Trascrizione completa di Genetics for the Pediatrician(Grand Rounds Episode for MOC credit)

to test when. 32 00:02:29,637 --> 00:02:35,517 And we're going to also consider briefly the risk versus the benefits of genetic 33 00:02:35,517 --> 00:02:39,417 testing so that we're not overwhelmed by these tests. 34 00:02:39,577 --> 00:02:43,217 And we can really focus on what all of you do best, which is engaging, 35 00:02:43,297 --> 00:02:46,317 interacting, and seeing your beautiful patient. 36 00:02:46,537 --> 00:02:50,837 So it's going to be a rapid approach, but you don't have to remember the details. 37 00:02:50,917 --> 00:02:53,357 It's more the philosophy that. 38 00:02:54,151 --> 00:02:58,871 I've learned by being with these patients for almost 20 years. 39 00:02:59,231 --> 00:03:03,231 So we're going to get objective one over with really fast. 40 00:03:03,431 --> 00:03:08,251 What are some of the top 10 genetic consults that I see in my general genetics clinic? 41 00:03:08,371 --> 00:03:13,171 I also do craniofacial vascular clinics as well. It's a lot of fun. 42 00:03:13,211 --> 00:03:17,851 But in my general bread and butter genetics clinic, I see a lot of autism. 43 00:03:18,031 --> 00:03:22,131 I see some patients with epilepsy, multiple congenital anomalies. 44 00:03:22,131 --> 00:03:26,991 My mentor used to tell me a rule of threes, three differences, 45 00:03:27,071 --> 00:03:33,291 such as a congenital heart disease, short stature, features that are different from the family. 46 00:03:33,331 --> 00:03:39,111 And now we're thinking maybe there is a genetic condition that ties the pieces of the puzzle together. 47 00:03:39,311 --> 00:03:44,551 Those neurocutaneous disorders, neurofibromatosis, tuberous sclerosis, 48 00:03:44,791 --> 00:03:50,051 those patients with sensory neural hearing loss, our connective tissue disorders. 49 00:03:50,051 --> 00:03:52,171 Does this patient have Marfan syndrome? 50 00:03:52,371 --> 00:03:57,131 We get a lot of referrals for Erlos-Danlos, but good news, you can't make that 51 00:03:57,131 --> 00:04:00,911 diagnosis unless somebody is post-puberty nowadays. 52 00:04:01,351 --> 00:04:07,611 They've changed the criteria so we can really focus on our patients in a new, different way. 53 00:04:08,351 --> 00:04:12,211 Skeletal dysplasia, movement disorders, newborn screening, metabolic disorders. 54 00:04:12,391 --> 00:04:17,751 These are kind of our top 10 categories where you think of referring to a geneticist. 55 00:04:17,751 --> 00:04:21,311 And most of the time, the patients I'm interacting with in clinic. 56 00:04:21,871 --> 00:04:28,011 And we also, throughout this lecture, objective number two, we're really going 57 00:04:28,011 --> 00:04:31,351 to think in terms of these broad genetic categories. 58 00:04:32,131 --> 00:04:36,651 This is the slide I'm going to focus on for actually a couple of minutes and 59 00:04:36,651 --> 00:04:42,011 kind of the work portion of this lecture, because it's so important to understand 60 00:04:42,011 --> 00:04:45,511 the categories, but to really memorize those categories. 61 00:04:45,511 --> 00:04:50,671 Were next to me to go through kind of genetics by the decade and put the categories 62 00:04:50,671 --> 00:04:53,091 in context with the history. 63 00:04:53,351 --> 00:04:58,591 But before I launch into the categories, I want to tell you a brief personal anecdote. 64 00:04:59,011 --> 00:05:03,371 So when I first became a genetics attending and I got a new job, 65 00:05:03,731 --> 00:05:09,771 my lovely, beautiful boss was so excited by my arrival and the extra help that 66 00:05:09,771 --> 00:05:13,891 she immediately went to a conference and then vacation. 67 00:05:14,931 --> 00:05:23,271 So I saw this baby who had microalpthalmia, deep set eyes, post-axial polydactyly. 68 00:05:24,131 --> 00:05:27,851 And I sat there and I wrote the most beautiful note. 69 00:05:27,991 --> 00:05:33,591 And I said, there was a differential and it included Smith-Lemley-Opeth syndrome and Joubert syndrome. 70 00:05:33,931 --> 00:05:39,771 And I had a long lift. And then she came back, took one look at the baby and said, I'm dead. 71 00:05:40,432 --> 00:05:44,772 You didn't send a karyotype for trisomy 13. This baby has trisomy 13. 