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Novel GABRG2 Mutations Cause Familial Febrile Seizures

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Novel GABRG2 Mutations Cause Familial Febrile Seizures Novel GABRG2 mutations cause familial febrile seizures Morgane Boillot ABSTRACT Mélanie Morin-Brureau, Objective: To identify the genetic cause in a large family with febrile seizures (FS) and temporal PhD lobe epilepsy (TLE) and subsequently search for additional mutations in a cohort of 107 families Fabienne Picard, MD, with FS, with or without epilepsy. PhD Methods: The cohort consisted of 1 large family with FS and TLE, 64 smaller French families re- Sarah Weckhuysen, MD, cruited through a national French campaign, and 43 Italian families. Molecular analyses consisted PhD of whole-exome sequencing and mutational screening. Virginie Lambrecq, MD, * PhD Results: Exome sequencing revealed a p.Glu402fs 3 mutation in the g2subunitoftheGABAA GABRG2 Carlo Minetti, MD, PhD receptor gene ( ) in the large family with FS and TLE. Three additional nonsense and GABRG2 * * * Pasquale Striano, MD, frameshift mutations (p.Arg136 , p.Val462fs 33, and p.Pro59fs 12), 1 missense PhD mutation (p.Met199Val), and 1 exonic deletion were subsequently identified in 5 families of the Federico Zara, PhD follow-up cohort. Michele Iacomino, PhD Conclusions: We report GABRG2 mutations in 5.6% (6/108) of families with FS, with or without Saeko Ishida, PhD associated epilepsy. This study provides evidence that GABRG2 mutations are linked to the FS phe- Isabelle An-Gourfinkel, notype, rather than epilepsy, and that loss-of-function of GABAA receptor g2 subunit is the probable MD, PhD underlying pathogenic mechanism. Neurol Genet 2015;1:e35; doi: 10.1212/NXG.0000000000000035 Mailys Daniau Katia Hardies, PhD GLOSSARY Michel Baulac, MD FS 5 febrile seizures; GEFS1 5 genetic epilepsy with febrile seizures plus; GTCS 5 generalized tonic-clonic seizures; 5 5 5 Olivier Dulac, MD NMD nonsense-mediated-decay system; TCS tonic-clonic seizures; TLE temporal lobe epilepsy. Eric Leguern, MD, PhD Febrile seizures (FS) are the most frequent convulsive event in early infancy, affecting an estimated Rima Nabbout, MD, – 1 PhD 2% 5% of children. They usually occur between 6 months and 5 years of age in the presence of Stéphanie Baulac, PhD fever. The prognosis is usually good, although children who have experienced FS have a higher risk of developing epilepsy later in life. Despite a clear genetic component, the genetics of FS is still poorly 2,3 understood. Sodium channel and GABAA receptor gene mutations have been reported in familial Correspondence to syndromes including FS, such as genetic epilepsy with febrile seizures plus (GEFS1).4 Mutations in Dr. Baulac: [email protected] 3 ion channel genes collectively account for ;15% of GEFS1 families: SCN1B encoding the voltage-gated sodium channel b1subunit,5 SCN1A encoding the a1 subunit of the voltage-gated 6 7 type I sodium channel, and GABRG2 encoding the g2 subunit of the GABAA receptor gene. Mutations in the SCN1A gene are the most frequent cause of GEFS1 to date.8–10 Recently, mutations in STX1B, encoding the presynaptic protein syntaxin-1B, were found in 6 families with FS and epilepsy.11 We performed whole-exome sequencing in a large French family with FS and From Sorbonne Universités (M.B., S.I., M.D., S.B., M.M.-B., E.L., S.W., M.B., V.L., I.A.-G.), UPMC Univ Paris 06, UM 75, ICM; INSERM, U1127 (M.B., S.I., M.D., S.B., M.M.-B., E.L., S.W., M.B., V.L., I.A.-G.), ICM; CNRS (M.B., S.I., M.D., S.B., M.M.-B., E.L., S.W., M.B., V.L., I.A.-G.), UMR 7225, ICM; ICM (M.B., S.I., M.D., S.B., M.M.-B., E.L., S.W., M.B., V.L., I.A.-G.), Paris, France; Department of Neurology (F.P.), University Hospitals of Geneva (HUG), Switzerland; Centre de Reference Épilepsies Rares, Epilepsy Unit (S.W., M.B., V.L., I.A.-G.), and Département de Génétique et de Cytogénétique (E.L.), AP-HP Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Pediatric Neu- rology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Uni- versity of Genova (C.M., P.S.), and Laboratory of Neurogenetics, Department of Neurosciences (F.Z., M.I.), “G. Gaslini” Institute, Genova, Italy; Neurogenetics Group, VIB-Department of Molecular Genetics (K.H.), and Laboratory of Neurogenetics, Institute Born-Bunge (K.H.), University of Antwerp, Belgium; Centre de Reference Épilepsies Rares (O.D., R.N.), Department of Pediatric Neurology, Necker Enfants Malades Hospital, AP-HP, Paris; INSERM (O.D., R.N.), U1129, Necker, Paris, France; and University Paris Descartes (O.D., R.N.), Paris, France. 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 Institut du Cerveau et de la Moelle (ICM). 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 © 2015 American Academy of Neurology 1 ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. temporal lobe epilepsy (TLE) and identified a causality of sequence variants in human disease as outlined.14 . 