**3. Diagnostic testing in epilepsy genetic clinical practice: proposed workflow**

and 4.6% of patients in a study by Yang et al. [105]. NGS testing may be the only opportunity for diagnosis in life-limiting disorders or in postmortem setting when DNA samples can be limited [41]. Finally, novel disease genes are also not an unusual finding in a clinical practice with WES or WGS testing and were found in 3.3–8.1% of patients in various studies [37, 40, 102, 104] and 23% of patients in FORGE study [22]. Importantly, each successful discovery opens horizons for diagnostic, preventive, and therapeutic opportunities for the corresponding disease [33]. The most common reasons for patients not to receive a diagnosis prior to WES in FORGE study were a significant genetic heterogeneity of the interrogated disorder, atypical presentation, missed diagnosis by other methods, and novel and ultrarare disorders [22].

Given all the complexities of genetic diseases' clinical presentation and phenotype evaluation, choice of the right genetic testing strategies, interpretation of genetic testing results and their communication to patients and families, genetic counseling regarding further risks and possibilities for prenatal diagnostics, and finally, sensitive and respectful consideration of all the psychosocial/bioethical aspects related to genetic diseases and genetic/genomic testing, the role of a clinical geneticist in the whole pathway of genetic diagnostics of a patient with epilepsy or seizures is undisputed. In the contemporary clinical genetic practice, geneticists must possess not only proper clinical skills but also abilities to use a vast range of bioinformatic tools and databases and have a deep knowledge of not only clinical genetics but also multiple

Success of both targeted genetic testing and untargeted NGS approach is crucially dependent on the completeness and accuracy of phenotype evaluation [24, 26, 106]. Given the vast phenotypic variability of human monogenic and chromosomal disorders involving epilepsy or seizures, illustrated by EpiGene database (http://www.kimg.eu/en/tools/epigene-database), phenotyping of patient may include not only neurological examinations and tests but also thorough assessment of dysmorphic features, cutaneous signs, congenital malformations, variable symptoms of any other organ or organ system impairment, results of prior laboratory/radiological and other testings, information on cognitive functioning, etc. Family history/ genealogy data may be helpful. Contrary to expectations of some people, with the advent of NGS testing, importance of thorough phenotyping did not diminish [106]. On the contrary, the final stages of variant annotation (gene level) and accurate variant interpretation are crucially dependent on the full phenotypic picture of a patient. Besides, as in many cases, phenotype-driven diagnostic hypothesis is not raised; a constant contact between laboratory and clinics with possibilities to perform a "reverse phenotyping" or "genotype to phenotype" correlation of identified variants is very important. Indeed, diagnostic yields were lower in studies where exome sequencing and interpretation of results were done in laboratories separate from clinical units (e.g., gene panel of 447 genes in 148 patients with a suspicion of mitochondrial diseases gave a diagnostic yield of only 9.4% in a separate laboratory [107] in comparison to 39% yield in a group of 109 patients tested with a gene panel of 238 genes in a laboratory connected to clinical unit [55]). In a recently published study, discordance rate in the initial interpretation of causal variants between laboratory and clinical geneticists was approximately 10% [108]. Finally, standardization and automation of phenotyping may be

**2.9. The role of a clinical geneticist**

56 Seizures

genetic and genomic testing specificities.

facilitated by tools like PhenoTips [109].

Currently, there are no recommendations or guidelines for genetic testing in epilepsy patients addressing specificities of NGS technologies [28]. We propose a simplified diagnostic workflow based on expected diagnostic yields and cost-effectiveness in various clinical situations encountered in epilepsy genetic clinical practice (**Figure 1**). The choice of a diagnostic route that is the most appropriate in a given clinical situation requires not only deep knowledge of

**Figure 1.** Provisional diagnostic workflow in patients with epilepsy or seizures.

a genetic architecture and a molecular pathology of a disorder; multiple technical specificities and limitations/disadvantages of diagnostic methods must be taken into consideration.

[9] Helbig I, Tayoun AA. Understanding genotypes and phenotypes in epileptic encepha-

Diagnostic Testing in Epilepsy Genetics Clinical Practice http://dx.doi.org/10.5772/intechopen.69930 59

[10] Malek N, Stewart W, Greene J. The progressive myoclonic epilepsies. Practical

[11] Busch RM, Najm I, Hermann BP, Eng C. Genetics of cognition in epilepsy. Epilepsy

[12] Guerrini R, Dobyns WB. Malformations of cortical development: Clinical features and genetic causes. Lancet Neurology. 2014 Jul;**13**(7):710-726. DOI: 10.1016/S1474-4422(14)

[13] Longo MG, Vairo F, Souza CF, Giugliani R, Vedolin LM. Brain imaging and genetic risk in the pediatric population, part 1: Inherited metabolic diseases. Neuroimaging Clinics

[14] Longo MG, Félix TM, Ashton-Prolla P, Vedolin LM. Brain imaging and genetic risk in the pediatric population, part 2: Congenital malformations of the central nervous system. Neuroimaging Clinics of North America. 2015 Feb;**25**(1):53-67. DOI: 10.1016/j.

[15] Patel J, Mercimek-Mahmutoglu S. Epileptic encephalopathy in childhood: A stepwise approach for identification of underlying genetic causes. Indian Journal of Pediatrics.

[16] Weiss MM, Van der Zwaag B, Jongbloed JD, Vogel MJ, Brüggenwirth HT, Lekanne Deprez RH, et al. Best practice guidelines for the use of next-generation sequencing applications in genome diagnostics: A national collaborative study of Dutch genome diagnostic laboratories. Human Mutation. 2013 Oct;**34**(10):1313-1321. DOI: 10.1002/

[17] Mercimek-Mahmutoglu S, Patel J, Cordeiro D, Hewson S, Callen D, Donner EJ, et al. Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia.

[18] López-Pisón J, García-Jiménez MC, Monge-Galindo L, Lafuente-Hidalgo M, Pérez-Delgado R, García-Oguiza A, Peña-Segura JL. Our experience with the aetiological diagnosis of global developmental delay and intellectual disability: 2006-2010. Neurologia.

[19] Soden SE, Saunders CJ, Willig LK, Farrow EG, Smith LD, Petrikin JE, et al. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Science Translational Medicine. 2014 Dec 3;**6**(265):265ra168.

[20] Monroe GR, Frederix GW, Savelberg SM, de Vries TI, Duran KJ, van der Smagt JJ, et al. Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability. Genetics in Medicine. 2016 Sep;**18**(9):949-956.

Neurology. 2015 Jun;**15**(3):164-171. DOI: 10.1136/practneurol-2014-000994

Behaviour. 2014 Dec;**41**:297-306. DOI: 10.1016/j.yebeh.2014.05.026

of North America. 2015 Feb;**25**(1):31-51. DOI: 10.1016/j.nic.2014.09.004

2016 Oct;**83**(10):1164-1174. DOI: 10.1007/s12098-015-1979-9

2015 May;**56**(5):707-716. DOI: 10.1111/epi.12954

2014 Sep;**29**(7):402-407. DOI: 10.1016/j.nrl.2013.10.006

DOI: 10.1126/scitranslmed.3010076

DOI: 10.1038/gim.2015.200

lopathies. Molecular Syndromology. 2016 Sep;**7**(4):172-181

70040-7

nic.2014.09.003

humu.22368