72 00:05:45,372 --> 00:05:50,692 And I thought, am I going to be fired today? Because I had never seen a baby 73 00:05:50,692 --> 00:05:56,512 with trisomy 13 in my fellowship that didn't have a cleft palate or holoprosencephaly, 74 00:05:56,652 --> 00:05:59,312 but she did fire me. She was lovely. 75 00:05:59,492 --> 00:06:04,212 And then had me follow up with the patient where I told the patient, 76 00:06:04,292 --> 00:06:05,792 you're having a lot of apnea. 77 00:06:05,812 --> 00:06:10,692 I was was concerned because so many patients with trisomy 13 passed away, 78 00:06:10,932 --> 00:06:17,972 but that patient, here I was wrong again, that patient was one of the 10% long-term survivors. 79 00:06:18,272 --> 00:06:22,372 And that patient happened, the mother happened to take her to the playground 80 00:06:22,372 --> 00:06:27,172 where my children played for the next six years that I lived in Rhode Island. 81 00:06:27,412 --> 00:06:31,012 And it taught me, we became quite unfriendly terms, 82 00:06:31,012 --> 00:06:36,652 but I've always remember two things from that encounter that the first thing 83 00:06:36,652 --> 00:06:42,572 I want to do when I get to the bedside is I don't want to miss a major chromosomal category. 84 00:06:42,732 --> 00:06:47,472 There are only five reasons we still send chromosomes for big disorders. 85 00:06:47,792 --> 00:06:52,072 Trisomy 21, 18, 13, Turner, Klinefelter. 86 00:06:52,172 --> 00:06:56,932 And we also send in mothers with recurrent miscarriages since they might have 87 00:06:56,932 --> 00:06:58,472 a balanced translocation. 88 00:06:58,552 --> 00:07:03,412 And otherwise, we rarely send our chromosomes, but I will never miss a trisomy 89 00:07:03,412 --> 00:07:07,152 13 or major chromosomal abnormality again. 90 00:07:07,232 --> 00:07:13,232 And

I also learned how little I know about prognosis and to remember those 10% 91 00:07:13,232 --> 00:07:19,012 of long-term survivors, even with complicated things like trisomy 13 and 18. 92 00:07:19,212 --> 00:07:22,972 So none of my fellows or residents missed that category. 93 00:07:23,192 --> 00:07:28,572 We start with And then we have the microdeletion duplication syndromes where 94 00:07:28,572 --> 00:07:33,592 you're not missing a whole chromosome, but you're missing a small piece of chromosome, 95 00:07:34,012 --> 00:07:37,352 maybe containing about 20, 23 genes. 96 00:07:37,532 --> 00:07:42,232 It could be missing, it could be doubled. And those are your classic microdeletion 97 00:07:42,232 --> 00:07:44,492 pediatric board syndromes. 98 00:07:44,492 --> 00:07:48,832 You all know 22q11 deletion syndrome, Williams, Smith-Beginnis, 99 00:07:48,852 --> 00:07:51,752 where they have the behavioral problems and trouble sleeping, 100 00:07:51,992 --> 00:07:53,712 Kredischat, Wolf-Hirschhorn. 101 00:07:53,892 --> 00:08:00,032 And now, of course, you have hundreds and hundreds of micro deletion duplication 102 00:08:00,032 --> 00:08:05,992 syndromes. And you can go on rarechromo.org if there's a new one you haven't heard of. 103 00:08:06,032 --> 00:08:10,172 But your main idea is that it's groups of genes missing or added. 104 00:08:10,292 --> 00:08:12,532 So you really will be seeing... 105 00:08:13,282 --> 00:08:16,962 What we call dysmorphic features are features different than the parents, 106 00:08:17,002 --> 00:08:20,442 unless the parent is also affected with the same microdeletion duplication syndrome, 107 00:08:20,542 --> 00:08:21,362 which happens all the time. 108 00:08:21,422 --> 00:08:26,822 But you'll be seeing differences on their physical exam most of the time when 109 00:08:26,822 --> 00:08:28,942 you have a chromosomal microdeletion syndrome. 110 00:08:29,822 --> 00:08:33,182 Next, we have our single gene testing category. 111 00:08:33,322 --> 00:08:37,122 Again, this slide is kind of the bulk of the work. But if you don't know your 112 00:08:37,122 --> 00:08:41,182 categories, you're not going to know where to kind of put a patient. shift. 113 00:08:41,242 --> 00:08:47,882 So single gene disorders, this is one gene at a time out of our 20,000 genes. 114 00:08:48,422 --> 00:08:55,262 A patient comes and they have very tall stature and they have a pectus and they 115 00:08:55,262 --> 00:09:02,062 have aortic dilation and they have a positive wrist sign and a thumb sign. 116 00:09:02,322 --> 00:09:07,142 And you're thinking they might have Marfan syndrome, a change in just one fibrillin 117 00:09:07,142 --> 00:09:13,382 gene out of the 20,000, like 90% of people who meet that Gantt score calculator do. 118 00:09:13,522 --> 00:09:15,462 This is a single gene disorder. 119 00:09:16,282 --> 00:09:21,762 Next, we have our repeat disorders. That is where, and there are only about 120 00:09:21,762 --> 00:09:25,202 five of them for you all

