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So it's time to start.
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Hello everyone, and welcome to today's educational webinar titled Decoding Epilepsy, Exploring the Power of Genetic Testing.
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My name is Tina Boppio and I have the privilege of hosting today's webinar.
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Please submit any questions you may have in the questions box.
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You can submit them throughout the webinar and we will answer as many as possible at the close of the webinar.
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We are very excited to have Emily Partack, Master of Science Certified Genetic Counsellor, as our presenter today.
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Emily received her Bachelor of Science in Biology and Psychology from the University of Missouri, Columbia and her Master of Science in Medical Genetics from the University of Cincinnati.
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She's certified by the American Board of of Genetic Counselling.
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Prior to joining Quest Diagnostics in in 2019, she worked in clinical practice specializing in the field of epilepsy and as a laboratory genetic counsellor specializing in genetic testing stewardship.
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In her current role, Emily provides client and operational support related to genomic testing for individuals with rare disease.
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Thank you for being here today.
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Please, Emily, Thank you so much.
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Welcome, everybody.
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I'm so excited to talk to you today about a topic that's near and dear to my heart, epilepsy genetics.
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So these are the learning objectives for today.
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I'm going to describe epilepsy and the role of genetic testing in patients with epilepsy, identify professional guideline recommendations for genetic testing and those with unexplained epilepsy, and compare multi gene epilepsypanels and whole XM sequencing testing approaches, specifically at Blueprint Genetics.
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So first, some definitions for seizures and epilepsy.
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A seizure is described as an abnormal, excessive, sudden discharge of neurons.
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It's like an electrical storm in the brain.
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Epilepsy is recurrent, unprovoked seizures.
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So this means that a single seizure is not epilepsy because it's not recurrent.
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And a provoked seizure, such as seizures that occur from illness, trauma, or substances, would also not be considered epilepsy because the seizures are provoked by something.
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Seizures and epilepsy are both fairly common.
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Around one in 10 people have had a seizure in their lifetime and one in 26 people have epilepsy.
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Seizures can be classified into focal seizures or generalized seizures.
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Focal seizures are seizures that start in one region of the brain.
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Generalized seizures start in the deep structures of the brain and spread to the cortex bilaterally.
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Seizures can begin as a focal seizure and turn into a generalized seizure and spread to the entire brain, typically resulting in bilateral tonic clonic seizure.
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Seizures may also have unknown onset.
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There are many different causes of seizures, including, of course, genetic causes we'll talk about today.
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There are also brain structural causes, such as malformations of cortical development, vascular malformations, stroke, trauma, tumors, things like that.
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There are infectious causes, a number of metabolic disturbances including a number of genetic conditions that impact metabolism, and immune causes for seizures as well.
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Additionally, it's not uncommon for the cause of seizure to be unknown.
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Seizures can also present at any age from the new needle.
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All the way through to adulthood.
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So this side it's not a complete list of seizure causes, but it demonstrates that certain certain causes may be considered based on the age of the patient as well as the clinical history.
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So, for example, birth complications or lack of oxygen from a difficult birth could be the cause of seizures in a very young baby.
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And febrile seizures or seizures caused by fever are fairly common in childhood, but often children grow out of them and they're not as common in adulthood.
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Genetic factors can be a cause of seizures and epilepsy regardless of the age of the patient.
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While genetic disorders commonly present in infancy or childhood, they really can present at any age.
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In 2017, the International League Against Epilepsy, or ILAE, presented a revised operational classification of seizure types.
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The ILAE is a group full of members across the world whose mission is to ensure that there are educational and research resources to understand, diagnose and treat people with epilepsy.
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This revised classification of seizures was performed so that there was more transparent and consistent naming for seizure types, to recognize that seizures may have either a focal or generalized onset, for example motorseizures, and just really to allow classification when the onset is unknown.
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These are some of the common diagnostic tools that are made to make a diagnosis of epilepsy.
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The clinical history and a description of the seizure is very important in making a diagnosis because there are many things that look like seizures but aren't.
