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Genetics and Precision Medicine in LGS

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Katherine Helbig, MS, LCGS, discusses genetics and precision medicine in Lennox-Gastaut Syndrome

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Genetics and Precision Medicine in LGS

  1. 1. Genetics and Precision Medicine in LGS: A 2017 Update Katherine Helbig, MS, LCGC Division of Neurology Children’s Hospital of Philadelphia
  2. 2. Overview • Introduction to genetics concepts/terminology • Overview of LGS genetics • Precision medicine in LGS
  3. 3. Overview • Introduction to genetics concepts/terminology • Overview of LGS genetics • Precision medicine in LGS
  4. 4. Genetics 101 Cincinnati Children’s Hospital
  5. 5. Genetics 101 Cincinnati Children’s Hospital
  6. 6. Genetics 101 Nucleotides: building blocks of DNA; come in four different forms, represented by the letters A, T, G, and C Amino acids: building blocks of proteins; there are 20 different amino acids. Three-nucleotide increments are translated to one amino acid
  7. 7. What types of genetic tests for LGS? • Not typically offered clinically • Time and cost intensive Single gene testing • Looks for copy number variants • Larger pieces of chromosomes that are extra or missing Chromosomal microarray • Testing 10 – 1000 genes simultaneously • Disorder-specific (i.e. epilepsy, autism, neurodevelopmental disorders) Comprehensive epilepsy panel • Testing exons of all ~20,000 genes simultaneously • Parents often tested along with child Whole Exome Sequencing
  8. 8. Genetics 101 Interpretation of genetic tests can be difficult
  9. 9. Missense Variant U.S. National Library of Medicine p.Arg190Trp Protein Reference amino acid Amino acid position Variant amino acid
  10. 10. Nonsense Variant U.S. National Library of Medicine p.Arg235* Protein Reference amino acid Amino acid position Stop
  11. 11. Frameshift Variant U.S. National Library of Medicine p.Leu130Aspfs*11 Protein Reference amino acid Amino acid position Variant amino acid Frameshift and STOP after 11 amino acids
  12. 12. Splice Site Variant Cincinnati Children’s Hospital National Cancer Institute c.235-1G>A Coding DNA 1 nucleotide into intron Nucleotide Position (in exon) Reference nucleotide Variant nucleotide
  13. 13. Recommendations/Guidelines • Currently no formal guidelines regarding genetic testing • ILAE recommendations:1 – Genetic counseling for all patients with infantile seizures – Genetic evaluation in setting of Dravet syndrome and other epileptic encephalopathies • Minimum care for adult patients with ID and epilepsy:2 – Genetic evaluation as standard component of care 1Wilmshurst JM, Gaillard WD, Vinayan KP, et al. Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia 2015;56:1185-1197. 2Devinsky O, Asato M, Camfield P, et al. Delivery of epilepsy care to adults with intellectual and developmental disabilities. Neurology 2015;85:1512-1521.
  14. 14. However… • Implementation in clinical practice is often inconsistent • 109 neurologists were asked the following question: – 19% saw primarily pediatric patients – 76% treated mostly adult patients – 5% treated an equal mix of pedatric and adult patients “An 18-year-old man has global developmental delay and a history of infantile spasms, which led to Lennox-Gastaut syndrome. An MRI shows some enlargement of the right ventricle but no other findings, and the exam is nonfocal. The seizures are drug resistant. Metabolic testing was negative. Would you order genetic testing?”
  15. 15. 80% 20% 33% 67% 0 10 20 30 40 50 60 70 80 90 Yes, I would order genetic testing No, I would not order genetic testing Percentage Pediatric Adult Ferraro L, Pollard JR, Helbig I. Attitudes Toward Epilepsy Genetics Testing Among Adult and Pediatric Epileptologists-Results of a Q- PULSE Survey. Epilepsy Curr 2016;16:46-47.
