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Germline and Somatic Mutations in the MTOR Gene in Focal Cortical Dysplasia and Epilepsy

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Germline and Somatic Mutations in the MTOR Gene in Focal Cortical Dysplasia and Epilepsy Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy Rikke S. Møller, PhD* Sarah Weckhuysen, MD, PhD* ABSTRACT Mathilde Chipaux, MD, Objective: To assess the prevalence of somatic MTOR mutations in focal cortical dysplasia (FCD) PhD and of germline MTOR mutations in a broad range of epilepsies. Elise Marsan, MSc Methods: We collected 20 blood-brain paired samples from patients with FCD and searched for Valerie Taly, PhD somatic variants using deep-targeted gene panel sequencing. Germline mutations in MTOR were E. Martina Bebin, MD, assessed in a French research cohort of 93 probands with focal epilepsies and in a diagnostic MPA Danish cohort of 245 patients with a broad range of epilepsies. Data sharing among collaborators Susan M. Hiatt, PhD allowed us to ascertain additional germline variants in MTOR. Jeremy W. Prokop, PhD Kevin M. Bowling, PhD Results: We detected recurrent somatic variants (p.Ser2215Phe, p.Ser2215Tyr, and Davide Mei, MSc p.Leu1460Pro) in the MTOR gene in 37% of participants with FCD II and showed histologic Valerio Conti, PhD evidence for activation of the mTORC1 signaling cascade in brain tissue. We further identified Pierre de la Grange, PhD 5 novel de novo germline missense MTOR variants in 6 individuals with a variable phenotype from Sarah Ferrand-Sorbets, focal, and less frequently generalized, epilepsies without brain malformations, to macrocephaly, MD with or without moderate intellectual disability. In addition, an inherited variant was found in Georg Dorfmüller, MD a mother–daughter pair with nonlesional autosomal dominant nocturnal frontal lobe epilepsy. Virginie Lambrecq, MD, Conclusions: Our data illustrate the increasingly important role of somatic mutations of the MTOR PhD gene in FCD and germline mutations in the pathogenesis of focal epilepsy syndromes with and Line H.G. Larsen, MSc without brain malformation or macrocephaly. Neurol Genet 2016;2:e118; doi: 10.1212/ Eric Leguern, MD, PhD NXG.0000000000000118 Renzo Guerrini, MD, FRCP GLOSSARY Guido Rubboli, MD ADHD 5 attention-deficit/hyperactivity disorder; ADNFLE 5 autosomal dominant nocturnal frontal lobe epilepsy; CADD 5 Gregory M. Cooper, PhD Combined Annotation Dependent Depletion; DEPDC5 5 Dishevelled, Egl-10, and Pleckstrin domain-containing protein 5; DEPTOR 5 domain-containing mTOR-interacting protein; dPCR 5 digital PCR; ELM 5 eukaryotic linear motif; ExAC 5 Stéphanie Baulac, PhD Exome Aggregation Consortium; FAT 5 FRAP, ATM, TRRAP; FCD 5 focal cortical dysplasia; GATOR1 5 GTPase-activating protein activity toward Rags complex 1; HEAT 5 huntingtin, elongation factor 3, protein phosphatase 2A, and TOR1; H&E 5 hematoxylin and eosin; mTOR 5 mammalian target of rapamycin; NPRL 5 nitrogen permease regulator–like. Correspondence to Dr. Baulac: A new class of genes encoding components of the mechanistic target of the rapamycin (mTOR) signal [email protected] transduction pathway has recently been involved in familial focal epilepsies.1 Dishevelled, Egl-10, and Pleckstrin domain-containing protein 5 (DEPDC5) together with nitrogen permease regulator–like Supplemental data 2 (NPRL2) and nitrogen permease regulator–like 3 (NPRL3) form the GTPase-activating at Neurology.org/ng *These authors contributed equally as coauthors. From The Danish Epilepsy Centre Filadelfia (R.S.M., G.R.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Sorbonne Universités (S.W., E.M., V.L., E.L., S.B.), UPMC Univ Paris 06 UMR S 1127, Inserm U1127, CNRS UMR 7225, AP-HP, Institut du cerveau et la moelle (ICM)–Hôpital Pitié-Salpêtrière, Paris, France; Epilepsy Unit (S.W., V.L.), AP-HP Groupe hospitalier Pitié-Salpêtrière, Paris, France; Neurogenetics Group (S.W.), VIB-Department of Molecular Genetics; Laboratory of Neurogenetics (S.W.), Institute Born-Bunge, University of Antwerp, Belgium; Department of Neurology (S.W.), University Hospital Antwerp, Belgium; Department of Pediatric Neurosurgery (M.C., S.F.-S., G.D.), Fondation Rothschild, Paris, France; Université Paris Sorbonne Cité (V.T.), INSERM UMR-S1147 MEPPOT, CNRS SNC5014, Centre Universitaire des Saints-Pères, Paris, France; Department of Neurology (E.M.B.), University of Alabama at Birmingham; HudsonAlpha Institute for Biotechnology (S.M.H., J.W.P., K.M.B., G.M.C.), Huntsville, AL; Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories (D.M., V.C., R.G.), Neuroscience Department, A Meyer Children’s Hospital, University of Florence, Florence, Italy; Genosplice (P.d.l.G.), Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Amplexa Genetics (L.H.G.L.), Odense, Denmark; Department of Genetics and Cytogenetics (E.L., S.B.), AP-HP Groupe hospitalier Pitié-Salpêtrière, Paris, France; and University of Copenhagen (G.R.), Denmark. Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing charge was paid by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY- NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially. Neurology.org/ng © 2016 American Academy of Neurology 1 ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. protein activity toward Rags complex 1 from FCD IIa to megalencephaly.18 Evi- (GATOR1), an amino acid–sensitive dence for mTORC1 hyperactivity was inhibitor of mTORC1.2 Germline muta- shown in resected brain tissue after epilepsy tions in the GATOR1-encoding genes surgery.15,16,18 (DEPDC5, NPRL2,andNPRL3)havebeen Rare germline heterozygous missense muta- reported in numerous familial and sporadic tions in MTOR have also been reported in focal epilepsies.3–9 In addition to nonlesion- a subset of patients with megalencephaly, al focal epilepsies, GATOR1 mutations intellectual disability, and seizures.18–22 have also been recognized in epilepsies asso- In this study, we compared the prevalence ciated with developmental cortical malfor- and type of MTOR somatic mutations in mations such as focal cortical dysplasia a cohort of FCD patients, with MTOR germ- (FCD), in particular FCD type IIb (with line mutations in cohorts of patients with epi- balloon cells) and IIa (without balloon lepsy with or without brain malformations. cells).10–14 Recent studies reported brain somatic METHODS Patients. As a first step, 3 different cohorts were missense mutations in the MTOR gene itself screened for pathogenic variants in MTOR (figure 1). in 3 patients with hemimegalencephaly,12 in First, for mosaic mutation detection, we prospectively re- 12/77 (15%) with FCD II,15 in 6/13 (46%) cruited a cohort of 20 participants with FCD who underwent surgery to treat drug-resistant focal epilepsy. The cohort consisted 16 17 with FCD IIb, in 1 with FCD IIa, and in of 18 children operated at the Fondation Rothschild (Paris, 10 with various developmental disorders France) between 2015 and 2016 and 2 adult participants Figure 1 Workflow of the study FCD 5 focal cortical dysplasia; MCD 5 malformation of cortical development. 2 Neurology: Genetics ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. operated at the Pitié-Salpêtrière hospital (Paris, France) and at the Picoliter droplet-based digital PCR. Somatic p.Ser2215Phe Swiss Epilepsy Center (Zurich, Switzerland). and p.Ser2215Tyr mutations were confirmed by digital PCR Second, for germline mutation detection, we included a previ- (dPCR). Genomic DNA was extracted from a second piece of ously described French research cohort of 93 unrelated European the same tissue block from participants 1–5 and was tested for patients with focal epilepsy, including 55 probands with familial the presence of specific MTOR mutations. No brain tissue of focal epilepsy, 9 sporadic patients with nonlesional focal epilepsy, patient 6 was left. Custom LNA double-dye probes designed to 14 patients with familial focal epilepsy, and at least one family detect both mutant alleles c.6644C.T (p.Ser2215Phe) and member with FCD, and 15 sporadic patients with focal epilepsy c.6644C.A (p.Ser2215Tyr) and wild-type were purchased from and FCD.8 In this cohort, 7 individuals were previously shown to Eurogentec. RainDrop Digital PCR system (Raindance Tech- have a mutation in one of the GATOR1-encoding genes.8 We nologies Billerica) was used as previously described23 with the also screened a third Danish cohort of 245 unrelated patients with following modifications: dPCR was performed with Taqman various forms of childhood-onset epilepsies referred for diagnostic Universal Master Mix (life Technologies), 125 nM final con- gene panel testing. The phenotypic spectrum within this cohort centration of both probes and 250 nM final concentration of was broad and ranged from benign familial neonatal/infantile primers. epilepsy to generalized epilepsies, focal epilepsies, and severe epi- Targeted gene panels for detection of germline variants. In leptic encephalopathies. the French cohort of 93 patients with focal epilepsies, the search In addition, we collected 5 previously unreported patients for heterozygous variants in genomic blood DNA was accom- with MTOR mutations through data sharing with Italy and the plished by a previously reported methodology and research epi- United States. The Italian cohort consisted of 40
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