OBJECTIVE: Although genetic causes of drug-resistant focal epilepsy and selected focal malformations of cortical development (MCD) have been described, a limited number of studies comprehensively analysed genetic diagnoses in patients undergoing pre-surgical evaluation, their outcomes and the effect of genetic diagnosis on surgical strategy. METHODS: We analysed a prospective cohort of children enrolled in epilepsy surgery program over January 2018-July 2022. The majority of patients underwent germline and/or somatic genetic testing. We searched for predictors of surgical outcome and positive result of germline genetic testing. RESULTS: Ninety-five patients were enrolled in epilepsy surgery program and 64 underwent resective epilepsy surgery. We ascertained germline genetic diagnosis in 13/74 patients having underwent germline gene testing (pathogenic or likely pathogenic variants in CHRNA4, NPRL3, DEPDC5, FGF12, GRIA2, SZT2, STXBP1) and identified three copy number variants. Thirty-five patients underwent somatic gene testing; we detected 10 pathogenic or likely pathogenic variants in genes SLC35A2, PTEN, MTOR, DEPDC5, NPRL3. Germline genetic diagnosis was significantly associated with the diagnosis of focal epilepsy with unknown seizure onset. SIGNIFICANCE: Germline and somatic gene testing can ascertain a definite genetic diagnosis in a significant subgroup of patients in epilepsy surgery programs. Diagnosis of focal genetic epilepsy may tip the scales against the decision to proceed with invasive EEG study or surgical resection; however, selected patients with genetic focal epilepsies associated with MCD may benefit from resective epilepsy surgery and therefore, a genetic diagnosis does not disqualify patients from presurgical evaluation and epilepsy surgery.

• Klíčová slova
• Focal drug-resistant epilepsy, Genetic testing, Malformations of cortical development, Paediatric epilepsy surgery, mTOR,
• MeSH
• dítě MeSH
• epilepsie parciální * komplikace   MeSH
• epilepsie * genetika   chirurgie   komplikace   MeSH
• fibroblastové růstové faktory genetika   MeSH
• genetické testování MeSH
• lidé MeSH
• malformace mozkové kůry * genetika   MeSH
• prospektivní studie MeSH
• proteiny aktivující GTPasu genetika   MeSH
• proteiny nervové tkáně genetika   MeSH
• refrakterní epilepsie * diagnóza   genetika   chirurgie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• FGF12 protein, human MeSH Prohlížeč
• fibroblastové růstové faktory MeSH
• NPRL3 protein, human MeSH Prohlížeč
• proteiny aktivující GTPasu MeSH
• proteiny nervové tkáně MeSH
• SZT2 protein, human MeSH Prohlížeč

• MeSH
• lidé MeSH
• missense mutace MeSH
• nemoci svalů * patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH

BACKGROUND: Variants of GATOR1-genes represent a recognised cause of focal cortical dysplasia (FCD), the most common structural aetiology in paediatric drug-resistant focal epilepsy. Reports on familial cases of GATOR1-associated FCD are limited, especially with respect to epilepsy surgery outcomes. METHODS: We present phenotypical manifestations of four unrelated patients with drug-resistant focal epilepsy, FCD and a first-degree relative with epilepsy. All patients underwent targeted gene panel sequencing as a part of the presurgical work up. Literature search was performed to compare our findings to previously published cases. RESULTS: The children (probands) had a more severe phenotype than their parents, including drug-resistant epilepsy and developmental delay, and they failed to achieve seizure freedom post-surgically. All patients had histopathologically confirmed FCD (types IIa, IIb, Ia). In Patient 1 and her affected father, we detected a known pathogenic NPRL2 variant. In patients 2 and 3 and their affected parents, we found novel likely pathogenic germline DEPDC5 variants. In family 4, we detected a novel variant in NPRL3. We identified 15 additional cases who underwent epilepsy surgery for GATOR1-associated FCD, with a positive family history of epilepsy in the literature; in 8/13 tested, the variant was inherited from an asymptomatic parent. CONCLUSION: The presented cases displayed a severity gradient in phenotype with children more severely affected than the parents. Although patients with GATOR1-associated FCD are considered good surgical candidates, post-surgical seizure outcome was poor in our familial cases, suggesting that accurate identification of the epileptogenic zone may be more challenging in this subgroup of patients.

• Klíčová slova
• Epilepsy surgery, Focal cortical dysplasia, Focal epilepsy, GATOR1, Malformations of cortical development, Targeted gene panel sequencing,
• MeSH
• dítě MeSH
• fenotyp MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• malformace mozkové kůry genetika   chirurgie   MeSH
• mladiství MeSH
• nádorové supresorové proteiny genetika   MeSH
• proteiny aktivující GTPasu genetika   MeSH
• refrakterní epilepsie genetika   MeSH
• retrospektivní studie MeSH
• zárodečné mutace MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• DEPDC5 protein, human MeSH Prohlížeč
• nádorové supresorové proteiny MeSH
• NPRL2 protein, human MeSH Prohlížeč
• NPRL3 protein, human MeSH Prohlížeč
• proteiny aktivující GTPasu MeSH