**Diagnostic Testing in Epilepsy Genetics Clinical Practice**

**Diagnostic Testing in Epilepsy Genetics Clinical Practice**

DOI: 10.5772/intechopen.69930

Birute Tumiene, Algirdas Utkus, Vaidutis Kučinskas, Aleš Maver and Borut Peterlin Kučinskas, Aleš Maver and Borut Peterlin Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Birute Tumiene, Algirdas Utkus, Vaidutis

http://dx.doi.org/10.5772/intechopen.69930

#### **Abstract**

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32 Seizures

Changing landscape of epilepsy genetic testing gives vast opportunities to both patients and clinicians. Significance of precise genetic diagnosis in patients affected by epilepsy cannot be overestimated: it not only gives the opportunities of personalized therapeutical approaches but is also associated with multiple additional benefits for patients, their families, and society. Although the burden of Mendelian and chromosomal diseases amenable to current diagnostic testing measures is unknown, recently, we have comprised a database of more than 880 human genes associated with monogenic diseases involving epilepsy or seizures, EpiGene database (http://www.kimg.eu/en/tools/epigene-database). Besides, more than 50 chromosomal syndromes are related to epilepsy or seizures. Currently, there are no recommendations or guidelines for genetic testing in epilepsy patients addressing specificities of next-generation sequencing technologies. However, as every genetic testing modality has its own characteristics of specificity/sensitivity, range of clinical indications, and possible bioethical and psychosocial implications, genetic testing in epilepsies must be properly selected and applied along with proper clinical genetics/genetic counseling services. In this chapter, an overview of genetic testing modalities and workflows taking into account genetic architecture of epilepsies is given, and practical aspects of genetic testing in epilepsies, including advantages/limitations and clinical utility of tests, are discussed.

**Keywords:** algorithm, diagnostic yield, clinical utility, next-generation sequencing, exome, molecular karyotyping

#### **1. Introduction**

Recent genetic revolution due to advancements in genomic testing technologies evolves into fundamental changes in clinical practice of not only clinical genetics but also other medical specialties. Changing landscape of epilepsy genetic testing gives vast opportunities

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

to both patients and clinicians, however, not without additional challenges. Although the burden of Mendelian and chromosomal diseases, amenable to current diagnostic testing measures, among all patients with epilepsy or seizures is currently unknown, significance of precise genetic diagnosis in patients affected by epilepsy cannot be overestimated: it not only gives the opportunities of personalized therapeutical approaches but is also associated with multiple additional benefits for patients, their families, and society. However, as every genetic testing modality has its own characteristics of specificity/sensitivity, range of clinical indications, and possible bioethical and psychosocial implications, genetic testing in epilepsies must be properly selected and applied along with proper clinical genetics/ genetic counseling services. In this chapter, an overview of genetic testing modalities and workflows taking into account genetic architecture of epilepsies is given, and practical aspects of genetic testing in epilepsies, including advantages/limitations and clinical utility of tests, are discussed.

For many years the prevailing "dogma" was that epilepsy is a channelopathy [7], and the first unveiled channelopathy due to mutations in nicotinic acetylcholine receptor gene CHRNA4 became one of long-standing prototypes of genetic epilepsies [8]. Multiple channelopathies presenting with variable phenotypes are currently known (e.g., epileptic encephalopathies (due to mutations in genes HCN1, KCNA2, KCNB1, SCN8A, SLC13A5, STXBP1, and SYN1), benign neonatal seizures (genes KCNQ2 and KCNQ3), a spectrum of generalized epilepsy plus to Dravet syndrome due to SCN1A gene mutations). One of the major targets of current epilepsy genetic research is a group of disorders defined as epileptic encephalopathies; more than 70 genes have been related to this phenotype, explaining 20–25% of epileptic encephalopathy cases [9]. Relatively, homogenous clinical presentation of this epilepsy phenotype may aid in the recruitment of patients for genetic testing in both clinical setting and research. Distinct group of inherited epilepsies comprises progressive myoclonic epilepsies—an umbrella term for childhood- or adolescence-onset conditions characterized by myoclonus and relentlessly progressive neurodegeneration [10], including Unverricht-Lundborg, Lafora disease, neuronal ceroid lipofuscinoses, type 1 sialidosis, GM2 gangliosidosis, Gaucher disease, MERRF, and some other mitochondrial diseases—and other progressive myoclonic epilepsies due to mutations in genes ASAH1, CERS1, GOSR2, KCNC1, PRICKLE1, PRICKLE2, and SERPINI1. Other epilepsy phenotypes are much more heterogeneous. Surprisingly, the most extensive group of monogenic epilepsies is inherited metabolic diseases, encompassing 373 genes (42% of all genes) in EpiGene database (discussed more extensively below). The most frequent genetic epilepsy-associated symptoms are psychomotor retardation and intellectual disability (419 and 386 EpiGene diseases, respectively). Indeed, epilepsy is a frequent comorbidity (20–30% of cases) of syndromic and non-syndromic intellectual disabilities and vice versa; 30% of patients with epilepsy have intellectual disabilities [11]. Epilepsy or seizure is an accompanying symptom of a vast range of inherited neuromuscular and neurologic diseases, sometimes preceding development of other neurologic symptoms such as spastic paraplegias (SPG6, SPG11, SPG18, SPG35, SPG47, SPG49, SPG50, SPG51, and SPG52), muscular dystrophies (dystroglycanopathies due to mutations in genes B4GAT1, DAG1, FKRP, FKTN, GMPPB, ISPD, LARGE, POMGNT1, POMK, POMT1, and POMT2, congenital megaconial dystrophy (CHKB), merosin-deficient muscular dystrophy (LAMA2)), hereditary ataxias (spastic ataxia 5, ataxia with oculomotor apraxia (APTX), and ataxia-telangiectasia (ATM), spinocerebellar ataxias (SCA) SCA10 (ATXN10), SCA13 (GRM1), SCA15 (KIAA0226), SCA20 (SNX14), SCA17 (TBP), SCA12 (WWOX)), demyelinating diseases (e.g., hypomyelinating leukodystrophy due to mutations in genes AIMP1, FAM126A, GJC2, HSPD1, POLR3A, TUBB4A, leukoencephalopathy with vanishing white matter, megalencephalic leukoencephalopathy with subcortical cysts (HEPACAM, MLC1), adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe disease); and hereditary dystonias (dentatorubropallidoluysian atrophy, dystonia 24 (ANO3), juvenile onset Parkinson disease 19 (DNAJC6), infantile striatonigral degeneration (NUP62)). Paving embryonic neurodevelopmental processes, epilepsy or seizures are very frequent symptoms in syndromes with malformations of cortical development, including megalencephalies (AKT3, EZH2, FGFR3, and PIK3CA), lissencephalies (ARX, RELN, VLDLR, ACTB, ACTG1, DCX, DYNC1H1, KIF2A, LIS1, TUBA1A, TUBB2B, and TUBG1), polymicrogyrias (NDE1, WDR62, FH, KIAA1279, NSDHL, OCLN, GPSM2, RAB3GAP1, RAB3GAP2, RAB18,

Diagnostic Testing in Epilepsy Genetics Clinical Practice http://dx.doi.org/10.5772/intechopen.69930 35
