The Genetic Causes of Birth Defects

Ajouté : 2026-05-22

[00:00:09]hi welcome to this afternoon's webinar the genetic causes of birth defects what we know and what we don't know my name is vanita leedam and i am with the national birth defects prevention network today we will welcome dr sonja rasmussen mdms who is with a professor at the department of pediatrics obstetrics and gynecology and epidemiology at the university of florida dr rasmussen is a professor at university of florida in the college of medicine and college of public health and health professions in this role she serves as a clinical geneticist seeing a broad range of genetics patients and as director of uf's precision health program which focuses on integration of genomics into clinical care dr rasmussen recently joined uf after 20 years at cdc in atlanta while at cdc dr rasmussen worked on the national birth defects prevention network study and bdps study a large case control study to identify genetic and environmental risk factors for birth defects and on studies to better understand the morbidity and mortality associated with genetic conditions she also served as the deputy director of the influencer coordination unit responsible for cdc's pandemic influenza preparedness activities as the act director of the office of public health preparedness and response responsible for cdc's public health preparedness and response activities and editor-in-chief of cdc's morbidity and mortality weekly report series dr rasmussen was lead author of the paper confirming zika virus as the cause of birth defects published in the new england journal of medicine in 2016. she served in leadership roles during several tv responses to public health emergencies including 20 the 2009 h1n1 influenza h797 influenza middle east respiratory syndrome and zika virus she also co-edited the latest cdc field epidemiology manual and most excitingly she works with my program here in south carolina um with the south carolina birth defects program we're very excited to work with her and very excited to have her here on our webinar today we thank the march of dimes for co-sponsoring and as a quick note of housekeeping and please enter your questions into the text during the webinar if you'd like but we'll save all questions to the end thank you so much for joining us today and welcome dr rasmussen great um thank you so much fanita i'm excited to be here and to be talking about something else other than kovid right now um i'm vanita said i'm going to be talking about the genetic causes of birth effects what we know and what we don't know and i am appreciative to the national birth of x prevention network and to the march of dimes for sponsoring the webinar and um also for the south carolina birth effects program for getting me involved in birth defects again so thank you venina so um i'm going to just give you an overview of what i'm going to talk about first i'm going to talk about what do we know about causes of birth defects in general how often do they occur it's surprising that we have a fairly limited information about this i'm going to talk about the types of genetic causes so chromosome abnormalities single gene disorders and then that multifactorial that kind of group that we don't understand very well and then i'm going to give some case examples um case examples of different types of relatively common birth effects for which i'm going to give you some examples of causes um to give you some sense of the um genetic causes i am going to have to give you a brief uh primer on um genetic testing but i'll try to keep that to a minimum so what are the causes of birth effects as i said there are genetic factors um and the main categories that those fall into are chromosome abnormalities and single gene disorders there's non-genetic factors and of course we're all trying to understand those better because those are things that we can change we can try to be sure that a woman gets folic acid during her pregnancy so that she doesn't have a baby with spina bifida we know certain medications increase the risk of birth defects we know there's maternal conditions like diabetes or obesity increased risk of birth effects infections of course and you heard about zika cmv toxoplasmosis and of course the original one of rubella and then environmental exposures like alcohol and other environmental exposures like mercury um then there's this big category of multifactorial and this is really a combination of multiple genes and environmental factors and i think this is something that we're going to learn more about as time goes on human disease in general and birth effects i think we're going to learn that more are uh due to multifactorial uh origin but i'm hoping that we're going to be able to understand what those multiple genes are and what those environmental factors are so um i'm going to start with this paper by one of my mentors dr lou holmes and his colleagues in boston and it was published in birth fx research in 2018 and it used data from the active malformation surveillance program at the brigham and women's hospital i had the opportunity to work with lou on this project back in well a whole long time ago when i was still a medical student in 1990 and uh this is a very nice program that's been uh collected data for a lot of years it looked at the presence of malformations diagnosed in the first five days of life among almost 300 000 births over a 41 year period they identified about 7 000 infants and fetuses with one or more birth defects and that was about 2.4 percent now remind as a reminder that it's in the first five days of life so that compares to for example the metropolitan atlanta congenital defects program are some of the other surveillance programs that have a higher rate maybe more in the range of three percent and then they classified the etiology as best they could into mendelian or single gene disorders chromosome abnormalities multifactorial and other other types and this is the results here you can see on the left side um you can see the actual the actual table that was in the paper and i'm going to focus on these data um not the earlier data that ended in 1985 but the total um from 1972. they had a little a bit of a gap in there but then until 2012.