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So further work up may be needed depending on the clinical history to determine if the patient is in fact having a seizure.
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EEG measures the electrical activity in the brain and it can give a clue as to the origin of seizures.
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It can also help classify type of seizure and identify abnormalities in between seizures.
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An EEG may be normal between seizures.
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So sometimes a video EEG is done with the goal of capturing the seizure on EEG along with a recording of the patient's behavior on video to help in diagnosis and classification of seizure type.
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HCT and MRI are imaging modalities used to evaluate for structural causes of epilepsy.
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Blood work can be used to help evaluate for a number of things that can cause seizures, such as infectious causes or electrolyte imbalances.
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And then other work up may be done depending on the history, such as a lumbar puncture with ceremal spinal fluid studies, an EKG, sleep study, or more other specialized studies, particularly if the patient is undergoing work upfor surgery.
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More and more genetic testing is being used to assist in understanding the etiology of epilepsy.
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While genetic testing cannot diagnose epilepsy, it can be used to understand the underlying cause for seizures and assistance treatment and management.
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Speaking of treatment, treatment for epilepsy consists of three main categories, Anti seizure medications or ASM.
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They're usually the first line of treatment for epilepsy.
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The ketogenic diet is used to treat epilepsy, which is a low carb, very high fat and protein diet, and there are also a variety of surgical options such as the vagus nerve stimulator, deep brain stimulation, and a variety ofother surgical option.
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Individuals with a diagnosis of epilepsy may also have a range of additional comorbidities.
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It is common for people to endorse having problems with things like learning and attention, sleep disorders, developmental delay and intellectual disability, mood disorders, anxiety, movement disorders, and autism spectrumdisorder, just to name a few.
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Additionally, many of these comorbid conditions are also seen in individuals who are known to have a genetic condition.
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Each individual with epilepsy is unique, and comorbid conditions also show a wide range in type and severity.
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So one person may be experiencing some mild learning difficulties, while another may experience more significant intellectual disability.
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And another important paper from 2017, the International League Against Epilepsy, presented a position paper introducing a framework for the classification of epilepsy.
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The framework presents 3 levels, starting with seizure type, as defined by the 2017 seizure classification position paper that I showed a few slides earlier.
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After a diagnosis of seizure type, the next step is a diagnosis of epilepsy.
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Types of vocal, generalized, combined, and unknown.
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The third level of classification, down at the bottom there is that of an epilepsy syndrome.
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A specific diagnosis of an epilepsy syndrome can be made in many cases and along the right hand side of this image, you'll see that the etiology for epilepsy should be considered at each step in the diagnostic pathway as theetiology often carries significant treatment implication.
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Similarly, on the left hand side of this image, comorbidities should also be considered at every stage of the classification.
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This classification framework enables appropriate diagnosis in management of epilepsy as well as those comorbid conditions.
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An epilepsy syndrome refers to a cluster of features that incorporating seizure types, EEG, and clinical features that tend to occur together.
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It may have age dependent features such as the typical age of onset or typical age of remission.
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It may have other features such as common seizure triggers, daily patterns, or distinctive comorbidities such as intellectual disability or psychiatric features.
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It may have an associated etiology, prognosis, and treatment implications.
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And some epilepsy syndromes are more likely to have a monogenic or single gene cause.
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So for example, Jarvis syndrome and some epilepsy syndrome are caused by many different genes with or without environmental factors, such as childhood absence epilepsy and juvenile myochronic epilepsy.
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When considering genetic testing, it's important to consider that genetic tests are often designed to identify those monogenic or single gene causes, but they really don't do as well at identifying conditions that are due tomultiple genes.
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To understand more about epilepsy syndromes and definitions, the ILAE hosts a website calledepilepsydiagnosis.org to help those who are caring for people with epilepsy to kind of understand concepts related to seizures andepilepsy and have a number of epilepsy syndromes.
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On that website, let's dive into the types of genetic variants that exist.
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A genetic variant is defined as a difference in the DNA sequence of a gene.
