Møller Rikke S, Weckhuysen Sarah, Chipaux Mathilde, Marsan Elise, Taly Valerie, Bebin E Martina, Hiatt Susan M, Prokop Jeremy W, Bowling Kevin M, Mei Davide, Conti Valerio, de la Grange Pierre, Ferrand-Sorbets Sarah, Dorfmüller Georg, Lambrecq Virginie, Larsen Line H G, Leguern Eric, Guerrini Renzo, Rubboli Guido, Cooper Gregory M, Baulac Stéphanie
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.
Neurol Genet. 2016 Oct 31;2(6):e118. doi: 10.1212/NXG.0000000000000118. eCollection 2016 Dec.
To assess the prevalence of somatic mutations in focal cortical dysplasia (FCD) and of germline mutations in a broad range of epilepsies.
We collected 20 blood-brain paired samples from patients with FCD and searched for somatic variants using deep-targeted gene panel sequencing. Germline mutations in were assessed in a French research cohort of 93 probands with focal epilepsies and in a diagnostic Danish cohort of 245 patients with a broad range of epilepsies. Data sharing among collaborators allowed us to ascertain additional germline variants in .
We detected recurrent somatic variants (p.Ser2215Phe, p.Ser2215Tyr, and p.Leu1460Pro) in the gene in 37% of participants with FCD II and showed histologic evidence for activation of the mTORC1 signaling cascade in brain tissue. We further identified 5 novel de novo germline missense variants in 6 individuals with a variable phenotype from focal, and less frequently generalized, epilepsies without brain malformations, to macrocephaly, with or without moderate intellectual disability. In addition, an inherited variant was found in a mother-daughter pair with nonlesional autosomal dominant nocturnal frontal lobe epilepsy.
Our data illustrate the increasingly important role of somatic mutations of the gene in FCD and germline mutations in the pathogenesis of focal epilepsy syndromes with and without brain malformation or macrocephaly.
评估局灶性皮质发育不良（FCD）中体细胞突变的患病率以及广泛癫痫类型中胚系突变的患病率。
我们收集了20例FCD患者的血脑配对样本，并使用深度靶向基因panel测序寻找体细胞变异。在一个由93例局灶性癫痫先证者组成的法国研究队列以及一个由245例患有广泛癫痫类型的患者组成的丹麦诊断队列中评估了胚系突变。合作者之间的数据共享使我们能够确定更多的胚系变异。
我们在37%的FCD II型参与者中检测到基因中的复发性体细胞变异（p.Ser2215Phe、p.Ser2215Tyr和p.Leu1460Pro），并在脑组织中显示出mTORC1信号级联激活的组织学证据。我们进一步在6名具有可变表型的个体中鉴定出5种新的新生胚系错义变异，这些个体的表型从局灶性癫痫（较少见全身性癫痫）、无脑畸形，到巨头畸形，伴有或不伴有中度智力残疾。此外，在一对患有非病变性常染色体显性夜间额叶癫痫的母女中发现了一个遗传变异。
我们的数据说明了基因的体细胞突变在FCD中的作用日益重要，以及胚系突变在伴有或不伴有脑畸形或巨头畸形的局灶性癫痫综合征发病机制中的作用。