[00:06:31]and here you can see i think the biggest story here is how many times we really just don't have an idea of what caused a baby's birth effects you can see more than half of the time we can't tell families what caused their baby's birth effect but um and here you can see this multifactorial group the multifactorial group is really important too because for those families we know that they have an increased risk in future pregnancies um a small increased risk but yet an increased risk but in most cases we don't understand what those genes and what those environmental factors are then i'm going to talk here so this study dr holm's project includes babies with post axial pot polydactyly when you have an extra little pinky finger which i know some programs don't include and that's in the orange here but i'm going to have you focus here on this little blue slice and the gray slice the gray is the ones with chromosome abnormalities and the blue is with single gene disorders now keep in mind this was a big number of years and so in recent years we have more information about chromosome abnormalities and so if you we looked at a single time say we looked just uh in the last five years i think we would see that chromosome abnormality rate be higher and i think we would see single gene disorders be higher too but i think this study is helpful in that it emphasizes how much we don't know about causes and how important research into birth defects is so there are some study limitations first it was limited to diagnoses made in the first five days of life the diagnostic studies chromosome microarray and exome sequencing for example that i'm going to talk to you about that are really the exciting area and are allowing us to make a lot of more diagnoses of genetic conditions than we could in the past that was used in only a few infants the study was over 41 years which is you know a lot of positives but it also the negative is that on included times where we didn't you know we were um using very limited genetic analyses and then another thing is about 20 percent of the malformations were actually in pregnancy terminations um which complicated the diagnostic assessment so i want to just begin you know i'm a geneticist so i think this is really really important but why is making a clinical genetic diagnosis important and there's a lot of reasons one is for families they have a baby with a birth defect one of the questions they want to know is why did this happen to me and is it going to happen again in a future pregnancy we really need to figure out if there's a genetic diagnosis to be able to give them that information [Music] what about what other organ systems are involved and i'm going to show you an example of a case that actually um i have seen um that where by identifying what the genetic diagnosis was it made us look for other things that we wouldn't have actually probably recognized right away and that helped the child's health so are there other defects that need to be looked at um are there uh you know for example a child that has a a cleft lip um if it's a condition that uh also kids have heart defects then you need to be sure that you do an echocardiogram so it helps doctors to think about what other tests need to be done it also helps to assess the risk for neurodevelopmental delays for newborns and infants and that can help to make sure that child gets referred or early intervention services early so that they have the best chance at reaching their full potential and then finally it provides more accurate prognosis is this a condition that the child is going to do well and that we know that children are going to grow up or is this a condition that may have a limited type of lifespan so i want to just start with talking about genetic studies and how much genetics has changed as far as the studies i started in genetics as a genetic counselor in genetic counseling school in 1981 i finished medical school in 1990 i finished my genetics residency in 1996 huge changes in that time in what we know about genetic causes because of improvements in genetic testing really in those days when i was a genetic counselor medical student and even a fellow really all we had was cytogenetics and and some limited information about single gene disorders but not really good testing for them in general so what that means though is that there's a huge increase in the number of genetic tests and um this is a paper that was published by katherine phillips in 2018 you can see the huge number of genetic tests on the market and how rapidly they're increasing and as of 2017 she reported that there were 75 000 genetic tests currently on the market with more than 10 000 unique test types and 10 more genetic tests were being added each day so it means as a clinical geneticist as a genetic counselor every time i see a patient i have to think is there a new test that i should be thinking about for this child it really is um rather overwhelming but exciting at the same time so what are the types of genetic testing in general because i'm going to talk about a couple of these and then some i'm not going to address at all first of all most of what we're going to be talking about is diagnostic testing the kind of testing that you do when you're a clinician you're looking at a child you're trying to figure out what the cause is i'm trying to come to a diagnosis so that's diagnostic testing there's also prenatal testing and that's done by ob gyns maternal fetal metal medicine specialists that prenatal testing can be screening or it can be diagnostic testing and it's really really important to figure out which one you're looking at whether it's a prenatal screening with course known about prenatal screening we were doing afp screening even back in 1981 when i started in genetics as a counselor then looking at that knuckle translucency and then now there's non-invasive prenatal screening where you you actually draw the mom's blood and you can look at some of the fetal cells and i'm going to be talking about that because um i think it comes up pretty frequently i know some of the attendees are um are um