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All of us have unique genetic variants, and many variants do not seem to have any impact on our health.
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However, sometimes the genetic variant will impact a gene function.
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So if you think of our DNA as a string of letters that provide the instructions to make a protein, a change in the string of letters can result in that specific biological function not being performed or not being performed aseffectively.
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And all of our genes are packaged into the nuclear genome or the mitochondrial genome.
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So there's some figures on the top of the screen here.
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Most human genes are within the nuclear DNA, which is called nuclear because it's located within the cell's nucleus.
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The nuclear DNA is packaged into chromosomes as depicted on the top left image.
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If you zoom in really closely on those chromosomes, you can see that they're made-up of that nuclear DNA.
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And then inside our cells, we also have mitochondria, which are like the powerhouse of the cell.
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Mitochondria is where a cell's energy is made.
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Mitochondria have their own circular genome which contains 37 genes as depicted in the figure.
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On the upper right hand side, mitochondrial DNA is inherited exclusively from the mother.
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And then at the bottom of the screen, there are images showing the basic anatomy of a gene.
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So a gene is made-up of axons, which are the white boxes, and entrons, which are the blue lines in between.
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The majority of genetic variants that are associated with causing disease are expected to be in the axons or the white box.
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They're the part of the gene that contain instructions to make a protein that then goes out and performs that specific biological function.
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To put it very simply, there are single nucleotide variants, which would be, you know, one single DNA nucleotide change.
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The pink star on this diagram represents a single nucleotide variant in the Exxon or the quoting region of the gene.
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And there are copy number variants in which larger regions of the nucleotides is either they're either missing, so there's one copy when there should be two or contain extra copies, maybe there's 3 when there should be two.
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And on the bottom right, I've depicted a single Exxon copy number variant.
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The pink brackets indicate that one copy of the Epson has been deleted resulting in one remaining copy of the Axon.
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Well, normally there'd be two.
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And in individuals with epilepsy, we have found a large number of genetic variants that are located in both the nuclear and the mitochondrial genome.
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Most of the variants are those single nucleotide variants, but it has been reported that approximately 10% or so of the pathogenic variants within the epilepsy population have been copy number of variants, Exxon level copynumber of variants making that very important to consider as well.
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So just some background on these types of variants as we walk through the various types of tests and just to kind of talk about the importance of genetic etiology, it can really guide treatment in epilepsy.
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This figure is from one of many papers out there that demonstrate the importance of knowing the genetic etiology for epilepsy.
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The first column on the left identifies a number of epilepsy syndromes, including the very first one on the list called paradoxin dependent epilepsy.
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In this epilepsy syndrome, the treatment is right there in the name.
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Seizures are very responsive to treatment with paradoxin, which is the B6 vitamin.
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And this chart also demonstrates that sometimes even knowing the specific variant in a gene can be helpful when choosing a treatment.
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So in the example for SCN 2A down more towards the bottom, there sodium channel blockers should could be considered for gain of function variants, which is a particular type of variant in the in the gene that kind of creates anew protein function.
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And sodium channel blocker should be avoided for loss of function variants.
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So again, another type of variant in which the protein function is reduced or lost.
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There are many examples of how the genetic etiology can guide treatment and management decisions such as the ones listed on the screen.
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So why do genetic testing for epilepsy?
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There are many reasons as I showed it, it can really assist in making a diagnosis of a specific epilepsy syndrome, guiding treatment and prognosis discussions, and ending the diagnostic odyssey, which can have huge psychologicalbenefits for patients.
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Testing can also allow for participation in research and clinical trials.
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It can allow for patients to participate in community support and advocacy organization.
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And as more and more genetic epilepsies are identified, there have really been more and more epilepsy advocacy organizations that are starting up.
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And these goals, these organizations have a lot of goals of improving care, developing registries, increasing funding for epilepsy research, not to mention just the benefit patients get from connecting with other people who havethe same rare condition as them.
