Genetic testing in the epilepsies—Report of the ILAE Genetics Commission

In this report, the International League Against Epilepsy (ILAE) Genetics Commission discusses essential issues to be considered with regard to clinical genetic testing in the epilepsies. Genetic research on the epilepsies has led to the identification of more than 20 genes with a major effect on susceptibility to idiopathic epilepsies. The most important potential clinical application of these discoveries is genetic testing: the use of genetic information, either to clarify the diagnosis in people already known or suspected to have epilepsy (diagnostic testing), or to predict onset of epilepsy in people at risk because of a family history (predictive testing). Although genetic testing has many potential benefits, it also has potential harms, and assessment of these potential benefits and harms in particular situations is complex. Moreover, many treating clinicians are unfamiliar with the types of tests available, how to access them, how to decide whether they should be offered, and what measures should be used to maximize benefit and minimize harm to their patients. Because the field is moving rapidly, with new information emerging practically every day, we present a framework for considering the clinical utility of genetic testing that can be applied to many different syndromes and clinical contexts. Given the current state of knowledge, genetic testing has high clinical utility in few clinical contexts, but in some of these it carries implications for daily clinical practice.

[1]  J. Gécz,et al.  Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X) , 2010, European Journal of Human Genetics.

[2]  I. Scheffer,et al.  Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. , 2009, Human molecular genetics.

[3]  G. Incorpora.  Dravet syndrome , 2009, Italian journal of pediatrics.

[4]  Christian E Elger,et al.  CLCN2 variants in idiopathic generalized epilepsy , 2009, Nature Genetics.

[5]  I. Scheffer,et al.  Early‐onset absence epilepsy caused by mutations in the glucose transporter GLUT1 , 2009, Annals of neurology.

[6]  I. Scheffer,et al.  SCN1A duplications and deletions detected in Dravet syndrome: Implications for molecular diagnosis , 2009, Epilepsia.

[7]  I. Scheffer,et al.  Dravet syndrome or genetic (generalized) epilepsy with febrile seizures plus? , 2009, Brain and Development.

[8]  H. Lerche,et al.  Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy , 2009, Human Mutation.

[9]  S. Hauser,et al.  Personalized genetic scans: With gifts like these… , 2009, Annals of neurology.

[10]  S. Berkovic,et al.  A neurologist’s guide to genome-wide association studies , 2009, Neurology.

[11]  Christoph Lossin.  A catalog of SCN1A variants , 2009, Brain and Development.

[12]  Y. Makita,et al.  A de novo KCNQ2 mutation detected in non-familial benign neonatal convulsions , 2009, Brain and Development.

[13]  Jingyue Ju,et al.  Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4) , 2009, European Journal of Human Genetics.

[14]  P. de Jonghe,et al.  Genetics of epilepsy syndromes starting in the first year of life , 2009, Neurology.

[15]  Christian E Elger,et al.  15q13.3 microdeletions increase risk of idiopathic generalized epilepsy , 2009, Nature Genetics.

[16]  W. Löscher,et al.  The clinical impact of pharmacogenetics on the treatment of epilepsy , 2009, Epilepsia.

[17]  C. Depienne,et al.  Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients , 2008, Journal of Medical Genetics.

[18]  A. Konagaya,et al.  Microchromosomal deletions involving SCN1A and adjacent genes in severe myoclonic epilepsy in infancy , 2008, Epilepsia.

[19]  R. Ottman,et al.  Penetrance of LGI1 mutations in autosomal dominant partial epilepsy with auditory features , 2008, Neurology.

[20]  W. van Paesschen,et al.  Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1 , 2008, Brain : a journal of neurology.

[21]  T. Hampton.  Congress passes bill to ban discrimination based on individuals' genetic makeup. , 2008, JAMA.

[22]  F. Mottaghy,et al.  GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. , 2008, The Journal of clinical investigation.

[23]  Andrew Menzies,et al.  X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment , 2008, Nature Genetics.