abstractors and so that comes up there then there's prenatal diagnostic testing and you can do tests that you can do on a on an infant you can do during pregnancy but you've got to get access to those samples and the way to do that is either by amniocentesis or chronic phyllis sampling then there's these other types of testing that i'm not really going to be talking about but i just want to mention them the um the predictive testing for cancer predisposition for example brca1 and brca2 carrier testing or heterozygote testing for example tay sachs testing for people of ashkenazi jewish background cystic fibrosis sickle cell disease and then newborn screening is actually a really important area of uh genetic testing um and we all know uh those of us in public health know that every baby that's born has the opportunity to have this newborn screening done often a lot of those are genetic tests and to determine um whether the baby has something that if they get treatment for they can prevent severe outcomes so i'm going to divide for the diagnostic testing i'm going to divide it into two categories to identify chromosome abnormalities and then to identify single gene disorders um to identify chromosomal matter melodies there's really primarily a karyotype and a chromosome microarray and then single gene disorders you can if you know what the kid has you think you know what the child has you can send just looking for a single gene these days we don't always have to be that smart anymore we can do a multi-gene panel we can say well i know this child has developmental delay or has autism and i can send a panel of genes or i can do exome sequencing or i can do genome sequencing and i'm going to talk about all of those the exome is really focusing on the coding regions the exons of the genes where the genome sequencing is really sequencing uh all of the genome so i just want to tell you about how we're going from big changes to smaller changes so this is for routine chromosomes to looking at chromosome microarrays we're going from 10 million to 0.01 million so um or the same thing here a picture here you can see how with a karyotype we would be looking for maybe that little tiny piece of chromosome 5 missing or extra um where with chromosome microarrays we can see even a smaller piece than maybe could be seen under a microscope and then this is the gene analysis where we're looking at dna sequencing previously we were doing something called saying our sequencing but with this next generation sequencing or massively parallel sequencing we can do it a lot faster and a lot cheaper so i'm going to start with chromosomes chromosome analysis karyotype this is something that still has an important role in working up certain kids it's looking at an individual's collection of chromosomes it's trying to look at abnormal numbers or structures of chromosomes so in some cases for example i'm going to show you in a minute you can have a whole extra chromosome 21 that means a child has down syndrome or you can have a little tiny piece of a chromosome missing and you can see if you have a little tiny piece missing here um you might not be able to see it on these on this karyotype um in in the old days we used to try to stretch those chromosomes out if you caught them at a certain time in their division they would be stretched out more and you'd had a better chance if you were uh had a lot better eye than i ever did you could see the piece missing but the limit of resolution you have to have three to five mega bases missing lots and lots of of those letters missing to be able to see that on a karyotype um then there's a chromosome microarray this allows us to see much smaller areas of loss or of gain of chromosome material from one kilobase 000 bases too many megabases and of course um one of the people i work with says this is one of those times when it's location location location we can have areas where you have an extra piece um or a missing piece of chromosome that doesn't really matter um because it doesn't have any genes in that area but depending on the size or the genomic location of that copy number variant that extra are missing um sounds like my amazon package is here so um the deletion or duplication can include zero one or many genes and it's also important to look at with these results that the variants can be benign they can be pathogenic that means that they can be known to be associated with uh problems for the child or they can be of uncertain significance and this is one of the things that i think is um one of the really hard things about genetics these days is dealing with the uh variants of uncertain significance which we see both on chromosome microarray and on some of the other tests that we do so just when do you do a karyotype when do you do a chromosome microarray chromosome microarray is more sensitive at detecting small areas of missing or extra material and so oftentimes you are going to focus on you doing a chromosome microarray it can detect copy number variants little pieces extra missing as small as 100 kilo bases or as small as a single exon in a gene and it is really thought to be the first line test for persons with developmental delay intellectual disability multiple congenital anomalies and or autism spectrum disorder typically insurance pays for it this is one of the issues with genetic studies is we still struggle with getting insurance to pay for some of this testing and this is typically paid for and when i think about the times when i used to see patients when i was at cdc i saw patients at emory for a while the yield of a karyotype for those kids is about three percent of the time you get a diagnosis where the yield with the chromosome microarray is much better about 15 to 20 so your chances of finding something are a lot higher with the chromosome micro ring so then uh what about those so i'm just going to go back here there are times though that a karyotype is still needed and that's because we know that there's extra missing material but we don't know how it's arranged and for example if you have a child with down syndrome i'm going to give