to remember for all of your boards, 121 00:09:25,382 --> 00:09:31,542 but that is where, for example, you have a child with intellectual disability 122 00:09:31,542 --> 00:09:40,322 and that child has a long face and you start thinking about fragile X and they 123 00:09:40,322 --> 00:09:43,482 have CGG repeats greater than 200, 124 00:09:43,682 --> 00:09:49,482 which affects the FMR1 gene and causes differences in brain development. 125 00:09:49,662 --> 00:09:53,042 And you only have to know about five repeat disorders. 126 00:09:53,442 --> 00:10:00,242 Then we have our next generation sequencing, where instead of testing one gene 127 00:10:00,242 --> 00:10:06,262 at a time, like for epilepsy, we test based on their presentation. 128 00:10:06,562 --> 00:10:13,322 So we'll put 100 genes for epilepsy, and we'll sequence all 100 at the same time. 129 00:10:14,344 --> 00:10:20,564 Next, we have our methylation disorder category, where you have the same sequence 130 00:10:20,564 --> 00:10:24,904 of DNA, but there's a change in expression, such as Angelman syndrome, 131 00:10:25,244 --> 00:10:27,824 Prader-Willi syndrome, Beckwith-Wiedemann syndrome, 132 00:10:28,384 --> 00:10:31,224 Russell-Silver syndrome, some types of diabetes. 133 00:10:31,684 --> 00:10:33,844 There aren't that many of those either. there. 134 00:10:34,404 --> 00:10:40,244 Next, we have our exome where we're going through all the 20,000 genes, 135 00:10:40,424 --> 00:10:47,164 those exiting portions, and we're closely analyzing those exons that might fit 136 00:10:47,164 --> 00:10:53,424 into the clinical phenotype that we write down for those labs because they really 137 00:10:53,424 --> 00:10:54,564 can't focus on everything. 138 00:10:54,744 --> 00:11:00,004 They're going to to analyze better the exons where there might be a clinical disorder. 139 00:11:00,504 --> 00:11:08,144 And now we have genome as well, where it's like the exome plus the microarray. But guess what? 140 00:11:08,184 --> 00:11:13,244 Many genomes do not pick up some of the repeat disorders and some of the methylation disorders. 141 00:11:13,584 --> 00:11:16,864 So genome does not mean that you've done every genetic test. 142 00:11:17,144 --> 00:11:22,884 So I know that's a very kind of hard slide, and I've talked a mile a minute, 143 00:11:23,064 --> 00:11:27,384 but we're going to break this slide down and think in terms of categories, 144 00:11:27,624 --> 00:11:30,244 which makes it a lot more fun and easy to remember. 145 00:11:30,964 --> 00:11:38,004 So, if you think about the expansion of genetics over the last decade, 146 00:11:38,144 --> 00:11:42,724 which is projected to continue, it really can be very overwhelming. 147 00:11:43,024 --> 00:11:47,424 Which category am I in? What test do I order? Do I just genome everybody? 148 00:11:48,444 --> 00:11:54,524 And by, again, looking at the history, we can make it less overwhelming and 149 00:11:54,524 --> 00:12:01,444 we can think in context of the decades and how we can still be with our patients. 150 00:12:01,484 --> 00:12:06,544 So I know there's this idea that Texans have a lot of pride. 151 00:12:06,804 --> 00:12:08,324 I don't know if that's true or not. 152 00:12:08,764 --> 00:12:14,804 I've only been to Texas twice, but I know you know that you became a state in in 1845. 153 00:12:15,724 --> 00:12:21,684 And so does anybody know when Hawaii and Alaska became a state and why that's 154 00:12:21,684 --> 00:12:25,024 important, why that was a very important year for geneticists? 155 00:12:25,884 --> 00:12:28,484 They became a state in 1959. 