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Additionally, there is the option to offer targeted testing for family members, allowing them to know if they're at risk to develop the same condition as their family member or if they aren't because maybe they have the genetictesting and it's negative and they that means they can forgo monitoring for that condition.
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Genetic testing can also provide recurrence risk information and help people make decisions about their family planning as well.
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This thing shows the timeline of gene discovery and phenotypic clarification in the field of epilepsy.
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The very first epilepsy gene was discovered in 1995 and with the introduction of next generation sequencing or NGF technology.
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There was a rapid expansion in the discovery of new epilepsy gene which is represented by the green area there in the figure, and now there are over 1000 genes associated with epilepsy and more being discovered every day.
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As genetic testing for epilepsy became more widespread, we started to be able to not only expand our knowledge of the genes associated with epilepsy, but also expanded what we knew about the phenotype of some of these epilepsysyndromes through large cohort studies.
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So we were able to gather larger groups of people who had epilepsy due to the same gene and sometimes even due to the same genetic variant, and study what features they had in common, what treatments worked for them, what didn'twork for them, things like that.
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More genes are being discovered all the time, as well as our understanding of the phenotype associated with genes and with genetic variants in those genes.
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There are a number of tests, a number of genetic tests for epilepsy.
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Each are designed to look at the nuclear and mitochondrial genomes in different ways.
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I've listed some of them here and we'll go into more detail about these tests and in some of the future slides.
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But knowing that there are several tests and over 1000 genes associated with epilepsy, you may be asking how do I start?
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Which test is best for a patient with epilepsy?
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Some years ago, many genetics and neurology professionals were struggling with that thing question.
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With so many tests available for epilepsy, which test is best?
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How do we start to answer this question?
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A group of epilepsy genetic counselors submitted a proposal to the National Society of Genetic Counselors to develop a practice guideline that outlined the optimal testing strategy for those with epilepsy.
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The first step of developing this guideline was to perform a systematic review of the evidence, and I had the pleasure of being an author on this systematic evidence review.
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Our main question when designing the systematic evidence review was can genetic testing be recommended and those with epilepsy?
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If so, which tests are more likely to result in a diagnosis?
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When planning a systematic review of all of the evidence in the literature, we wanted our search to be broad so that we could really capture who would benefit.
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So our population was individuals at any age with any type of epilepsy.
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Our intervention was genetic or genomic testing relevant to epilepsy and the review focused on genome sequencing, exome sequencing, multi gene panel and comparative genomic hybridization or CGH and chromosomal microarray or CMA.
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We focused on these tests because they were broad and they could identify many different epilepsy conditions.
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So we didn't include tests that were more targeted, for example single gene testing or mitochondrial genome sequencing alone.
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We kept the outcomes brought as well, looking for things like the ability to predict prognosis, changes in treatment, recurrence risk, counseling, measures of psychosocial well-being, and test yield.
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Our timing wasn't testified in the setting with any clinical or research setting.
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The literature reviewed was from epilepsy clinicians and researchers all over the world.
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However, in order to be included, the study needed to meet all inclusion criteria and have a full text paper available in the English language.
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So I mentioned the epilepsy systematic review focused on poor tests, comparative genomic hybridization or chromosomal microarray, which were grouped together because they look for similar types of variants and I'm going to referto those as CGHCMA multi gene panels, exome sequencing and genome sequencing.
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So I thought it would be helpful to go through and compare these four tests.
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Each test has its own benefits and limitations.
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This table is adapted from the epilepsy practice guidelines that I'm going to discuss in a little bit more detail soon.
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It's not specific to the epilepsy, it's specific to the type of test.
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All all four of these are used for indications other than epilepsy.
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Also, the table does not represent specific tests offered at specific labs.
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It's more general guidance about these tests so to go through to detect single nucleotide variants in the coding region or exons of the gene, the best options would be gene sequencing via multi gene panels, exome sequencing orgenome.
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CGHCMA methodology is designed to detect copy number variants.
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It's not gene sequencing so it will not detect single nucleotide variant.
