an update in genetics of epilepsy dr michelle demos pediatric neurologist, neurogeneticist bc...
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![Page 1: An Update in Genetics of Epilepsy Dr Michelle Demos Pediatric Neurologist, Neurogeneticist BC Children’s Hospital](https://reader036.vdocument.in/reader036/viewer/2022062308/56649d765503460f94a56d95/html5/thumbnails/1.jpg)
An Update in Genetics of Epilepsy
Dr Michelle DemosPediatric Neurologist, Neurogeneticist
BC Children’s Hospital
![Page 2: An Update in Genetics of Epilepsy Dr Michelle Demos Pediatric Neurologist, Neurogeneticist BC Children’s Hospital](https://reader036.vdocument.in/reader036/viewer/2022062308/56649d765503460f94a56d95/html5/thumbnails/2.jpg)
Outline
• Overview of Genetics
• Role of Genetics in Epilepsy– Implications for Patients/Families
• Advances in Genetics of Epilepsy and Genetic Testing
![Page 3: An Update in Genetics of Epilepsy Dr Michelle Demos Pediatric Neurologist, Neurogeneticist BC Children’s Hospital](https://reader036.vdocument.in/reader036/viewer/2022062308/56649d765503460f94a56d95/html5/thumbnails/3.jpg)
Overview of Genetics
• What is Genetics?
Study of heredity or how traits are passed from parent to child
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Overview of Genetics
• Traits:
– Notable feature or characteristic in a person
– Each person has a different combination of traits which makes us unique
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Physical Traits
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Physical Traits
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Examples of Traits:
• Height, body weight, health or disease
• Genetic and environmental contribution
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Examples of Traits:
• Height, body weight, health or disease
• Genetic and environmental contribution
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Gene
• Basic unit of heredity
• Made of lengths of DNA (deoxyribonucleic acid)
• Genes proteins normal body function
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DNA
Human Genetic Make-up
• ~ 20, 000 genes
• The entire collection of DNA is called your Genome
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Human Chromosomes
OR
MaleFemale
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Sex Chromosomes
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DNA, genetic code and making of human protein for normal function of human body
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Outline
• Overview of Genetics
• Role of Genetics in Epilepsy– Implications for Patients/Families
• Advances in Genetics of Epilepsy and Genetic Testing
![Page 16: An Update in Genetics of Epilepsy Dr Michelle Demos Pediatric Neurologist, Neurogeneticist BC Children’s Hospital](https://reader036.vdocument.in/reader036/viewer/2022062308/56649d765503460f94a56d95/html5/thumbnails/16.jpg)
Twin Studies
Vadlamudi et al. Neurology 2004. Lennox, JAMA 1951.
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Family Studies
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Linkage Analysis
EarlyEpilepsy Gene Discovery
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Types of Genetic Disorders in Epilepsy
• Single Gene
• Chromosome
• Complex
• Mitochondrial
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Genetic Changes that can Predispose to Epilepsy: Single Gene
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Single Gene Epilepsy Disorders
• caused by changes (mutations) in single genes
• recognizable inheritance pattern (dominant, recessive, X-linked) or arise by new mutation or de novo
• very few cause primary epilepsy syndromes– Childhood Absence Epilepsy – Juvenile Myoclonic Epilepsy
• many more will frequently have epilepsy as one of their symptoms
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Features of the single gene epilepsy disorders
• same gene mutation may produce multiple different seizure types or severity
• not all individuals inheriting the affected epilepsy gene will develop seizures
• more than one gene can cause the same disorder
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Types of Genetic Disorders in Epilepsy
• Single Gene
• Chromosome
• Complex
• Mitochondrial
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Genetic Change that can Predispose to Epilepsy: Loss of part of a chromosome
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Chromosome Disorders
• result in loss (deletion) or extra (duplication) chromosome content
• often new change in child so recurrence risk is low, but if present in parent then recurrence risk is 50%
• often associated with other medical problems
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Types of Genetic Disorders in Epilepsy
• Single Gene
• Chromosome
• Complex
• Mitochondrial
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Complex Disorders
• many epilepsies with a genetic basis– Childhood Absence Epilepsy– Juvenile Myoclonic Epilepsy
• interactions between multiple genes with or without environment
• pattern of inheritance less clear
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Types of Genetic Disorders in Epilepsy
• Single Gene
• Chromosome
• Complex
• Mitochondrial
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Mitochondria
Mitochondria
Chromosome
Nucleus
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Mitochondrial Disorders
• mitochondrial DNA is passed from mother to child
• every child of a mother carrying mitochondrial DNA mutation is at risk of being affected
• affects multiple organs within the body
• symptoms vary amongst individuals
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Mitochondrial Disorders
Insert pedigree here
Affected
Abnormal Mitochondria
Normal Mitochondria
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Question:
If a parent or child has epilepsy, what is the risk to other family members?