  16. 16. Overview • Introduction to genetics concepts/terminology • Overview of LGS genetics • Precision medicine in LGS
  17. 17. Overview • Introduction to genetics concepts/terminology • Overview of LGS genetics • Precision medicine in LGS
  18. 18. Interpretation: pathogenic de novo variants in 15% of patients Infantile Spasms Lennox-Gastaut Syndrome CONFIRMED 12/2013 CHD2, GABRA1, GRIN2B, GNAO1, SLC35A2, IQSEC2 Exome sequencing 264 trios Known epilepsy genes: SCN1A (n=7) STXBP1 (n=5) CDKL5 (n=3) SCN2A (n=2) SCN8A (n=2) KCNT1, DCX (1 each) Novel epileptic encephalopathy genes Recurrent: GABRB3, ALG13, HDAC4 Single hits: CHD2, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR, NEDD4L Epi4K Consortium (2013) Nature 501(7466):217 -221. CONFIRMED 9/2014 DNM1, RYR3, GABBR2, FASN EuroEPINOMICS- RES Consortium (2014) Am J Hum Genet 95(4):360- 370. CONFIRMED 11/2015 PURA, STX1B, KCNA2, HCN1 Epi4K Am J Hum Genet 2017 SLC1A2 CACNA1A GABRB3
  19. 19. Diagnostic exome sequencing › 1,131 consecutive patients referred for exome sequencing • ~300 patient-parent trios • Various epilepsy syndromes › Exome sequencing in epilepsy • Patients with LGS: 33% positive findings • 11% candidate gene finding • Most due to de novo variants Helbig KL, et al. (2016) Genet Med 18(9):898-905.
  20. 20. Take away messages: • De novo variants are an important cause of epileptic encephalopathies including LGS  >30% of patients • High genetic heterogeneity  No single gene accounts for more than 1-2% of patients Genetic heterogeneity: pathogenic variants in multiple genes can result in the same disease de novo: genetic change that occurs new in the child and is not passed on from mother or father
  21. 21. Causative genes found in patients with LGS ALG13 ANK3 ANO3 CACNA1A CDKL5 CHD2 CTNND2 DCX DNM1 EEF1A2 FASN FLNA FOXG1 GABRB3 GRIN2B HNRNPH1 HNRNPU IQSEC2 KCNA2 KCNQ3 MBD5 MTOR NALCN PPP3CA PURA RYR3 SCN1A SCN2A SCN8A SCN10A ST3GAL3 STXBP1 TIMM50 YWHAG And more…
  22. 22. Major classes of epilepsy genes Ion channels • Channelopathy concept • Expanding phenotypes for established genes (SCN1A, SCN2A, KCNQ2, CACNA1A) • Newly emerging genes: – SCN8A – GRIN1, GRIN2A, GRIN2B – KCNT1, KCNA2 – GABRB3 Synaptic Transmission • Synaptopathies • Important in epileptic encephalopathies • DNM1, SNAP25, STXBP1, STX1B, SYNGAP1
  23. 23. Dynamin 1 (DNM1) Neurology® 2017;89:385–394
  24. 24. • 21 patients identified – de novo variants • Epilepsy phenotype – West syndrome  LGS – Homogeneous phenotype • Accounts for ~2% of patients with LGS DNM1 encephalopathy
  25. 25. Dynamin 1 Ferguson & De Camilli (2012) Nat Rev Mol Cell Biol 13:75-88.