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To detect single nucleotide variants in the non coding region, the best option is to do genome sequencing.
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Genome sequencing can detect single nucleotide variants in the coding and the non coding region.
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For multi gene panels and AXIOM this is variable.
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Typically those non coding regions are not included because these tests target the axons.
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However, the lab may have designed their testing to include some genetic variants that are in those non cutting regions.
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For copy number variants the detection level really depends on the size of the copy number variant.
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So for single Axon copy number variants the best options would be those multi gene panel or genome sequencing.
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So CGHCMA may detect a CNV of that size.
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It just depends on the lab and how well that excellent covered.
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Many labs do include CNV detection for the genes that are on a multi gene panel.
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This would also be lab specific and for most exome sequencing test, detecting a single exome copy number variant is the limitation of that technology.
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It may be detected, but it's kind of a common limitation for exome sequencing as the copy number variants get a little larger.
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So for multi exon copy number variants all the way up to full gene copy number variants, any of these tests could detect that type of variant.
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Though again including copying of a variant detection on exome sequencing test is variable and that specific as well.
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If one is looking for a test with a targeted gene list, the only test to offer this would be that multi gene panel options.
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So they're helpful in instances in which you want to know exactly which genes are being tested.
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And then exome and genome sequencing are options that offer concurrent trio based analysis, which means the option to include parental samples at the same time assessing a patient, which can aid in variant interpretation andallow for quicker understanding of the variance inheritance because that information is typically shared at the same time of receiving the clinical genetic testing report.
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OK.
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So let's go back to the epilepsy systematic review we were discussing.
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After we completed our search and determined eligibility of all the papers and pulled them from the literature, we ended up with a lot of papers that were included especially for the outcome of diagnostic yield.
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There were 154 studies included in all, which included thirty 9094 diagnostic yield outcomes.
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As I mentioned, to be focused on those four tests against, I have them listed here.
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The overall yield for patients with epilepsy across all four of the tests was 17%.
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It was highest in the genome sequencing group at 48%.
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So there were only four studies included as at the time there were not as many published studies in genome sequencing at the time the systematic review was performed.
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Epsom sequencing showed a yield of 24%, multi gene panels had a diagnostic yield of 19% and CGHCMA had the lowest yield, though still impactful at 9%.
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We found that having a developmental and epileptic encephalopathy, or Dee, and neurodevelopmental disorders, or NDD, were each associated with an increased testing yield, both showing a yield of 22% across all four testingmodalities.
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Neurodevelopmental disorders were defined as developmental delay, intellectual disability, and autism spectrum disorder.
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In the six studies in which patients did not have a neurodevelopmental disorder, the yield was 8% overall, and in the 11 studies and patients that had focal epilepsy, the yield was 7% overall.
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I mentioned that the epilepsy systematic review also was that non yield outcome in the literature.
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Things like the ability to pick prognosis, changes in management, recurrence risk, counseling, and measures of psychosocial well-being.
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Out of the 154 studies included a systematic review, only 43 reported non yield outcomes addressing personal and clinical utility of testing.
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However, none were designed to systematically assess non yield outcomes.
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There were 24 studies that discussed how genetic diagnosis directly influence treatment.
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How often a genetic test result influence treatment in these 24 studies ranged from 12 to 80%, so quite a big range there.
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But some examples of how treatment was influenced included in voiding, stopping or initiating a specific anti seizure medication or the ketogenic diet or halting a plan for surgery in the presence of a specific genetic diagnosis.
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After the systematic evidence review was completed, the evidence was provided to the Epilepsy Practice Guidelines author group for review.
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So the guidelines are based primarily on the evidence from the systematic review, but data was also compiled from other sources, which is recently submitted conference abstracts and peer reviewed journal articles.
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And the recommendations are relevant to genetic testing and counseling for individuals with unexplained epilepsy.
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So the guideline notes that if a specific syndrome or genetic etiology is suspected, targeted testing most appropriate for that clinical indication should be considered and pursued separately.