156 00:12:30,284 --> 00:12:36,724 And the 1950s were a very exciting year for geneticists because before the 1950s, 157 00:12:36,724 --> 00:12:42,004 you could be a cardiologist, you could be a pediatrician, but you couldn't be a geneticist. 158 00:12:42,801 --> 00:12:49,701 In 1953, that's when Watson and Crick resolved the DNA structure of the double helix. There they are. 159 00:12:49,901 --> 00:12:55,601 In 1956, Tiho and Levin discovered that human cells contain 46 chromosomes. 160 00:12:56,181 --> 00:13:04,281 And then Lejeune in Paris in 1959 discovered that patients with Down syndrome had trisomy 21, 161 00:13:05,001 --> 00:13:10,481 the same year Alaska and Hawaii became states that I'm sure all of you have, 162 00:13:10,541 --> 00:13:12,361 many of you have traveled to and enjoy. 163 00:13:12,801 --> 00:13:17,181 And so here we are with our chromosomes, three copies. 164 00:13:17,781 --> 00:13:23,881 They had trisomy 21. Unfortunately, in the 1950s, many of these patients were 165 00:13:23,881 --> 00:13:26,461 institutionalized and marginalized. 166 00:13:27,361 --> 00:13:34,101 However, now we know with great loving care, these kids are such a joy and can 167 00:13:34,101 --> 00:13:35,641 grow up doing all sorts of things. 168 00:13:36,241 --> 00:13:40,761 And it's a lot of fun to interact in my daily clinics with many of the kids 169 00:13:40,761 --> 00:13:41,541 that have Abdown syndrome. 170 00:13:42,181 --> 00:13:47,961 So in the 1950s, you can see the ads about starting soda early. 171 00:13:48,141 --> 00:13:53,781 They say how soon is too soon and that drinking the soda can help you fit in. 172 00:13:53,961 --> 00:13:58,681 So hopefully we've learned a lot in the 1950s and we're no longer giving our 173 00:13:58,681 --> 00:14:04,461 babies the same baby bottles full of, you know, these soda drinks, 174 00:14:04,561 --> 00:14:07,921 although we are giving them our smartphones now and I'm not sure what's better 175 00:14:08,001 --> 00:14:09,421 or worse for brain development. 176 00:14:09,701 --> 00:14:16,121 But in the 1950s, we could start diagnosing trisomy 21, 18, 13, 177 00:14:16,221 --> 00:14:19,521 Klinefelter and Turner syndrome. And that was about it. 178 00:14:19,901 --> 00:14:24,941 And through the 1960s, the techniques with banding became more elaborate. 179 00:14:25,081 --> 00:14:28,861 And maybe all these kids that were

growing up on all the candy, 180 00:14:29,001 --> 00:14:33,041 one can argue that they pursued some other things in the 1970s. 181 00:14:33,041 --> 00:14:40,481 But regardless, meanwhile, here was Singer sequencing DNA in the 1970s for the first time. 182 00:14:41,676 --> 00:14:46,136 And then genomics began to amplify in the 1980s. 183 00:14:46,136 --> 00:14:50,616 And you started to be able to discover by the end of the 1980s, 184 00:14:50,616 --> 00:14:55,596 Francis Collins, there he is shaking somebody's Craig Ventures hand, 185 00:14:55,616 --> 00:14:59,076 but he was kind of the rock hero of genetics. 186 00:14:59,176 --> 00:15:03,296 And he actually plays genetic songs that everybody wants to go on YouTube. 187 00:15:03,556 --> 00:15:08,376 He plays the guitar. He's sort of the rock star of our field because he was 188 00:15:08,376 --> 00:15:10,696 the one in combination with Dr. 189 00:15:10,836 --> 00:15:15,236 Chi that sequenced one of the biggest genes, the CFTR gene. 190 00:15:15,776 --> 00:15:19,736 So remember when you were growing up or some of us, a lot of you are younger 191 00:15:19,736 --> 00:15:24,676 than I am, but you were growing up with your speaking spells and your cabbage touch kids in the 1980s. 192 00:15:24,676 --> 00:15:29,096 And this was happening at the same time, because if you could sequence the largest 193 00:15:29,096 --> 00:15:32,776 gene, that means you could sequence all the genes. 194 00:15:32,996 --> 00:15:39,776 So before Before late 1980s, early 1990s, you could not verify a diagnosis of 195 00:15:39,776 --> 00:15:42,336 Marfan syndrome. It was all clinical. 