[24]  Naomichi Matsumoto,et al.  De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy , 2008, Nature Genetics.

[25]  W. van Paesschen,et al.  Epilepsy as part of the phenotype associated with ATP1A2 mutations , 2008, Epilepsia.

[26]  I. Scheffer,et al.  Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants , 2007, Annals of neurology.

[27]  Jing Qian,et al.  Masking epilepsy by combining two epilepsy genes , 2007, Nature Neuroscience.

[28]  I. Scheffer,et al.  Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study , 2007, The Lancet Neurology.

[29]  R. Guerrini,et al.  The role of the nicotinic acetylcholine receptors in sleep-related epilepsy. , 2007, Biochemical pharmacology.

[30]  J. Mulley,et al.  A polygenic heterogeneity model for common epilepsies with complex genetics , 2007, Genes, brain, and behavior.

[31]  Gail Javitt,et al.  ASHG Statement* on Direct-to-Consumer Genetic Testing in the United States , 2007, Obstetrics and gynecology.

[32]  Shinji Saitoh,et al.  A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome). , 2007, American journal of human genetics.

[33]  E. Wirrell,et al.  Linkage and mutational analysis of CLCN2 in childhood absence epilepsy , 2007, Epilepsy Research.

[34]  P. Striano,et al.  A DE NOVO LGI1 MUTATION CAUSING IDIOPATHIC PARTIAL EPILEPSY WITH TELEPHONE-INDUCED SEIZURES , 2007, Neurology.

[35]  I. Scheffer,et al.  SCN2A Mutations and Benign Familial Neonatal‐Infantile Seizures: The Phenotypic Spectrum , 2007, Epilepsia.

[36]  I. Scheffer,et al.  A Multicenter Study of BRD2 as a Risk Factor for Juvenile Myoclonic Epilepsy , 2007, Epilepsia.

[37]  O. Steinlein,et al.  Benign familial neonatal convulsions: Always benign? , 2007, Epilepsy Research.

[38]  I. Scheffer,et al.  The spectrum of SCN1A-related infantile epileptic encephalopathies. , 2007, Brain : a journal of neurology.

[39]  M. Gardiner.  Molecular genetics of infantile nervous system channelopathies. , 2006, Early human development.

[40]  P. Striano,et al.  Cryptic chromosome deletions involving SCN1A in severe myoclonic epilepsy of infancy , 2006, Neurology.

[41]  I. Scheffer,et al.  Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. , 2006, Brain : a journal of neurology.

[42]  R. Guerrini,et al.  Mosaic SCN1A Mutation in Familial Severe Myoclonic Epilepsy of Infancy , 2006, Epilepsia.

[43]  K. Yamakawa,et al.  SCN1A Mutation Mosaicism in a Family with Severe Myoclonic Epilepsy in Infancy , 2006, Epilepsia.

[44]  R. Ottman,et al.  Ethical, Legal, and Social Dimensions of Epilepsy Genetics , 2006, Epilepsia.

[45]  I. Scheffer,et al.  A new molecular mechanism for severe myoclonic epilepsy of infancy: Exonic deletions in SCN1A , 2006, Neurology.

[46]  L. Lagae,et al.  Microdeletions involving the SCN1A gene may be common in SCN1A‐mutation‐negative SMEI patients , 2006, Human mutation.

[47]  C. Cianchetti,et al.  Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. , 2006, American journal of human genetics.

[48]  Samuel F. Berkovic,et al.  Human epilepsies: interaction of genetic and acquired factors , 2006, Trends in Neurosciences.

[49]  J. Gécz,et al.  ARX: a gene for all seasons. , 2006, Current opinion in genetics & development.

[50]  A. Heils,et al.  Evaluation of CACNA1H in European patients with childhood absence epilepsy , 2006, Epilepsy Research.

[51]  M. Baulac,et al.  Parental mosaicism can cause recurrent transmission of SCN1A mutations associated with severe myoclonic epilepsy of infancy , 2006, Human mutation.