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The Evidence based practice guidelines is from the National Society of Genetic Counselors and is endorsed by the American Epilepsy Society.
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The Epilepsy practice guidelines present 2 recommendations.
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Recommendation 1 is that it is strongly recommended that individuals with unexplained epilepsy be offered genetic testing without limitation of age.
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Comprehensive multi gene testing such as Epsom sequencing, genome sequencing and multi gene panel is strongly recommended as a first tier test followed by CGHCMA exome sequencing Slash genome sequencing is conditionallyrecommended over multi gene panel as the first tier test.
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Exome sequencing can be used as a first tier test as genome sequencing becomes more widely available and the multi gene panel should have a minimum of 25 genes and include copy number analysis.
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Recommendation 2 is that it is strongly recommended that genetic tests be selected, ordered and interpreted by a qualified healthcare provider in the studying of appropriate pretest and protest genetic counseling.
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A qualified healthcare provider is defined in the paper as an individual with specialized training or knowledge in genetics.
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Someone you can adequately discuss the benefits, limitations, and psychological implications of genetic testing.
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Someone who can evaluate and interpret genetic test results in the context of an individual's presenting phenotype.
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So why was Oxome and genome conditionally recommended over panels?
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Exome and genome showed a higher diagnostic yield.
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The diagnostic yield for panels in exome were comparable.
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So panels it was 19% and exome it was 24%.
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However, the guidelines discussed that the diagnostic yield of exome sequencing of the first tier test maybe higher than what was reported in the systematic review paper because some of those cohorts for axiom sequencing weremade-up of people who had negative genetic testing and then went on to have axiom sequencing.
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They may have had a negative panel and then went on to do axiom, or it was just not specified whether prior testing had been done before exome sequencing.
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So exome sequencing as a first tier test may show an even higher yield than in the systematic review paper.
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The yield for genome sequencing in the systematic review was higher than multi gene panels as well at 48% versus 19%.
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But you may remember that there were only four studies included, so the practice guidelines authors did note that the guidelines may need to be revisited after some time, especially as genome sequencing continues to be studiedand more widely adopted in the clinical space.
35:30
The higher diagnostic yield for EXIM and genome is probably attributable to genetic heterogeneity or how many genes there are that are associated with epilepsy as well as the rapid rate of gene discovery in epilepsy making itdifficult for labs to offer gene panels that accept for all of the epilepsy gene given that there are so many with more being discovered.
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Additionally, the recommendation for exome and genome as a first tier test an epilepsy mirrors that for other neurodevelopmental disorders and ACMG practice guidelines developed for genetic testing in individuals presenting withdevelopmental delay and intellectual disability.
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So remember that developmental delay, intellectual disability and autism spectrum disorders, those are frequently diagnosed in those with epilepsy.
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So they're highly comorbid conditions.
36:27
The 1st paper listed on the slide is a scoping review and meta analysis for Epsom sequencing in individuals with neurodevelopmental disorders, so global developmental delay, intellectual disability and autism spectrum disorders,which proposed a diagnostic algorithm with exome sequencing as the first year test in patients with unexplained NDD.
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The second paper on the slide is a practice guidelines put out by the American College of Medical Genetics or ACMG, in which it was strongly recommended that exome sequencing slash genome sequencing be considered as the first orsecond tier tests in patients with congenital anomalies, development of delay and intellectual disability.
37:17
So the epilepsy practice guidelines are consistent with some of the other guidelines that are out there as well.
37:25
OK, so now I'm going to move on to what tests are offered.
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We print genetics for epilepsy.
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All of our testing in Blueprint is offered via next generation sequencing.
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So I'm going to spend some time discussing next generation sequencing or NGS.
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We offer several multi gene panel options for epilepsy and whole exome sequencing, so I'll go through these options as well.
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At this time, Blueprint Genetics does not offer commensable microarray and whole genome sequencing is also not available at Blueprint Genetics on a clinical basis.
38:03
So I'll be focusing on the epilepsy panels and whole axiom sequencing.
