Wednesday, November 18, 2015

Genetics of epilepsy in clinical practice 2

Ream MA, Patel AD. Obtaining genetic testing in pediatric epilepsy. Epilepsia.
2015 Oct;56(10):1505-14.


The steps from patient evaluation to genetic diagnosis remain complicated. We discuss some of the genetic testing methods available along with their general advantages and disadvantages. We briefly review common pediatric epilepsy syndromes with strong genetic association and provide a potentially useful algorithm for genetic testing in drug-resistant epilepsy. We performed an extensive literature review of available information as it pertains to genetic testing and genetics in pediatric epilepsy. If a genetic disorder is suspected as the cause of epilepsy, based on drug resistance, family history, or clinical phenotype, timely diagnosis may reduce overall cost, limit the diagnostic odyssey that can bring much anxiety to families, improve prognostic accuracy, and lead to targeted therapy. Interpretation of complicated results should be performed only in collaboration with geneticists and genetic counselors, unless the ordering neurologist has a strong background in and understanding of genetics. Genetic testing can play an important role in the care provided to patients with epilepsy.

From the article:
The wide availability of large-scale genetic testing brings an overlap between clinical medicine and research since research findings can be applied for clinical purposes. Foregoing the need for an a priori genetic diagnosis, broad genetic screening such as with WES allows gene discovery. A VUS identified in one patient can be reclassified as disease causing if similar associations are found in other patients. Clinical discovery of variants can inform basic research regarding mechanisms that provide therapeutic targets. In addition, simple clinical observation regarding therapeutic responses in specific conditions can lead to further discovery of involved mechanisms, such as was noted in the exacerbating effect of sodium channel blockers in Dravet syndrome.

Despite the practical and theoretical challenges of genetic testing, genetic testing may offer advantages over retaining a diagnosis of “idiopathic” epilepsy. Certain results may guide and alter treatment decisions as in Dravet syndrome. The benefit of providing an answer to the diagnostic odyssey cannot be understated. Family anxiety can be eased, a more specific prognosis may be available, additional at-risk relatives can be tested, and a specific diagnosis may lead to networking with other similarly affected families. A diagnosis and its inheritance pattern may assist in future family planning; some families learn that they have a 25% or 50% risk of having another affected child, whereas other families are relieved to find out that their affected child carries a de novo mutation...
The use of genetic testing in pediatric epilepsy is complicated and the list of known epilepsy genes changes almost daily. Also as reimbursement for testing changes, the most cost-effective approach may change over time. Currently we recommend reserving WES for the most elusive cases, but in time sending one genetic test with the broadest genetic coverage may become practical; however, there are still technical limitations that will need to be addressed as WES becomes more utilized. It would be ideal if WES could be tailored for epilepsy patients by optimizing coverage of known epilepsy genes. If this were to occur, further need for testing with a panel first would not be necessary and would ultimately lead to cost savings by reducing the total number of tests ordered. Alternatively, reflex testing to WES is an option when an epilepsy gene panel is negative. A few commercial companies currently offer this option.
Careful consideration of each available test with its limitations must precede selection and ordering. A close partnership with genetics and genetic counseling is strongly recommend before pursuing testing that may reveal unexpected, and sometimes unrequested, results. Interpretation of complicated results should be performed only in collaboration with genetics providers unless the ordering neurologist has a strong background in and understanding of genetics. Genetic testing can play an important role in the care provided to patients with epilepsy.



  1. Epi4K Consortium; Epilepsy Phenome/Genome Project, Allen AS, Berkovic SF,
    Cossette P, Delanty N, Dlugos D, Eichler EE, Epstein MP, Glauser T, Goldstein DB,
    Han Y, Heinzen EL, Hitomi Y, Howell KB, Johnson MR, Kuzniecky R, Lowenstein DH, Lu YF, Madou MR, Marson AG, Mefford HC, Esmaeeli Nieh S, O'Brien TJ, Ottman R, Petrovski S, Poduri A, Ruzzo EK, Scheffer IE, Sherr EH, Yuskaitis CJ, Abou-Khalil B, Alldredge BK, Bautista JF, Berkovic SF, Boro A, Cascino GD, Consalvo D, Crumrine P, Devinsky O, Dlugos D, Epstein MP, Fiol M, Fountain NB, French J, Friedman D, Geller EB, Glauser T, Glynn S, Haut SR, Hayward J, Helmers SL, Joshi S, Kanner A, Kirsch HE, Knowlton RC, Kossoff EH, Kuperman R, Kuzniecky R,Lowenstein DH, McGuire SM, Motika PV, Novotny EJ, Ottman R, Paolicchi JM, Parent JM, Park K, Poduri A, Scheffer IE, Shellhaas RA, Sherr EH, Shih JJ, Singh R, Sirven J, Smith MC, Sullivan J, Lin Thio L, Venkat A, Vining EP, Von Allmen GK, Weisenberg JL, Widdess-Walsh P, Winawer MR. De novo mutations in epileptic encephalopathies. Nature. 2013 Sep 12;501(7466):217-21.


    Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.

  2. Vears DF, Dunn KL, Wake SA, Scheffer IE. "It's good to know": experiences of gene identification and result disclosure in familial epilepsies. Epilepsy Res. 2015 May;112:64-71.


    Recognition of the role of genetics in the epilepsies has increased dramatically, impacting on clinical practice across many epilepsy syndromes. There is limited research investigating the impact of gene identification on individuals and families with epilepsy. While research has focused on the impact of delivering genetic information to families at the time of diagnosis in genetic diseases more broadly, little is known about how genetic results in epileptic diseases influences people's lives many years after it has been conveyed. This study used qualitative methods to explore the experience of receiving a genetic result in people with familial epilepsy. Interviews were conducted with individuals with familial epilepsies in whom the underlying genetic mutation had been identified. Recorded interviews underwent thematic analysis. 20 individuals from three families with different epilepsy syndromes and causative genes were interviewed. Multiple generations within families were studied. The mean time from receiving the genetic result prior to interview was 10.9 years (range 5-14 years). Three major themes were identified: 1) living with epilepsy: an individual's experience of the severity of epilepsy in their family influenced their view. 2) Clinical utility of the test: participants expressed varying reactions to receiving a genetic result. While for some it provided helpful information and relief, others were not surprised by the finding given the familial context. Some valued the use of genetic information for reproductive decision-making, particularly in the setting of severely affected family members. While altruistic reasons for participating in genetic research were discussed, participants emphasised the benefit of participation to them and their families. 3) 'Talking about the family genes': individuals reported poor communication between family members about their epilepsy and its genetic implications. The results provide important insights into the family experience of genetic epilepsies and communication within families. This information can be used to inform the development of guidelines for genetic result disclosure and genetic counselling for individuals and families with epilepsies.