 Good morning. I'm Cynthia Powell. I'm a pediatrician and a clinical geneticist at the University of North Carolina at Chapel Hill And I'm going to be talking about a project That we have called NC nexus for North Carolina newborn exome sequencing for universal screening In this we are partnering with our TI international What I wanted to do is give you a brief background about standard newborn screening Which has been one of the most successful public health programs in our country's history What are some of the limitations to adding additional conditions to newborn screening the? Potential of using next generation Sequencing whether it's whole genome or whole exome sequencing in Screening of newborns and some of the ethical issues that have been raised about use of this new technology in newborn screening I'll explain our research study that examines the possibility and potential of using next-gen sequencing to improve the sensitivity and specificity of current newborn screening and to also increase the number of conditions that we might be able to screen for In newborns and ways in which we're exploring these issues and helping parents make decisions about whether they would like to have their child participate So newborn screening by definition is a public health program aimed at the early Identification of conditions for which early and timely intervention can prevent or reduce associated mortality and morbidity So on the left is a woman with untreated PKU This is how most individuals with condition called phenoketanuria used to end up Because they weren't diagnosed until they develop severe Intellectual disability what which in those days was called mental retardation and many ended up in institutions On the right is a young woman who was detected through newborn screening as having PKU She was started on a special diet within the first few weeks of life And although she has to drink a special supplement giving her appropriate proteins She's a cognitively normal normal intelligence leading a very normal life So number of years ago additional conditions Were able to be detected through newborn screening But there was a lot of variability in the country between one state to another Some states were only testing for three or four conditions and other states were testing for Up to 29 or 30 different conditions. So in order to make a more standardized number of conditions Across the US screen for in each state There were there was a task force organized through HRSA that Recommended 29 conditions. This has evolved into what's now called the advisory committee on heritable disorders in newborns and children new conditions can be nominated and some of the limitations to being able to screen newborns for various conditions is that there's no screening tool available or That the screening tool is too expensive or that there's no treatment as there is For classic conditions such as PKU There are now 32 conditions that are on this Recommended uniform screening panel and those include not only conditions that can be tested for through taking a blood sample the The heel prick that newborns have before they are discharged from the hospital as well as now Testing for a critical congenital heart defects through measuring the oxygen level in a baby's blood and also Newborn hearing screening which is also done prior to an infant being discharged from the hospital and Molecular genetic testing is being utilized more and more in standard newborn screening to Figure out exactly what an underlying problem is Whether it's as a second tier test after initial screening identifies the possibility of Cystic fibrosis or when a child is found to have an abnormal hemoglobin And it needs to be determined whether they have sickle cell disease or another type of What's called a hemoglobin apathy also after a screen positive case? Molecular genetic testing is often utilized to further characterize Conditions such as a severe combined immunodeficiency or hearing loss So theoretically a barrier to adding any condition to newborn screening can be overcome if the underlying molecular viology or cause of a condition is established Wilson and Younger initially came out with guidelines for screening in populations and These are some of the rules that have been followed as guidance for adding conditions to newborn screening But one of the things that they said a number of years ago is that the central idea of early disease Detection and treatment is simple But the path to its successful achievement is far from simple although it sometimes can appear easy So as we have looked at research projects Into the potential use of whole exome sequencing in newborns there are a lot of ethical issues that we are concerned about and Are studying and I wanted to review some of the ethical issues that have been raised One of those is the possibility of finding incidental or secondary things. So what are these? incidental findings are Regardless of what type of test you're talking about these are things that you find that aren't related to the original intent of testing and For example, if someone has a CT scan after they're in a car accident And they happen to find a tumor so that wasn't the initial purpose of having the CT scan But a tumor is found so that's an example of an incidental finding So we've been dealing with these for many years in health care So with next generation sequencing if we're looking at all of the coding regions of genes you might find that a person has a variant or Mutation in a gene that's related to breast or colon cancer or cardiac arrhythmias or intellectual disability And so what information should be reported back to patients or families? another issue is The fact that if we're testing newborns They really aren't old enough to consent to having these procedures done And so what about the rights of that child to decide later on whether