you an example of this later you need to know is that three separate chromosome 21s or is one of the chromosomes attached to another chromosome what's called a translocation that information is absolutely necessary to know not if the child has down syndrome or not the three sets of chromosomes three chromosome 21 tells you that but to tell the family whether they're going to have another baby with down syndrome they could have up to a hundred percent risk of having another baby with down syndrome depending on what that karyotype shows so if you if it's a child with down syndrome you really need to have still a karyotype so um single gene test this is when you are pretty sure that the child has um a single gene disorder and you know what that is and then you test for that single gene and you can either test um these days i think most of the time people are doing gene sequencing or and deletion duplication testing in the old days um maybe more common mutation panels then there's these multi-gene panels and we are using a lot of these in clinical genetics if you have a child with um uh autism and developmental delay um there are a number of genes that can be tested using this massively parallel sequencing the next generation sequencing um and it's cheaper and faster than doing it gene by gene by gene by gene if you think of maybe there's hundreds of genes you wouldn't want to do that one by one although i have to tell you sometimes i have to really point that out in letters to the insurance company that wants me to be able to do just single gene testing many disorders are genetically heterogeneous they look exactly the same with one gene or the other and of course so it's really important to be able to use this multi-gene testing and um i've talked to you already about intellectual disability autism there's also panels for hearing loss for retinitis pigmentosa for infertile seizures for congenital heart defects and so on an exome sequencing which looks at the exons so exons are the segment of dna that's containing information that codes for the protein it's the part that that you know remember that there are exons and introns introns are the intervening sequences they get snipped out and they don't end up coding so this is looking at just the part that ends up coding going into a protein exons only make up about one percent of the human genome the rest of it is non-coding one to two percent and all exomes in a gene gnome are known as the exome that's where the word comes from so the sequence of the exons is called exome sequencing or some people still call it whole exome sequencing i think we're trying to move towards exome sequencing and that's something you might say well why don't you just do that why would you do any of those multi-gene panels well one of the things when you do exome sequencing sometimes you find things that you didn't really want to know for example um and and you might find out about changes in genes that didn't don't have anything to do with the um for example you're seeing a child with autism and developmental disability and then you find out that the child has an increased risk for breast cancer has a mutation in the breast cancer gene of course that information might be helpful to the child later on to know that but typically we don't do that kind of testing in children and um so that is something that complicates the exome sequencing testing and then you can do genome sequencing genome sequencing i'm not going to talk about a lot because that is really primarily done right now more as a research study but i think in the next few years we'll be doing more of it so um here i've talked already about prenatal screening versus diagnostic testing it's important that screening is screening it's like screening that you do for prostate cancer where you look at a prostate-specific antigen and you see the psa is high and you say this person's at increased risk of having prostate cancer or a mammogram that's a screening to look for breast cancer doesn't mean that woman has breast cancer she has something on there that suggests that she might have breast cancer the screening versus diagnostic testing is really important in prenatal and especially for those of you that are doing um abstracting of charts so i'm going to talk about non-invasive prenatal screening because i have seen um this is really being widely used now it first became available in 2011. i remember when and genetics when people first started talking about this it seemed too good to be true you could know information about the fetus without doing an amniocentesis or a chorionic villus sampling that would put the fetus potentially at risk and so it is really an exciting thing in 2012 acog the american college of ob gyn approved its use for women that had increased risk and then in 2016 they said you know women should have the opportunity this test is available they can be educated about it about the pros and cons of the testing and make an informed decision deciding if they want to have the screening method done or not so it's also known as cell-free fetal dna screening it's done on drying blood from the mom about 10 weeks gestation or later um the pregnant pregnant woman's blood contains dna from her pregnancy from her placenta and then you can look at does the baby have does the fetus have trisomy 21 trisomy 18 tries to be 13. um some labs will also can also report other kinds of abnormalities can look at sex that will allow you that opportunity to look at sex chromosome abnormalities and other things you need to look at what the test that was done and what it shows and what it doesn't show so here you can see this is from a jam of paper a couple years ago so basically um this is the placenta and the placenta releases fetal uh dna fragments from the placenta into the maternal circulation and that's what you're testing so here uh you know there we go again okay so here you're looking at the the dna you have to be able to tell the mom from the fetus and then you can say if there's a pregnancy with trisomy 21 if there's three for example sequences triplication of sequences of chromosome 21.