3 pathogenic frameshift mutation in the GABRG2 Coverage of GABRG2 was satisfactory ( 250 ) except for exon 6, which was subsequently analyzed by traditional Sanger gene. We subsequently identified GABRG2 mu- sequencing. Filtered variants were validated by Sanger sequencing, tations in 5 of 107 families with FS. and segregation was analyzed in all available family members. Impact of mutations was assessed with Alamut version 2.4.3 (Interactive METHODS Patients. The French cohort consisted of 64 fam- Biosoftware). GABRG2 mutations were mapped on the immature 15,16 ilies with FS with or without epilepsy. All families were recruited peptide, according to the current convention. We compared the through a national French campaign on genetic studies of familial frequency of rare nonsynonymous GABRG2 variants (including FS conducted by Généthon in 1998–2000 (J.F. Prud’homme, missense, nonsense, essential splice-site, in-frame Indels) identified Evry, France). Inclusion criterion for this cohort was the presence in patients with epilepsy and those present in 33,370 European of at least 3 family members with FS (with or without associated cases from the publicly available Exome Aggregation Consortium epilepsy) with a transmission compatible with an autosomal dom- (ExAC) database (http://exac.broadinstitute.org) using Fisher exact inant trait. Family members underwent clinical assessment using tests (accessed July 2015). a detailed questionnaire. Information was also obtained retrospec- Linkage analysis. Pairwise LOD scores were calculated using tively from medical records. Probands of all families were negative the MLINK program of the FASTLINK package version 4.1 for SCN1A and SCN1B point mutations. assuming an autosomal dominant trait for FS with disease allele The Italian cohort consisted of 43 families with at least 2 first- frequency of 0.01 and incomplete penetrance of 85%. Because degree relatives with FS, with or without epilepsy. Patient evalu- the frequency of FS in the general population is approximately ation included details on clinical features of seizures (semiology, 2%–5%, we used a phenocopy rate of 3% as previously precipitating factors, duration), family and personal history of reported.17 We considered as affected all individuals with FS. seizures/epilepsy, and developmental milestones. All the probands were negative for SCN1A mutations. CGH array. CGH array was performed in the 43 probands of the Italian cohort using a custom 105K Agilent CGH array con- Standard protocol approvals, registrations, and patient taining 44K backbone genome-wide probes and approximately consents. Written informed consent was obtained from all par- 60K high-density probes spanning 440 genes encoding for ion ticipants (or the parents of minors). The study was performed channels (list available on request) according to previously with the approval of the Cochin-Port-Royal Hospital Ethics described protocols and bioinformatics pipelines.18 Committee and the G. Gaslini Institute (No. 003771-35). Whole-exome sequencing. Exome sequencing was performed RESULTS Exome sequencing. Exome sequencing re- on genomic DNA from peripheral blood of 3 affected members vealed a pathogenic mutation in GABRG2. Clinical (A/II-1, A/II-4, and A/II-9) of family A. Targeted exome features of family A were described previously.19 This sequencing, library preparation, capture (Human All exon kit large 5-generation French family included 9 individuals 1 V4 UTRs, 70 Mb, Agilent, Interactive Biosoftware, Rouen, with seizures (table). All 9 patients presented simple FS France), sequencing, and variant detection and annotation were in early childhood (age at onset range: 12 months to performed by IntegraGen (Evry, France) using a previously described procedure.12 Variants with low quality (,20) and 3 years), 7 of 9 individuals subsequently developed low VQSLOD (logarithm of odds ratio that a variant is real vs focal epilepsy with EEG and clinical features strongly not under the trained gaussian mixture model) (,0) were filtered suggestive of TLE, and 1 patient had only generalized out. Variants with a read depth .30 and allele read frequency tonic-clonic seizures (GTCS). Brain MRI showed . 0.30 were filtered. High-quality variants were further filtered normal hippocampal architecture and volume on both for those predicted to affect the protein-coding sequence sides in 5 patients. Interictal EEGs showed epileptiform (nonsense, missense, frameshift, or essential splice-site) and with a minor allele frequency (,1%) in the exome variant abnormalities localized in the temporal lobe in 6 patients, server (http://evs.gs.washington.edu/EVS/). and was normal in 1 patient (A/II-6) with FS only.
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