or not they even wanted this information? So this is something that's called protecting the autonomy of the child But then we also have to balance with that the rights of parents to have information about their children So a child's autonomy might be impacted if we're talking about Giving results back for adult onset conditions This may be part of what's called pre-symptomatic genetic testing where sometimes we do Do genetic testing on individuals for things that we know won't impact them until later on? Again, what about the right of a child not to know this information? There are also concerns about genetic discrimination when that child gets older Again versus the rights of parents to have information about their child As an example where we have shared this information for many years Testing newborns for sickle cell anemia has been done has been done since the 1970s and during that time in most states the Carrier status or what's called having sickle cell trait has been reported back to Individuals and nowadays in many states where genetic testing is done for CF carrier status For cystic fibrosis carrier status. This information is is typically revealed as well so There's been very limited data about this. What are the outcomes? And this is one of the the things that we hope to learn more about But in the the limited research studies that have been done in this area There have not been shown to be harmful or deleterious effects to children when they become adults and have learned this information So if we're testing children for certain conditions that may not impact them until their adults Let's look at that a little bit more and an example of that would be having a mutation in the breast cancer gene Such as what the actress Angelina Jolie learned about that was present in herself Based on the family history that she had with her mother having ovarian cancer So BRCA mutations BRCA one and two mutations are Associated with an increased risk of breast and ovarian cancer But the youngest age that it may manifest itself is usually Year 18 years of age and most women With this don't develop the cancer until they're at an older age But because it is an autosomal dominant condition, it's Likely inherited from a parent. So just to show this There's a child. Let's say identified with a BRCA one mutation. That's their father This is what we call a pedigree which we always do in our patients who come through our genetics clinics and then likely The child Inherited this from one parent or the other and in this example. It's been inherited from the mother so is saving the life of a parent because you learn this information through the child and then could test the parents and Let the mother know that she is at an increased risk for breast and ovarian cancer Is that enough to is that enough of a benefit to warrant testing a child? So but others have argued that children should not have screening to provide genetic information about their parents why not just Test the parents directly Another thing that we're looking at is broadening the definition of treatable So as I said conditions like PKU we can identify in a child put them on a special diet right away And we can prevent them from developing intellectual disability mental retardation but our Why screen for conditions that don't fulfill the definition of treatable in the traditional sense such as those associated with intellectual disability and One of the reasons for doing this is that it can help and what's called the diagnostic odyssey where parents are searching For the reason for problems in their child. Should they develop delays in development Development a late in you know speech development or possibly having a lot of medical problems this can avoid unnecessary and expensive testing and Decrease the time to intervention such as you know early intervention Services physical therapy and those types of things also it would allow the family to be informed about any potential Genetic risk if they have additional children So as you heard about the NIH Requested applications in this area to look at some of the implications and challenges and opportunities involving genomic sequence information In the newborn period So the overarching aims for our study are to look at how we might extend the utility of current newborn screening To devise a clinically oriented research framework for analysis of next-generation Sequencing in newborns and to develop best practices that might be incorporated into standard clinical care the groups that will be studying include children from early age up to age five years with Conditions that are currently identified through standard newborn screening Including PKU and other conditions Metabolic conditions cystic fibrosis hearing loss and then another group with Diagnosed conditions that are not currently on the newborn screening panel, but for which some people have Suggested you know might be important to include and those are listed there and then finally we have a group of Babies who whose mothers and fathers will be ascertained and recruited during their pregnancies with the child and This is what we're terming the well-child group and my co-principal investigator in this project Jonathan Berg has developed on what we call an age-based modified metric system Which looks at conditions And whether or not there's treatment or action ability for them versus the age of onset for conditions And so if you look at the upper upper left hand quadrant there You'll see conditions such as PKU So ones that are currently screened for and others that we think may be Beneficial to screen for and so we're calling this the next generation sequencing newborn screening category Then if you look at conditions Up in the upper right hand corner such as breast cancer gene mutations So those would be actionable you can do increased surveillance some mammography