196 00:15:43,656 --> 00:15:48,876 And then in the 1990s, not that much happened with testing except, 197 00:15:49,236 --> 00:15:56,556 remember the fish probes, is anybody as old as I am, where you could start to fish, 198 00:15:56,756 --> 00:16:00,816 meaning that if you had a group Proof of genes missing, you could design a fluorescent 199 00:16:00,816 --> 00:16:04,776 probe for something like 22q11 deletion syndrome, 200 00:16:05,016 --> 00:16:08,176 Wolff-Hirschhorn, Creedish, Schatz, Smith-McGinnis, Williams, 201 00:16:08,496 --> 00:16:11,096 and you could go after that one condition. 202 00:16:11,456 --> 00:16:14,616 And just to break it up, because I know it's early in the mornings. 203 00:16:22,414 --> 00:16:25,614 That was the top song in 1990 204 00:16:25,614 --> 00:16:30,774 rock set when all this fish stuff was happening just to bring you kind of back 205 00:16:30,774 --> 00:16:37,054 and wake you up in the morning but at that point i when i started training as 206 00:16:37,054 --> 00:16:42,094 a fellow i was so happy i was the tourist trap version of genetics because they 207 00:16:42,094 --> 00:16:45,114 were so academic They got to spend an hour with the patients. 208 00:16:45,334 --> 00:16:49,514 They could only order chromosomes and fish. Can you imagine? 209 00:16:50,334 --> 00:16:57,794 That was so much fun. So as the decades went

forward, we got the Human Genome Project. 210 00:16:59,314 --> 00:17:05,894 And here, if you remember, and this is not political, this is just about history, 211 00:17:06,034 --> 00:17:10,734 but here's Clinton with Francis Collins and Craig Venture. 212 00:17:11,334 --> 00:17:16,094 Francis Collins led the public effort for the sequencing of the Human Genome Project. 213 00:17:16,434 --> 00:17:21,894 And many of you might remember that Craig Venture featured in all these Time magazines of the year. 214 00:17:22,034 --> 00:17:26,454 He led the private effort, but then he ended up making that private information 215 00:17:26,454 --> 00:17:30,054 public to kind of validate the public genome. 216 00:17:30,334 --> 00:17:34,714 And by the year 2000, there was the first rough draft where, 217 00:17:34,754 --> 00:17:39,174 again, if you could sequence one gene, you can sequence all the genes. 218 00:17:39,174 --> 00:17:42,914 And now we could start testing for those single gene disorders. 219 00:17:43,974 --> 00:17:50,114 And, well, the year 2000, and let me just tell you what the top song was then. 220 00:17:57,643 --> 00:18:02,683 Were any of you Faith Hill fans, that was the top song in the year 2000. 221 00:18:02,903 --> 00:18:07,363 And while that was happening, something very interesting happened. 222 00:18:08,243 --> 00:18:14,483 These genome companies started popping up. And I had a very good friend, mentor. 223 00:18:14,743 --> 00:18:20,723 She was a lab director at Einstein, really good clinician. and her best friend 224 00:18:20,723 --> 00:18:23,983 went to work for one of these genetic companies. 225 00:18:24,623 --> 00:18:30,663 And they were kind of in their heyday. They were offering very expensive tests. 226 00:18:30,923 --> 00:18:35,623 And so her friend got the, you know, million dollar mansion. 227 00:18:35,883 --> 00:18:39,663 And I remember thinking, that's not why I went into medicine. 228 00:18:39,963 --> 00:18:44,263 But I could see that a lot of people were going to these companies and those 229 00:18:44,263 --> 00:18:45,663 tests were very expensive. 230 00:18:46,003 --> 00:18:50,643 And suddenly suddenly we had a new test, which was the microarray, 231 00:18:50,643 --> 00:18:57,043 where patients were getting these tests and figuring out diagnoses that they didn't know they had. 232 00:18:57,223 --> 00:19:01,643 And we were learning so much. So we went from only being able to order chromosomes, 233 00:19:01,883 --> 00:19:05,283 FISH, and a few single gene disorders like Marfan. 234 00:19:05,563 --> 00:19:10,483 We could also do some fragile X testing to suddenly being able to offer this 235 00:19:10,483 --> 00:19:17,823 to every child with major intellectual disability, delays, unusual family features, 236 00:19:18,083 --> 00:19:19,363 multiple congenital anomalies. 237 00:19:19,403 --> 00:19:25,563 And we started making a diagnosis of about 10 to 20% of kids in the year 2000. 238 00:19:26,403 --> 00:19:31,683 And so you can see, this is by Dr. Ledbetter et al. He goes through as well. 239 00:19:32,023 --> 00:19:36,503 Name your category. In the 1960s, those chromosomal disorders, 240 00:19:36,883 --> 00:19:39,083 we get better and better with span techniques. 