38:09
Leaperon Genetics uses next generation sequencing as I mentioned.
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So just to talk a little bit about what that is.
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So first we get adna sample from a patient.
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Typically that would be blood or saliva sample.
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We stabilize and prepare that sample for our laboratory processes.
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We then do targeted capture of specific gene regions, which I'll explain a little bit more on the next slide.
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But to put it simply, we're capturing specific parts of the patient's DNA sample in order in order to get a really closer look at it for our panels.
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This means we're capturing the exons for genes available on our panels, primarily the exons or whole Epsom sequencing.
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This means we're capturing the Epsoms of around 20,000 genes or so that are known to cause human diseases.
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And then we narrow down which variants could be causing the patient's symptoms in the analysis invariant interpretation stage.
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At the data analysis step, we use bioinformatics to compare the patient's unique DNA sequence to what we'd expect the DNA sequence to be from a reference sequence to find those genetic differences or variants.
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And our bioinformatics processes use the next generation sequencing data to find small nucleotide variants and those copy number of variants as well that I mentioned.
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Now STAR clinical interpretation team assesses the evidence that exists about the variants that are found in a patient and determines if the variant is thought to cause the disease in question.
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Lastly, we prepare a clinical report that details our findings and includes variants that are either known to cause or possibly to cause the disease in question.
40:16
OK, to talk a little bit more about our target region, this is the region of a patient's DNA again that we're targeting when we do the next generation sequencing.
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The figure on the screen may look familiar.
40:28
Again, it's showing the basic structure of that gene.
40:32
A gene is made-up of the axons, which are the white boxes, and the introns, which are the blue lines in between.
40:40
The majority of disease causing variants are expected to be in the Axon, since these are the parts of the gene that again contain those instructions to make a protein.
40:52
Our target region captures nearly all of those coding axons, so that's represented by the pink star on the diagram, as do many other labs to perform gene sequencing.
41:04
The difference between panels and whole exome sequencing is that for panels we're targeting the exons for the genes included on that panel and for whole exome we're targeting the exons of all of those 20,000 genes known to causehuman disease and then narrowing down the variance that could cause the patient's symptoms.
41:25
We sequence 20 base pairs into the intron and Exxon boundary, which is represented by the Black Star there, which is an important region because variance in that region may impact how a protein is assembled.
41:39
And additionally, we seek in sequence around some positions in the intronic space to target some non coding and intronic variance in those genes that were cataloged as disease causing by two databases when the test was designed.
41:54
So those non coding and intronic variants are represented by the blue star on the screen.
42:01
So we don't include all of the intronic regions as if you remember that for that you would need to do whole genome sequencing.
42:09
But by targeting the F sons and some of those non coding and deep intronic regions, we're targeting some of the most important regions of those genes and we're able to find many of those disease causing variants for our genepanels.
42:24
You can find a list of non coding and intronic variants on our website on each panel page under the panel content tab.
42:32
And then another thing to mention is that the entire mitochondrial genome is sequenced and is included for some of our epilepsy panels and also for a whole XM sequencing test.
42:45
The inclusion of some of those disease associated in the chronic variants and the mitochondrial genome are unique aspects of our testing compared to some others that are available.
43:00
We include copy number variant detection for variants in the nuclear and the mitochondrial genome.
43:06
This is called bioinformatically from that next generation sequencing data for all of our panels and exome and the sensitivity of our copy number variant detection can also be found on our website.
43:22
This side lists are epilepsy panel test.
43:25
We offer four smaller sub panels for various types of epilepsy and a larger comprehensive epilepsy panel which includes 511 genes.
43:36
All the genes on the smaller panels are included on the comprehensive epilepsy panel.
43:42
The epilepsy practice guidelines state that smaller epilepsy syndrome based multi gene panels should only be considered when a patient has a very specific phenotypic profile for which a defined set of genes has been identified.
43:58
So a good example of this is in the condition neuronal steroid lipofusinosis or professive myoclonic epilepsies.
44:08
There's a a subset of genes that 'cause that phenotype.