[52]  E. Bertini,et al.  Somatic and germline mosaicisms in severe myoclonic epilepsy of infancy. , 2006, Biochemical and biophysical research communications.

[53]  P. Striano,et al.  A Novel SCN2A Mutation in Family with Benign Familial Infantile Seizures , 2006, Epilepsia.

[54]  J. Phelan.  Geneticization of Deviant Behavior and Consequences for Stigma: The Case of Mental Illness∗ , 2005, Journal of health and social behavior.

[55]  R. Ottman.  Analysis of Genetically Complex Epilepsies , 2005, Epilepsia.

[56]  D. Bertrand,et al.  The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits , 2005, Neurobiology of Disease.

[57]  I. Scheffer,et al.  Susceptibility genes for complex epilepsy. , 2005, Human molecular genetics.

[58]  S. Lorenz,et al.  Association Analysis of Malic Enzyme 2 Gene Polymorphisms with Idiopathic Generalized Epilepsy , 2005, Epilepsia.

[59]  Jianmin Cui,et al.  Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder , 2005, Nature Genetics.

[60]  Steven Petrou,et al.  SCN1A mutations and epilepsy , 2005, Human mutation.

[61]  D. Kullmann,et al.  Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. , 2005, Brain : a journal of neurology.

[62]  E. Perez-Reyes,et al.  Functional Characterization and Neuronal Modeling of the Effects of Childhood Absence Epilepsy Variants of CACNA1H, a T-Type Calcium Channel , 2005, The Journal of Neuroscience.

[63]  C. Bladen,et al.  Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy , 2005, Annals of neurology.

[64]  N. Delanty,et al.  Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects , 2005, The Lancet Neurology.

[65]  J. Witte,et al.  Comparison of missing data approaches in linkage analysis , 2003, BMC Genetics.

[66]  C. van Broeckhoven,et al.  De novo KCNQ2 mutations in patients with benign neonatal seizures , 2004, Neurology.

[67]  S. Berkovic,et al.  Genetic Association Studies in Epilepsy: “The Truth Is Out There” , 2004, Epilepsia.

[68]  A. Gambardella,et al.  Mutations and polymorphisms of the CLCN2 gene in idiopathic epilepsy , 2004, Neurology.

[69]  R. Michelucci,et al.  A de novo LGI1 mutation in sporadic partial epilepsy with auditory features , 2004, Annals of Neurology.

[70]  M. T. Medina,et al.  Mutations in EFHC1 cause juvenile myoclonic epilepsy , 2004, Nature Genetics.

[71]  Luigi Ferini-Strambi,et al.  Autosomal dominant nocturnal frontal lobe epilepsy , 2004, Journal of Neurology.

[72]  Steven Petrou,et al.  GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. , 2004, Human molecular genetics.

[73]  W. Hauser,et al.  LGI1 mutations in autosomal dominant partial epilepsy with auditory features , 2004, Neurology.

[74]  I. Scheffer,et al.  Genetic variation of CACNA1H in idiopathic generalized epilepsy , 2004, Annals of neurology.

[75]  I. Scheffer,et al.  Benign familial neonatal‐infantile seizures: Characterization of a new sodium channelopathy , 2004, Annals of neurology.

[76]  C. van Broeckhoven,et al.  A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy , 2003, Neurology.

[77]  R M Gardiner,et al.  Sodium channel α1-subunit mutations in severe myoclonic epilepsy of infancy and infantile spasms , 2003, Neurology.

[78]  J. Hottenga,et al.  Novel mutations in the Na+, K+‐ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions , 2003, Annals of neurology.

[79]  O. Evgrafov,et al.  BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy. , 2003, American journal of human genetics.

[80]  Zhijian Yao,et al.  Association between genetic variation of CACNA1H and childhood absence epilepsy , 2003, Annals of neurology.

[81]  E. Bertini,et al.  Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy , 2003, Neurology.

[82]  E. Haan,et al.  Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. , 2003, American journal of human genetics.