[00:26:16]so now i'm just going to start going through some cases because i always think it's more interesting to hear about cases i hope you guys agree this is a full term infant born to a 26 year old mother the prenatal ultrasound an echocardiogram showed an atrial ventricular canal or an av canal or an avsd um non-invasive prenatal screening that nips study done at 10 weeks of pregnancy was positive for down syndrome and the mom didn't want to have any further testing done so um i think this is really i'm trying to do this to illustrate the importance of prenatal screening that this is screening so you read the if you go on the labs websites they talk about how accurate this information it is it does have high sensitivity if the fetus has down syndrome you have a 99 99.1 percent chance of identifying it um the specificity is high 99.9 but remember your epidemiology classes where they told you that positive predictive value really depends on how likely it was for the person to have down syndrome in the first place how likely was it for this mom at age 26 to have a fetus with down syndrome and for a 26 year old down syndrome is um the risk of it is pretty low so the positive predictive value the chance that the baby actually has down syndrome at that uh time is 59 so maternal age of 26 the positive predictive value is 59 for this test so you see it's very different if the mom is older if the mom's 40 she starts with a much higher risk for trisomy 21 in the first place then her positive predictive value is higher or 95 now we knew this baby had an av canal that's a fairly classic um defect in a child with down syndrome so i think you probably would have given this mom a higher risk than um than that 59 but it's important to note that um just because there's non-invasive prenatal screening that says down syndrome what it means is there's a risk for down syndrome it doesn't mean that the child has down syndrome the other thing as a reminder you really need a karyotype so because we want to know what kind of down syndrome it is so here the child is born has features of down syndrome and here's the cdc figure one of the figures that was drawn of child with down syndrome and so you can see some of those features and here's a karyotype this is actually a karyotype that is from a book but you can see the three separate chromosome 21s here that means his family for future pregnancies is at a low risk about one to two percent of having one of one percent to have another child with down syndrome um now if instead of seeing the three chromosome 21s we saw two and then one uh attached to chromosome 14 or if we'd seen even more so and i saw a child in clinic about a week ago that had two chromosome 21 stuck together then it was really essential for me to um look at the parents chromosomes because if the parents if one of them had that translocation where the two 21s were stuck together they would have a chance of 100 chance of having another child with down syndrome so um here are just for abstractors this is why having that karyotype is so important if you don't have the karyotype if you have a chromosome microarray you can say this is down syndrome unspecified but you need the karyotype to say is this uh trisomy 21 meiotic non-dysjunction is it mosaicism or is it a translocation and that's really important for uh coding and and even more important for the family for the recurrence risk information so case two this is a full-term infant born to a year old mother you do family history and the dad also has a cleft lip and the prenatal to ultrasound showed a cleft lip and palate a non-invasive prenatal screening done at 11 weeks of pregnancy was normal and mom declines further testing and um here's some pictures from cdc of cleft lip and cleft palate and this is a picture that jeff murray kindly lent to me this the physical exam shows lip pits and these lip pits really tell us that this is not just garden variety run-of-the-mill um cleft lip and palate it tells us to be thinking about this condition called vanderwood syndrome which is a single gene disorder due to pathogenic variants in a gene called irf6 so it really tells us to look at the irf6 gene you need you're not going to see that on a karyotype you're not going to see that on a chromosome microarray you're going to need to do molecular genetics testing of that gene and then the recurrence risk to that family dad given that the dad we heard that dad had a cleft 2 would be a 50 risk of passing on vanderwood to future children so this is a next child it's a six day old infant with a cardiac murmur um they do an echocardiogram and it shows a tetralogy of fellow um the family had had no prenatal care so you don't have any testing from during the pregnancy the family history is negative and genetics is consulted and genetics notes that there are some mild dysmorphic features but um but not uh something that is immediately recognized so a chromosome microarray is sent that would be the typically the first test that would be sent and it shows a 22q11.2 deletion this previously was called the george or sometimes called velocardia facial syndrome and what this tells us first of all it tells us that we need to look at the parents because sometimes parents who look pretty normal can have the deletion too and that puts them at increased risk for future pregnancies but it also tells us there's a number of other conditions that are seen in kids with 22q deletions and so we've got to think about those we had a kid recently a child a baby recently that was diagnosed with 22q deletion and then no one had noticed the baby had had some issues with feeding but no one had looked had gotten a good enough look back and um they were able to we were able to see that the child had a cleft of the soft palate that hadn't previously been recognized um calcium can be tested you can have hypocalcemia renal ultrasound should be done and that in this baby showed a renal problem and these are some of the physical features i think you can see that maybe this child has some minor dysmorphic features but typically um not something like down syndrome where i think um everybody recognizes this condition and this is just a study that lorenzo botto and a group of us from cdc and from children's hospital of atlanta did several years ago and i just want to show this that there are some of these heart defects that really have a pretty significant contribution to 22q 11.2 deletion if you look at interrupted aortic arch type b about half of those babies had 22q deletion truncus arteriosus is about 19 and then here's the case that i was telling you about tetralogy of flow about 12 there's some others that are lower rates you can see hypoplastic left heart it's not very common at all and among all babies with heart defects is it's about one and a half percent so now the last case um is a 34 year old mother who has diabetes she has type 2 diabetes um a prenatal ultrasound at 16 weeks shows spina bifida and