  26. 26. Dynamin 1 (DNM1) • 1/3 of patients with DNM1 encephalopathy • Most common known variant in epilepsy • Target for therapies Pathogenic variants cluster in GTPase and Middle domains
  27. 27. Major classes of epilepsy genes Ion channels • Channelopathy concept • Expanding phenotypes for established genes (SCN1A, SCN2A, KCNQ2, CACNA1A) • Newly emerging genes: – SCN8A – GRIN1, GRIN2A, GRIN2B – KCNT1, KCNA2 – GABRB3 Synaptic Transmission • Synaptopathies • Important in epileptic encephalopathies • DNM1, SNAP25, STXBP1, STX1B, SYNGAP1
  28. 28. GABRB3 • Encodes subunit of GABA(A) receptor • GABA is major inhibitory neurotransmitter in brain • De novo variants in GABRB3 cause a spectrum of epilepsies: – LGS – Epileptic encephalopathies – West syndrome – Dravet-like phenotypes – Myoclonic-atonic epilepsy (Doose syndrome) • Epi4K 2017: 4/11 (36%) LGS
  29. 29. GABRB3 LGS-associated variants Functional analysis: reduced sensitivity to GABA, loss-of-function
  30. 30. Epilepsy Genetics Initiative › What if whole exome sequencing is negative? • ~50% of patients • May still contain novel/candidate genes that are not reported › Citizens United for Research in Epilepsy (CURE) • Database for diagnostic exomes (Columbia University) • Re-analysis every 6 months › Data available to research community › www.cureepilepsy.org/egi/
  31. 31. Overview • Introduction to genetics concepts/terminology • Overview of LGS genetics • Precision medicine in LGS
  32. 32. Overview • Introduction to genetics concepts/terminology • Overview of LGS genetics • Precision medicine in LGS
  33. 33. Epilepsy precision medicine Child with unexplained epilepsy Identifying the genetic cause Understanding the disease mechanism Precision Medicine >30% explained Animal models cell models In silico analysis before after Daily seizures Improved treatment in > 20%
  34. 34. Epilepsy precision medicine Child with unexplained epilepsy Identifying the genetic cause Understanding the disease mechanism Precision Medicine >30% explained Animal models cell models In silico analysis before after Daily seizures Improved treatment in > 20%
  35. 35. Precision medicine in SCN2A SCN2A病的精准医疗
  36. 36. Precision medicine in SCN2A • Distinct phenotypes (201 patients) – Myoclonic-atonic epilepsy – Lennox-Gastaut Syndrome – Focal epilepsies with ESES – West syndrome (often to LGS): p.Arg853Gln in 6 patients • Review of sodium channel blockers in 66 patients – Seizure reduction/freedom in early infantile epilepsies – Other antiepileptic drugs less effective – Rarely effective in epilepsies w/later onset, seizure worsening
  37. 37. Treatment response in SCN2A encephalopathy Phenytoin Carbamazepine Oxcarbazepine Lacosamide Lamotrigine ZonisamideTwo subgroups: 1. Early seizure onset (good response) 2. Later seizure onset (poor response) Correlation with functional effect? • Gain-of-function: good response, early-onset • Loss-of-function: poor response, later onset
  38. 38. Summary • Genetic evaluation indicated in unexplained LGS • Many genes can cause LGS – Mostly de novo variants – Genetic diagnosis in >30% of patients with LGS – DNM1: up to 2% of patients with LGS • Genetic diagnosis  precision medicine – SCN2A and therapeutic response to SCBs
  39. 39. EpiGC • 30+ genetic counselors specializing in epilepsy genetics • Resource for families and clinicians • www.epigc.net Beth Sheidley, MS, LCGC Program Director Epilepsy Genetics Program Boston Children’s Hospital Katherine Helbig, MS, LCGC Division of Neurology Children’s Hospital of Philadelphia helbigk@email.chop.edu
  40. 40. Thank you CHOP Neurogenetics Program • Holly Dubbs, MS, LCGC • Ethan Goldberg, MD, PhD • Ingo Helbig, MD • Eric Marsh, MD, PhD • Xilma Ortiz-Gonzalez, MD, PhD Epilepsy Genetics Research Program • Ingo Helbig, MD • Meg O’Brien • Mahgenn Cosico • Peter Galer, MSc • Shiva Ganesan, MS helbigk@email.chop.edu

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