or some individuals may elect to have mastectomies done to prevent Breast cancer and so this would be in the adult onset medically actionable category And then finally conditions that impact children, but for which there's no real treatment established treatment yet Oh, some you know might have some research protocols others such as Tay-Sachs disease really no Treatment at this point Rett syndrome is another example of that and so that's Childhood onset, but non medically actionable condition and finally those Conditions such as Alzheimer disease that wouldn't begin until adulthood and for which at least at this time Unfortunately, there's no treatment and that would be adult onset non medically actionable. So we are Breaking down these different categories in terms of what information might we want to give back to families and as you can see this Line here is can vary if you know better treatments become available more conditions would go into the NGS NBS category and the line between adult and childhood onset is often quite blurred Because many conditions can have onset in children or adulthood and there's no way of determining that and For our project we will not be returning or giving families the option of learning about any of the adult onset non medically actionable conditions, but again that category may change as you know treatments develop You know such as treatment for Alzheimer's if there was some way to you know Treat a child early on to prevent Alzheimer's then that you know Gene may may change Okay, so we score individual genes to determine what category they should be placed in and Again this NGS NBS category And the way that we do this involves what's the severity of the condition? What's the likelihood that if a person inherits the gene that they'll have a severe outcome? What types of interventions are available? How easy would it be to? You know intervene with with the intervention of the treatment How acceptable would it be is it getting? Daily shot is it being on a special diet? Is it you know having an organ removed something like that all plays a role into the acceptability? And then what's our knowledge base for some conditions? there's a lot of literature about the the genetic condition for other things there may only be one or two papers so we We score those conditions and So in doing this we take away those quote incidental findings so no genetic changes will be revealed Through sequencing that are incidental Isn't it just an example of one of the conditions that may fit into this next generation sequencing newborn screening category is? Called multiple endocrine neoplasia type 2b. This is this condition that causes thyroid cancer in infants with certain Jeanette types of gene changes in the ret gene and All children with these certain mutations will develop thyroid cancer 50% will develop another type of tumor called a pheochromocytoma At least half of the individuals don't have a positive family history the condition arises due to what's called a new mutation And it's not suspected unless there is a family history and infants at birth look Perfectly normal and healthy so the benefit of identifying the mutation would be that you could prevent the cancer by removing the thyroid and you could monitor the occurrence of the other tumors through special screening of biochemical levels and So this would really impact a person's medical management So looking at this with in terms of the information that would be reported back We will be Randomizing people who decide to participate in the project into different groups one will only get The information related to their child's underlying condition if that's known or to What's in that that next gen sequencing newborn screening category others will have the option of getting additional information such as non-medically actionable childhood onset or adult onset medically actionable conditions or Carrier status and we will not analyze this information unless the parents request it and One other thing is that this adult onset non medically actionable We will not analyze or report back So this is what the the groups look like in terms of those with known conditions those in the healthy cohort Again, they'll be randomized into one who won't get any additional results and those with the Ability to make decisions about what information they would like to have we're utilizing a saliva samples instead of blood spots just because of sort of the the timing of when we'll obtain the samples after getting consent from families and the Another part of our project or the LC component of our project is to develop best practices to Incorporate next-gen newborn screening into clinical care by exploring these ethical legal and social issues involved in informed decision-making and return of results and Our colleagues at RTI have developed a decision aid tools to help families do this And this is just one screenshot from one of the decision aids And it will help families to have a better understanding about what newborn screening is it will Explain traditional newborn screening conditions and those in these additional categories that we'll be looking at so And then it will let us see how parents are thinking about this because we're very interested in that Information so do they want to have their child go through genomic sequencing? Are they not sure? do they you know decide no I don't want to have this done and so that's one of the things that will be studying in our research project and These are many people who make up the team our NC nexus team both at UNC and RTI And I'd like to acknowledge all of them, especially my other PI Jonathan Berg Don Bailey at RTI Chris Rene Who's at UNC in charge of our project three and Megan Lewis who's our? Project three co-PI at RTI and our project coordinator Laura Milko and many others who help us in the Actionability scoring