the baby is born at term um baby is non-dysmorphic no other abnormal findings a chromosome micro ray is sent and the baby has normal results and this is spina bifida um the most common uh cause of spina bifida is multifactorial etiology and that's a combination and we all know about the importance of folic acid in spina bifida so it's a combination of nutritional factors genetic factors and other environmental factors like diabetes like certain medications and but we don't completely understand those genetic factors we have some studies that have told us about those but we don't completely understand those yet we know that there are gene environment interactions there though that some of the genes that seem to be important are ones that are associated with how folic folate is metabolized and just for this case it's important to know that multi-factorial etiology because that's a child that you would want the mom in a future pregnancy to get a higher dose of folic acid starting one month before becoming pregnant and during the first three months of pregnancy before that happened um before we were able to recommend that people got folic acid to prevent recurrence the high dose the high-dose folic acid to prevent recurrence um the recurrence risk was two to five percent and that has been substantially decreased uh when women get folic acid in future pregnancies get supplementation in future pregnancies so i just want to talk a little bit about rapid exome sequencing because this is becoming more and more common at lots of hospitals across the united states and some of you might work in some of those hospitals this has been shown to have a high diagnostic yield and result in changes in clinical management it's usually done right now in kids that are critically ill and where there's a suspected single gene or monogenic disorder and this is a paper that was just published recently there's been a number of these papers and i just chose this one because it was a recent one so here you can see um this study included 131 infants and children that were either in the neonatal intensive care unit or in the pediatric intensive care unit that were critically ill they were excluded for different reasons they ended up with 108 that underwent ultra rapid exome sequencing they can do this exam sequencing in 24 to 48 hours you know obviously you have to have a lab that's ready to take the specimens and jump on them right away of these 51 so 55 out of 108 had a molecular diagnosis made and um 42 out of 108 or 39 change the clinical management now there's a number of different studies of course it all depends on how you uh what cases are included in the study in the first place and so sometimes those numbers are higher sometimes they're lower but you can see that this really could make a difference especially in these kids that have critical illness at the time of uh their evaluation in either the nicu or the picu and here is a table and i just picked one of these here one of the babies that had birth effects um the baby had severe high drops and joint contractures and they were able to identify uh condition lethal congenital contracture syndrome 11 no one would have come up with that diagnosis without doing a study without doing a laboratory study because these different types of congenital contracture syndrome look similar and they look similar to some other conditions as well this allowed them to uh direct the care towards palliative care for the family within 24 hours of getting the results so this is a paper written by stephen kingsmore who's at rady children's hospital in san diego he's been doing this rapid exum sequencing and been one of the leads in this area for several years and this is a paper he wrote you can see hot off the press november 2020 in in journal of pediatrics is rapid exam sequencing standard of care in the neonatal and pediatric intensive care units and he argues that we need to be thinking about that uh rapid exome sequencing or kids where there are they're critically ill to try to come up with a diagnosis and if possible change care so i am going to finish up and then i know that diana has some questions that people sent in and i can see that there are looks like there's some other questions that have come in but just to summarize birth defects often have a genetic cause it can be due they can be due to chromosome abnormality a single gene condition or multi-factorial where in most time we don't really understand what those genetic factors are as we learn more and genetic testing improves we're gonna identify more genetic causes and it's incredible to me in the um years since 1981 when i started in genetics how much more we know than now than we did then and it's incredible i think it's an advantage uh a huge advantage because we can tell families the likelihood of it happening again we can help give a better prognosis for their child and we can take better care of their child now than we could in the past we can tell them that we need to look for certain other conditions and rather than waiting for that to be identified when the child gets sick with a heart problem or a kidney problem and um then the other thing is information on genetic causes is really essential not only for appropriate patient care but also for the counseling of family regarding their recurrence risk and and of course families when they have a child with a problem they do want to know for a future child what my chances are of this happening again so i'm happy to answer any questions thank you so much dr rasmussen for a great and informative presentation um we do have a few questions coming in feel free to keep chatting them in and we'll track them as they come i've kind of grouping similar questions um we'll start with a fun one what do you view as the iconic birth effect for which we have little information on ideology yeah i saw this question before and this is a tough question so um the person who asked it this is a hard question um i i think that we don't know a lot about things that are more rare but when because they're we just don't have enough um cases to be able to do a lot of studies on them but one of the defects that i think is really that we just don't have enough information on is gastroschisis gastroschisis seems to go up and down and seems to be almost occurring in outbreaks and seems to be among younger women and lots of times doesn't have a chromosome abnormality most the time doesn't have chromosome abnormality doesn't have single gene conditions so you know that would be and it's also a defect i'm really interested in so i'm sure there's others too but that i'm going to choose that one for today i feel like we don't know very much about gastroschisis and it's really a challenging defect thank you um how do we integrate genetic and social science research to learn more about what we don't know and apply it yeah i think the social science research is so important especially when when we start understanding