44:13
But because many epilepsy syndromes have a phenotypic overlap, if a specific syndrome is not suspected and there's a broad range of things that could be causing epilepsy or if a cause is unknown, it might make more sense toorder the comprehensive epilepsy panels.
44:30
As I mentioned, all of our panels include that copy number variant detection in the panels that have an* next to the number of genes in the middle column.
44:40
That means that they include the mitochondrial genome as well.
44:45
And the turn around time for our panels is 4 weeks.
44:50
Blueprint Genetics also offers whole axiom sequencing.
44:54
This is the test that targets all of those coding regions of the nuclear and mitochondrial gene.
45:02
So we can identify loss and loss of variants with whole axiom on our report, we include variants that are most applicable to the patient's features.
45:13
There are patients, there are variants that are known to cause or possibly cause disease and either they're known to be related or or possibly related to the patient's presenting features.
45:25
So it's important for us to know what the patient's presenting features are with this test.
45:31
Full Epsom sequencing is most suitable for patients who have a complex phenotype with multiple differential diagnosis, genetically heterogeneous disorders such as epilepsy, suspected genetic disorders where a specific gene testis not available, or a patient who has had inconclusive previous genetic testing.
45:57
With whole XM sequencing, there's the option to include family members in the analysis by ordering whole XM sequencing family.
46:05
An individual with having whole XM sequencing can opt in or opt out for analysis and reporting of secondary findings.
46:15
Secondary Findings refers to a list of genes and variants as determined by the American College of Medical Genetics policy statement stated on this slide, which are unrelated to the indication for testing but that havesignificant clinical utility.
46:30
For example, there may be significant preventative measures or treatments that can be taken if you know about the condition before developing symptoms.
46:41
The turn around time for whole exome sequencing is 6 weeks.
46:48
This site summarizes some reasons for why one may consider ordering an Epsom test versus reasons why a multi gene panel could be considered.
46:58
Exome allows for analysis of all known epilepsy genes, including newly identified and candidate genes, and a panel will include a subset of those genes.
47:09
With Epsome you can incorporate biological parents with a trio based analysis which aids in very interpretation and Epsom reanalysis can be performed if axiom sequencing is negative.
47:22
So reanalysis means that after some time has passed, or maybe after a patient has developed new features, the axiom sequencing data is reanalyzed to see if any newly discovered conditions arise or if they there have been any newfindings in the literature since the patient's first axiom was performed.
47:44
With the goal of identifying a new diagnosis.
47:49
A panel could be considered when a patient presents with a defined epilepsy syndrome for which a subset of genes should be interrogated more robustly than for eczema sequencing.
48:03
If urgent results are required and rapid exome or genome is not available, the targeted panel may be considered because the turn around time can be faster and when when access to Axiom or genome sequencing or the additionalgenetic counseling required to implement such testing may be limited.
48:24
Panel can also be considered when the panel includes additional methodologies to detect variants.
48:32
So an example on this slide is for repeat expansions.
48:36
So detecting repeat expansions, which is another type of variant where the the variant the sequence is a repetitive region.
48:46
It's a limitation of short read next generation sequencing, which is what we use that blueprint.
48:52
So if a condition is suspected that commonly has repeat expansion variants, that's because it might make sense to use a panel that can evaluate for that type of variant.
49:06
So some key takeaways from the talk.
49:08
So epilepsy has been associated with many different genes and our understanding of the genetic causes and associated phenotypes continues to expand.
49:18
Understanding the genetic cause for epilepsy has many benefits and improves care.
49:23
And individuals with epilepsy guidelines support offering genetic testing and unexplained epilepsy regardless of age.
49:32
And depending on the clinical scenario, a multi gene panel or whole Epsom sequencing are both good options.
49:38
And individuals with epilepsy and Epsom sequencing can be used as a first tier test in epilepsy as whole genome sequencing becomes more widely available.
49:53
All right, thank you so much.
49:54
At this time, I'm happy to take any questions.
