio exome sequencing – several known 'epilepsy genes' and a number of novel candidates were proposed. One candidate, DNM1, was then confirmed by merging data from consortia, illustrating the frequent need for large numbers of patients to formally declare the culpability of a given gene. Amongst many other genes, mutations in PURA,WWOX,SLC13A5,DOCK7 and SZT2 have been reported in a wide variety of epileptic encephalopathies, some, but not all, associated with other distinctive features. Given the richness of the emerging data, there is considerable scope for data mining and novel analytic methods, some to predict new genes for epileptic encephalopathy, with methods also to prioritize genes. Another very interesting discovery has been that of mutations in DEPDC5 in several familial and sporadic epilepsy phenotypes. These findings are of especial interest as DEPDC5 is part of the mTOR pathway, activity within which can be manipulated using the existing drug rapamycin. Neuropathological studies support the involvement of mTOR disorder beyond focal cortical dysplasia and tuberous sclerosis alone.
Recent Research Findings
Much of the preceding considers what might be done by a practicing neurologist seeing a patient in whom a genetic diagnosis is suspected. Can there be an epilepsy in which there is no genetic contribution? Is it simply a matter of time and numbers before every brain-expressed or mutation-intolerant gene is implicated in some epilepsy? The pace of gene discovery in epilepsy over the recent past has certainly been breath-taking. Careful quality control and use of next-generation sequencing data have been critical in ensuring discoveries can be considered robust. Discoveries have been too numerous to list each individually. Progress has been most dramatic for the epileptic encephalopathies. Though individually rare, the encephalopathies account for an important part of the burden of the epilepsies and often seem to be caused by variants of large effect, making them tractable. A set of genes and related pathways responsible for a number of epileptic encephalopathies was reported using trio exome sequencing – several known 'epilepsy genes' and a number of novel candidates were proposed. One candidate, DNM1, was then confirmed by merging data from consortia, illustrating the frequent need for large numbers of patients to formally declare the culpability of a given gene. Amongst many other genes, mutations in PURA,WWOX,SLC13A5,DOCK7 and SZT2 have been reported in a wide variety of epileptic encephalopathies, some, but not all, associated with other distinctive features. Given the richness of the emerging data, there is considerable scope for data mining and novel analytic methods, some to predict new genes for epileptic encephalopathy, with methods also to prioritize genes. Another very interesting discovery has been that of mutations in DEPDC5 in several familial and sporadic epilepsy phenotypes. These findings are of especial interest as DEPDC5 is part of the mTOR pathway, activity within which can be manipulated using the existing drug rapamycin. Neuropathological studies support the involvement of mTOR disorder beyond focal cortical dysplasia and tuberous sclerosis alone.
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