241 00:19:39,363 --> 00:19:44,223 In the 1990s, we start recognizing microdeletion duplication syndromes. 242 00:19:44,223 --> 00:19:51,423 And in the year 2000, we start going across the genome for big pieces missing or added. 243 00:19:52,308 --> 00:19:57,388 And then something new happens. All these panels start coming out with single 244 00:19:57,388 --> 00:19:58,648 gene disorders together. 245 00:19:58,888 --> 00:20:05,028 And then Exome only emerged in 2005 or so as a major player. 246 00:20:06,068 --> 00:20:09,328 And now they're saying, if you just take somebody with autism, 247 00:20:09,388 --> 00:20:10,608 intellectual disability, 248 00:20:11,188 --> 00:20:16,888 non-dysmorphic, you have more of a 30 to 40% chance of a diagnosis with Exome 249 00:20:16,888 --> 00:20:21,748 versus your 10 to 20% chance with that SNP array looking for pieces missing. 250 00:20:22,308 --> 00:20:28,348 Are added. So it's been really interesting to practice with this exome test available. 251 00:20:29,588 --> 00:20:33,708 And then of course, in 2010, genome started emerging, 252 00:20:33,968 --> 00:20:40,508 but it's really only starting to make its way into clinic right now, 253 00:20:40,588 --> 00:20:45,788 where we're deciding, oh, do we order exome, which has a lot more data and analysis in it? 254 00:20:45,848 --> 00:20:51,568 Or again, do we order that genome, which includes, it's basically like an exome 255 00:20:51,568 --> 00:20:55,368 plus micro deletion and duplications, but it's not perfect either. 256 00:20:55,508 --> 00:20:57,788 And it has a lot more variants of unknown significance. 257 00:20:58,048 --> 00:21:00,628 So that's the framework where we are now. 258 00:21:00,988 --> 00:21:05,908 And as all of this genetic testing expands, we are challenged. 259 00:21:05,928 --> 00:21:09,068 And this has been a question since 2010. 260 00:21:09,308 --> 00:21:13,988 It was very trendy for people to write articles, genotype first. 261 00:21:14,148 --> 00:21:17,508 We just have a newborn screen. We genotype type everybody for everything. 262 00:21:17,928 --> 00:21:23,828 But I want to tell you that I truly believe that we all became doctors. 263 00:21:23,928 --> 00:21:28,828 We're pediatricians. I'm a geneticist because we like being with our patients. 264 00:21:28,908 --> 00:21:31,128 And that is still a skill. 265 00:21:31,588 --> 00:21:38,748 And AI isn't going to smile, interact with them, get to know what's special about them. 266 00:21:38,848 --> 00:21:41,848 So I would argue it's more fun. 267 00:21:42,008 --> 00:21:45,408 It's more interesting. And it's also more medically critically impactful, 268 00:21:45,728 --> 00:21:49,028 especially because if you just order all these genetic tests, 269 00:21:49,188

--> 00:21:53,148 you're going to get so many variants and you won't be able to explain any of 270 00:21:53,148 --> 00:21:57,488 those variants if you haven't been with your patient to get to know them, 271 00:21:57,708 --> 00:22:04,328 their natural history and what they have and place that into context with any result you get back. 272 00:22:04,588 --> 00:22:13,608 So I want to say, let's continue on as long as we can enjoy the phenotype first model. 273 00:22:13,848 --> 00:22:21,868 And then we'll use our genotypes in a smart, very thoughtful way that keeps 274 00:22:21,868 --> 00:22:25,748 us engaged with our patients and having fun with them. 275 00:22:26,468 --> 00:22:31,488 And so there's a three-step solution for people who would like to continue, 276 00:22:31,628 --> 00:22:36,648 as long as we can ride this out, our phenotype first model. 277 00:22:36,928 --> 00:22:39,808 We do a detailed clinical analysis. 278 00:22:40,108 --> 00:22:46,968 Then we use our resources. You only need two as a pediatrician to be like a geneticist. 279 00:22:47,924 --> 00:22:52,964 Go to OMIM and do the clinical synopsis button. That will tell you the features 280 00:22:52,964 --> 00:22:54,384 of a particular disorder. 281 00:22:54,724 --> 00:22:58,344 And you can also type gene reviews with an S for any disorder. 