CAUSE
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Cause is Known
Acquired brain injury including stroke, brain tumor, brain infection or severe head trauma
Risk is not significantly increased
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Cause is Known
Genetic Disorder (single gene, chromosome, mitochondrial)
Risk will depend on genetic cause
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Single Gene Disorders
• New dominant mutation recurrence risk is low – severe epilepsy disorders
• If not new, depends on inheritance pattern– Dominant, recessive, X-linked
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Dominant Inheritance: 50% risk
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Recessive Inheritance: 25% risk
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X-linked Inheritance: 50% risk to have an affected son
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Cause Unknown
• Many of epilepsy syndromes with genetic basis (Childhood Absence Epilepsy)
• Complex inheritance
• Risk is an estimate based on past studies
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Estimated Risks
• Risk in close relatives is about 2 to 4 times higher than people in general population
• Risk is less than 1 in 10 that a child of a person with epilepsy will also develop epilepsy
• Risk is higher in relatives of a person with generalized epilepsy, young onset epilepsy and mothers vs fathers with epilepsy
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Outline
• Overview of Genetics
• Role of Genetics in Epilepsy– Implications for Patients/Families
• Advances in Genetics of Epilepsy and Genetic Testing
![Page 42: An Update in Genetics of Epilepsy Dr Michelle Demos Pediatric Neurologist, Neurogeneticist BC Children’s Hospital](https://reader036.vdocument.in/reader036/viewer/2022062308/56649d765503460f94a56d95/html5/thumbnails/42.jpg)
Epilepsy Genetics and Genomics – Now
• Chromosome Microarray or Array Comparative Genomic Hybridization (CGH)
• Next-Generation Sequencing
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Methods: Array CGH
Normal Control DNA
From http://www.utoronto.ca/cancyto
DNA fragments
Patient DNA
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Examining chromosomes or genomes for genomic imbalances or Copy Number Variants
(CNVs) causing Epilepsy
ArrayCGH1000X resolutionKaryotype
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Copy Number Variants
• Deletion or Copy Loss
• Duplication or Copy Gain
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Chromosome Microarray in Epilepsy: What have we found?
• A cause or abnormal CNV is identified in up to 15% of patients– Treatment resistant epilepsy or other severe forms of
epilepsy– Epilepsy plus other neurological problem or birth
defect
• A cause is identified less often in patients with benign epilepsy syndromes (Juvenile Myoclonic Epilepsy)
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Chromosome Microarray in Epilepsy: What have we found?
• Limitations to testing: negative test does not rule out genetic cause
• Results of unclear significance
• Incidental findings: finding an abnormality in a gene predisposing to unrelated health problem (example breast cancer gene)
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Chromosome Microarray in Epilepsy: Who should be Tested?
• Cause of Epilepsy is unknown and: – a more severe form of epilepsy or – epilepsy plus global delay, intellectual disability,
autism, other neurological problem and/or birth defect
• Patient and/or Family who has received appropriate genetic counselling
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Epilepsy Genetics and Genomics – Now
• Chromosome Microarray or Array Comparative Genomic Hybridization (CGH) and Copy Number Variants
• Next-Generation Sequencing
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Examining genes, exomes and genomes for sequence variants causing Epilepsy
Sanger sequencing Next-generation sequencing
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Next-generation sequencing
• Massively parallel sequencing
• Sequence millions of fragments simultaneously
• Whole genome, exome (protein coding), targeted or gene panels
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Whole genome, exome or targeted sequencing in Epilepsy
Targeted= 10 to 500 epilepsy genes
Whole Genome
Exome = 1 %
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Whole Exome sequencing
• 20 000 variants per individual• Exome contains 85% of disease-causing mutations
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Next Generation Sequencing: What is the impact?
Rapid increase in Gene Discovery
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Next Generation Sequencing:Epilepsy Impact
• ~ 500 genes associated with epilepsy
• Significant increase in diagnoses:– Diagnosis 10 – 50% of those tested – Severe epilepsy conditions or Epilepsy plus– New dominant mutations in multiple different genes
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Next Generation Sequencing:Challenges
• Negative test does not rule out genetic cause• Variants of unclear significance• Proving new or novel gene identified is the
cause of epilepsy• Availability in Canada • Ethical Issues• Cost
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Whole Genome Sequencing
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Next Generation Sequencing:Positive Impact on Patients/Families
• Earlier diagnosis including disorders with specific treatment implications
• More accurate counselling regarding outcome and recurrence risk
• Prevent additional investigations
• A clear genetic diagnosis improves access to therapies/community support
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Next Generation Sequencing:Negative Impact on Patients/Families
• Identifying a disease without specific treatment
• Discrimination regarding life, disability or long-term care insurance
• Incidental findings (finding an abnormality in a gene that increase risk for developing cancer)
• Genetic Counselling Before Testing
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Genetic Testing in Patients/families with Epilepsy
Chromosome Microarray Analysis:• Available in BC• Indicated in patients with epilepsy of unknown
cause and:– Severe forms of epilepsy– Epilepsy plus delay, intellectual disability, autism,
other neurological/behavioral problems and/or other congenital abnormalities
• Pre-test genetic counselling required
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Genetic Testing in Patients/families with Epilepsy
Next Generation Sequencing:• Limited Availability in BC
– Research, MSP funding
• Consider in patients with negative chromosome microarray and:– Severe forms of epilepsy– Epilepsy Plus – Early onset epilepsy
• Pre-test genetic counselling required
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Future Directions
• Standardized approach to genetic testing
• Genetic discoveries leading to development of better treatment options
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Future Directions
Pharmacogenomics of Epilepsy:• The study of the interaction of an individual's
genetic makeup and response to a drug.– Adverse drug reactions (HLA-B*1502)
– Seizure control
• Aim to individualize and optimize treatment based on genetic make-up
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Summary• Genetic factors play a role in many epilepsy disorders
• New technology (Chromosome Microarray and Next-Generation Sequencing) has revolutionized gene discovery and genetic testing in epilepsy
• Recent discoveries and further advances in diagnosis and pharmacogenomics will likely lead to improved individualized treatment of epilepsy
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Questions?
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Helbig I, et al, 2008.
Acquired (low)
Complex
Genetic Contribution to Epilepsy
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Genetic (high)