causes of birth defects when we know about for example accutane as causing severe birth defects the acne medication causing severe birth effects how do we how do we make sure that women know that when they're taking accutane that if they get pregnant they can have a baby with a severe birth effect um and so i feel like that's one of the important areas i think um you know i don't think this has been used very much but i think it might be interesting to maybe do some focus groups and understand what women think about caught birth effects causes what do they think has caused your baby's birth effects and certainly we know examples in the past where mom's um proposals have ended up you know for example rubella the story about rubella is that it was moms in the waiting room of the ophthalmologist that came up with um knowing that it was they all had a rash like illness they all had rubella in the during their pregnancy but i think that might be interesting too but that's sort of speculation but i think the big thing is trying to make sure that for what we do know the causes that women get that information and are able to act on it okay okay uh next one are there genetic links between birth defects and subsequent development of cancer that is an area that um is uh of great interest to me and several of my colleagues uh it does appear that there that children with birth defects do have an increased risk certain types of birth effects do have an increased risk of cancer and of course it's incredibly important for us to understand the reason why in part because we want to know which of those kids do we need to screen so we know kids actually for example with certain genetic disorders like beckwith syndrome is a condition that's associated with omphalocele those kids um are an increased risk of liver tumors uh hepatoblastoma and of wilms tumors tumors of the kidney and so it's those kids if we can identify the beckwith wiedemann syndrome um then we can uh do ultrasounds do afps on those kids and prevent them not prevent them from getting cancer but know early on and so at a time when it's more treatable um i think the question is for the ones that we don't identify a syndrome is there a gene that's important or could it be a common environmental cause that increase the risk of both the birth effect and the cancer and i think we don't know the answer to that right now and it's really critical research to be done in the future so great question thanks why does cdc exclude select defects with genetic ideologies in bd steps yeah so when you're doing epidemiologic studies you'd like to have the groups as as homogeneous as possible if you have cases in there that maybe are have a different uh pathogenesis um and and i think you know some people have proposed that you shouldn't do that some people have said well gosh if you looked at kids with down syndrome who have a heart defect versus don't have a heart defect maybe you could identify what the causes of heart defects are in down syndrome um other people say well because we know the cause it was the down syndrome it was related to that extra chromosome 21 and so that's not a case you should be looking at other environmental factors i think that is you know i was involved in some of those early decisions for the national effects prevention study and i think that's what we were thinking then is that we want it as clean of group as as homogeneous a group as possible to maximize the chances of identifying risk factors which chromosomal genetic defects have a significant difference in incident rates by race or ethnicity um for chromosome or genetic birth defects i'm not aware that there are a lot that have big differences you've seen for example spina bifida um can be more freaking frequent among women of hispanic background and some of that may be differences in getting uh um amounts of folic acid but that's not a genetic cause that's a multi-factorial cause so for chromosome and genetic birth effects i think sometimes we see differences for example we see differences in rates of down syndrome um because there may be a different rate in pregnancy termination among different race ethnicity otherwise i can't think of any differences in incidence rates right off the top of my head so okay do you know of any researchers who are using epigenetic analysis to study association or potential causes of birth defects since such as vader or vectoral um you know known syndromes with genetic associations that are not yet known yeah i think there are people that are doing that i couldn't tell you off the top of my head but i think really there are a number of um areas of research that are being proposed because as i told you there's so many kids with birth defects that we don't know the causes that i think people are looking at more um things like epigenetics and other types of causes that that um just trying to get to the bottom of this okay can you think of a good example of a multi-factorial cause of a birth defect where a direct interaction of genetic abnormality with other factors can lead to a specific defect yeah um you know we we used to try um you know when i was at cdc we tried to look at some of the people that had um um that not taking folate and um having different um uh genes for folate metabolizers um i never it never was a completely convincing story to me and it's always hard to know really whether the woman was getting folic acid or not um and then looking at the um genes someone else on the call might have a better more recent data on that i think that's that's the thing that would be kind of a nice story if we could put it all together and certainly i think there are some researchers that feel that that's true um but otherwise i don't know of other ones and i was never completely convinced um in the data that i've seen in the past um do you have any information about the new information uh regarding children born with cerebral palsy where that's considered possibly genetic um findings of linked genes um or genes that kind of control how the brain circuits being wired during early development in some genetics yeah there are a number of genes being identified i didn't focus on that uh because um cerebral palsy is more of adult mental disability than it is a birth defect um it is something we as clinicians are starting to send panels of genes for cerebral palsy and actually oftentimes families come to me after the neurologists have sent um panels of jeans and they get some they get results that they um are asking for help in interpreting especially when they get variants of uncertain significance they have sent families to us to say do you think this is what really caused the cerebral palsy or is this a variant of uncertain significance doesn't mean anything at all so and another kind of similar um not necessarily a birth defect question but leading to that do you see low birth weight with infant death as a possible birth defect with genetic causes um you know i think there