282 00:22:58,484 --> 00:23:03,484 And it'll tell you everything any geneticist knows if you're suspecting a condition. 283 00:23:03,744 --> 00:23:09,464 So let's take this beautiful child and let's think with a phenotype-first approach. 284 00:23:09,724 --> 00:23:14,404 But there is one problem to it. You have to be there next to the patient. 285 00:23:14,404 --> 00:23:19,544 You have to actually do the work as a doctor to have this model, 286 00:23:19,664 --> 00:23:27,164 but it will save you so much time of unnecessary testing, and it'll also make life more fun. 287 00:23:27,324 --> 00:23:30,364 So let's try it for the patient I just showed you. 288 00:23:30,624 --> 00:23:36,684 So in the phenotype first approach, you think what condition might match. 289 00:23:36,824 --> 00:23:41,804 You think about the history of their present illness. So this child came and 290 00:23:41,804 --> 00:23:46,304 she had a little bit of delay and she has a father who was a little delayed. 291 00:23:46,404 --> 00:23:49,964 And when he was younger, he was obsessed with dinosaurs. 292 00:23:50,144 --> 00:23:58,604 And she is kind of obsessed with a certain television show and only wants characters from that. 293 00:23:58,704 --> 00:24:02,284 And she came in because she was a little bit small for her age. 294 00:24:02,284 --> 00:24:07,524 And on physical exam, we noticed the hyper telurism, the wide space nipples, 295 00:24:07,604 --> 00:24:13,444 and she was sent to the cardiologist and they had a little bit of pulmonic stenosis. 296 00:24:13,584 --> 00:24:17,324 So of course, our clinical conclusion is Noonan syndrome. 297 00:24:17,544 --> 00:24:22,684 And we ask ourselves, is genetic testing indicated in the first place? Well, sure. 298 00:24:23,224 --> 00:24:27,944 And we are thinking of rasopathies, the most common being PTPN11, 299 00:24:28,184 --> 00:24:32,364 which is a single gene autosomal dominant disorder. Of course, 300 00:24:32,404 --> 00:24:33,604 we could have de novo people. 301 00:24:33,924 --> 00:24:38,684 And so once we've done our clinical analysis, we suspected Noonan syndrome, 302 00:24:38,844 --> 00:24:41,624 we sent a single gene, she has Noonan syndrome. 303 00:24:41,704 --> 00:24:48,824 And 99% of the time, if we just fill in this box, we can make diagnoses quite 304 00:24:48,824 --> 00:24:51,544 easily in genetics, it's really not hard. 305 00:24:51,704 --> 00:24:54,184 It just takes the right process. 306 00:24:54,384 --> 00:25:00,164 And really, I try to get the fellows and the residents to just fill in the blanks. 307 00:25:00,164 --> 00:25:03,564 And I try to do it on every patient, every time myself. 308 00:25:03,864 --> 00:25:08,244 So if we think about it, we're going to practice doing this together, 309 00:25:08,384 --> 00:25:13,684 because practice every patient, every time makes the right approach. 310 00:25:13,964 --> 00:25:21,764 And so we see these lovely ladies and they might have a bit of a wide spaced. 311 00:25:23,528 --> 00:25:28,888 Neck. They might've come because of short stature. They may have had swollen 312 00:25:28,888 --> 00:25:32,488 hands and feet in particular when they were younger. 313 00:25:32,768 --> 00:25:37,248 They're doing well in school most of the time. They may be petite. 314 00:25:37,608 --> 00:25:40,408 And so what category are we thinking? 315 00:25:40,808 --> 00:25:45,228 We're thinking chromosomal. What decade could we have diagnosed them? 316 00:25:45,308 --> 00:25:49,808 We could have diagnosed them in 1960, right? 317 00:25:49,948 --> 00:25:52,608 And what test? Our chromosomal test. 318 00:25:52,968 --> 00:25:55,568 Please feel free in your chat to make a guess. 319 00:25:56,088 --> 00:26:03,448 Now, what about this? These lovely girls, they also have short stature. 320 00:26:03,608 --> 00:26:05,188 One of them has a cleft palate. 321 00:26:05,348 --> 00:26:09,828 One of them has tetralogy of fallot. They have hypocalcemia. 322 00:26:10,748 --> 00:26:16,608 One of them has immune problems. All of you are thinking, what category? 323 00:26:17,788 --> 00:26:21,968 Microdeletion duplication disorders. What decade could we have diagnosed them. 324 00:26:22,028 --> 00:26:27,728 We could have fished in the 1990s. Today, we send a chromosomal or microarray or snip array. 325 00:26:28,708 --> 00:26:36,048 Right? What about this one? What is our category? These patients have a little periorbital edema. 326 00:26:36,608 --> 00:26:42,508 They might have kind of loose joints. They may be delayed, but super social and interactive. 327 00:26:42,748 --> 00:26:46,468 They'll run in your lap. They might be small for their age. 328 00:26:47,942 -->