[83]  Ying-Hui Fu,et al.  A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures , 2002, Annals of neurology.

[84]  I. Scheffer,et al.  Sodium-channel defects in benign familial neonatal-infantile seizures , 2002, The Lancet.

[85]  O. Steinlein,et al.  LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizures , 2002, Annals of neurology.

[86]  Uwe Runge,et al.  A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. , 2002, Archives of neurology.

[87]  Wei-Yang Lu,et al.  Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy , 2002, Nature Genetics.

[88]  I. Scheffer,et al.  Generalized epilepsy with febrile seizures plus: Mutation of the sodium channel subunit SCN1B , 2002, Neurology.

[89]  R. Siebert,et al.  Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. , 2002, Human molecular genetics.

[90]  Steven Petrou,et al.  Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. , 2002, American journal of human genetics.

[91]  W. Hauser,et al.  Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features , 2002, Nature Genetics.

[92]  Michael G Hanna,et al.  Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel , 2001, The Lancet.

[93]  W Burke,et al.  Categorizing genetic tests to identify their ethical, legal, and social implications. , 2001, American journal of medical genetics.

[94]  K. Yamakawa,et al.  Nav1.1 mutations cause febrile seizures associated with afebrile partial seizures , 2001, Neurology.

[95]  L. Lagae,et al.  De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. , 2001, American journal of human genetics.

[96]  Michel Baulac,et al.  First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the γ2-subunit gene , 2001, Nature Genetics.

[97]  I. Scheffer,et al.  Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus. , 2001, American journal of human genetics.

[98]  A. James Barkovich,et al.  Malformations of cortical development and epilepsy , 2001, Brain and Development.

[99]  A. Ballabio,et al.  The nicotinic receptor β2 subunit is mutant in nocturnal frontal lobe epilepsy , 2000, Nature Genetics.

[100]  A. Spauschus,et al.  Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability , 2000, Annals of neurology.

[101]  I. Scheffer,et al.  A de novo mutation in sporadic nocturnal frontal lobe epilepsy , 2000, Annals of Neurology.

[102]  T. Mayer,et al.  Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. , 2000, American journal of human genetics.

[103]  Stéphanie Baulac,et al.  Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2 , 2000, Nature Genetics.

[104]  A. Spauschus,et al.  A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. , 1999, Brain : a journal of neurology.

[105]  A. Spauschus,et al.  Functional Characterization of a Novel Mutation in KCNA1 in Episodic Ataxia Type 1 Associated with Epilepsy , 1999, Annals of the New York Academy of Sciences.

[106]  Samuel F. Berkovic,et al.  Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel ß1 subunit gene SCN1B , 1998, Nature Genetics.

[107]  Douglas C. Wallace,et al.  Radicals r'aging , 1998, Nature Genetics.

[108]  S. Berkovic,et al.  A potassium channel mutation in neonatal human epilepsy. , 1998, Science.

[109]  I. Scheffer,et al.  A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy , 1995, Nature Genetics.

[110]  J. S. Alper,et al.  The genetic analysis of human behavior: a new era? , 1992, Social science & medicine.

[111]  S. Sisodiya,et al.  Epilepsy pharmacogenetics. , 2009, Pharmacogenomics.

[112]  S. Moshé,et al.  Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy. , 2005, American journal of human genetics.

[113]  L. Ferini-Strambi,et al.  Autosomal dominant nocturnal frontal lobe epilepsy , 2004, Journal of Neurology.

[114]  I. Scheffer,et al.  Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy , 2002, Nature Genetics.

[115]  I. Scheffer,et al.  CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. , 2001, American journal of human genetics.

[116]  David A. Williams,et al.  Mutant GABAA receptor γ2-subunit in childhood absence epilepsy and febrile seizures , 2001, Nature Genetics.

[117]  Robin J. Leach,et al.  A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family , 1998, Nature Genetics.

[118]  Mark Leppert,et al.  A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns , 1998, Nature Genetics.