is a lot of overlap between low birth weight and genetic disorders and i think whenever you see a child that has low birth weight it's important to look especially carefully to see if there is something else going on if there is a genetic condition we know not infrequently there is for kids that have either low birth weight or failure to thrive um but sometimes it's something totally separate it's not genetic at all it's something that happened during the pregnancy where the mom maybe wasn't getting sufficient nutrition or the placenta wasn't working right so it is something to always when you see a child of low birth weight that think about the possibility of a genetic cause but usually you need something else to sort of push you over the edge to start doing genetics testing oh this says with infant death infant death would certainly um increase your suspicion so okay we have just a couple more questions um so if there are uh participants with questions please feel free to type them in the chat we have plenty of time with dr rasmussen uh next one is what do you think is the way forward to solve many of the birth effects with unknown ideologies what's kind of the map for the future yeah i do think we need to continue to do the careful sort of epidemiologic studies and i know it it seems that they take a long time and they take a lot of money but we've you know the national birth effects prevention study bd steps those are important ways to look at environmental factors it's important to also continue to do those genetic studies and now that we have better genetic tools we have tools that we didn't have in the past it's really important to be able to use those tools i i do think you know trying to look at those gene environment interactions is going to be really important but it takes huge numbers that's what um what sort of my conclusion was of the the work that we did in national birth effects prevention study when we try to look at genetic factors and environmental factors is once you're looking at a child with a certain birth defect and then you're looking at okay the mom has to have been exposed to this or not exposed to this and then she has to have this genetic variant or not you're getting into you've taken what looked like big numbers and end up being pretty small numbers and so then it's harder to see the effects that's why we need funding to be able to look at bigger numbers to be able to see these effects so this may fall under the funding part as well but kind of following up on that infant death looking or recognizing that fetal death is often related to birth defects or you know they each have a higher rate when they're combined um do you foresee it being a possibility of actually doing genetic testing or more testing on stillborns um to trace some of those genetic factors and or likelihood of syndromes or birth defects yes yes and there are um some recommendations already that some geneticists have put together about what kinds of studies should be done on on a cell birth um you don't want a a baby that's been stillborn um there are um so i am now working with pediatrics but i'm also working with ob gyn at university of florida and when we see um fetuses that have um defects and sometimes we can see it's a fetus that is likely to eventually be a stillborn we try to be thinking right ahead of what kinds of studies need to be done because you need to be able to get those studies off quickly because that's the only way the family's going to know what their recurrence risk is in the future so i think we need more studies but also clinically i think it's starting to be used clinically as well so you talked a little bit about the um folic acid connection obviously to spina bifida and the really relation between genetics and and the medication what about looking at kind of the opposite side um medications that are actually known to anagens and related to the genetic susceptibility yeah i think that's something we really need to understand too it'll help us understand what the mechanism of the the uh teratogenicity is you know what is it because maybe the woman could stay on the medication and there would be a way to interrupt that keratogenic effect or maybe some women would be at lower risk based on their genetic findings certainly there were some studies many years ago looking at this for anticonvulsant medications that some women were at increased risk and someone were at lower risk so i i think that is going to be really important to look at as well and last question i currently have unless new ones come in um can you talk a little bit about the male female survival rate among conditions with genetic defects yeah in general it's an interesting um thing uh we all know that that women live longer than men that is true for babies that's true for babies with um prematurity for example um females females at the same uh gestational age tend to live longer i'm not sure we understand exactly why that is but there does seem to be a difference for some defects as well and some chromosome abnormalities for example tries me 13 18. okay so we'll give it a couple of minutes for additional questions to come in um on behalf of mbdpn march of dimes i want to thank you so much dr rasmussen um for this wonderful informative talk again the webinar will be available on the nbdpn site and bdpn.org for members if participants have questions about becoming a member you can also get that information on mbdpn.org um dr russ listen did you want to share contact information if there's additional questions or i think you have one more slide yes i want to acknowledge jeff murray and jamie frias i use some of their pictures for this presentation and um there is my contact information if anybody wants to reach out it's the same first four letters that i had at cdc for those 20 years and then it's just ufl.edu it's hard to break habits right they did that i didn't even do it but i think they just knew how forgetful i was i love it um you can also submit questions online to even need a ledum who sent out a lot of the information regarding this webinar and we do have future webinars planned one for january on birth effects prevention month activities and some ideas for that and again we thank all the participants for joining um on behalf of mbdpn and also thanking mbdpn and march of dimes for co-hosting and thank you venita litum for leading a lot of this and thank you again dr rasmussen this was a wonderful presentation and we will definitely follow up with questions um a lot of thank yous and a lot of positive compliments coming in excellent as always great topic very informative talk so a lot of good feedback um again we thank all of the participants please feel free to reach out with questions nbdp nbdpn.org for more information and we appreciate everybody participating and again mostly dr rasmussen for such a wonderful presentation thanks so much for all signing in now back to covington thanks you guys thank you bye bye