00:26:52,422 They may have lips that look a little bit thick as they get older and gaps between 329 00:26:52,422 --> 00:26:55,562 their teeth. They might have hypercalcemia. 330 00:26:55,762 --> 00:27:01,562 And because this is a microdeletion duplication syndrome, we have Williams syndrome. 331 00:27:01,642 --> 00:27:07,702 Again, FISH or microarray analysis, again, could have diagnosed them in 1990 or 2000. 332 00:27:09,042 --> 00:27:13,382 And with Williams syndrome, it's important, a pearl to remember is that aside 333 00:27:13,382 --> 00:27:17,882 from the supravalvular aortic stenosis, renal artery stenosis due to the elastin changes. 334 00:27:18,222 --> 00:27:22,442 Please remember to take care of these kids during anesthesia because there can 335 00:27:22,442 --> 00:27:26,162 be sudden death. So don't do unnecessary anesthesia with these children. 336 00:27:26,622 --> 00:27:31,242 And then what about this condition? Again, you're seeing facial features, 337 00:27:31,422 --> 00:27:35,002 the prominent forehead, the hyper telurism that are different. 338 00:27:35,062 --> 00:27:41,602 And most of these kids have serious epilepsy and they're diagnosed and nobody 339 00:27:41,702 --> 00:27:45,182 reminds them to go to neurology and they come in in status. 340 00:27:45,722 --> 00:27:51,782 This is, again, microdeletion or duplication syndrome. Could have diagnosed them in 1990, 2000. 341 00:27:52,242 --> 00:27:57,222 We can send either our fish, which nobody ever does, or a micro-erase nip. This is Will Pershorn. 342 00:27:57,462 --> 00:28:00,742 And please remember that they really have epilepsy. 343 00:28:01,002 --> 00:28:04,702 So be proactive about getting them to a neurologist who's on board with treating 344 00:28:04,702 --> 00:28:05,862 them early and aggressively. 345 00:28:06,482 --> 00:28:11,602 And then we have these kids. Again, this was, there was an article in the New 346 00:28:11,602 --> 00:28:14,782 York Times in around 2004 talking about them. 347 00:28:14,982 --> 00:28:20,562 They have small palpebral fissures, a broad flat nose, autism. 348 00:28:20,922 --> 00:28:26,162 Because they have more facial features that are different from their parents, 349 00:28:26,462 --> 00:28:29,862 they would have been better candidates for microarray. 350 00:28:29,862 --> 00:28:35,882 They have 16p11.2 duplication, but microarray testing versus exome approach, 351 00:28:36,062 --> 00:28:40,822 which is better for those kids that are kind of non-dysmorphic severe autism. 352 00:28:42,242 --> 00:28:46,222 And so I already had mentioned, now we're in a new category. 353 00:28:46,802 --> 00:28:50,162 This is a child, we talked about this a little bit earlier. 354 00:28:51,805 --> 00:28:54,885 Say that a lot of my patients with connective tissue disorders, 355 00:28:54,985 --> 00:28:59,105 instead of the Leonardo da Vinci circle, they're ovals, right? 356 00:28:59,785 --> 00:29:04,705 Long, long arms, might have a pectus, might have a high arched

palate, 357 00:29:04,985 --> 00:29:07,645 may have flat feet with hind foot deformity. 358 00:29:07,745 --> 00:29:12,245 This is Marfan fibrillin mutate variant, pathogenic variant. 359 00:29:12,345 --> 00:29:16,765 We would have been able to diagnose him by about 1991 or 1992. 360 00:29:17,445 --> 00:29:25,545 And this is another patient next who has, again, a single gene disorder, short stature. 361 00:29:25,825 --> 00:29:32,465 I'm sure you can recognize that the single gene change in FGFR3 causes over 362 00:29:32,465 --> 00:29:34,945 inhibition of the chondrocytes. 363 00:29:35,125 --> 00:29:39,605 But what's really exciting about achondroplasia is that there are new treatments 364 00:29:39,605 --> 00:29:43,905 that stimulate those chondrocytes. 365 00:29:44,045 --> 00:29:48,865 And the two clinical pearls as a pediatrician to remember for achondroplasia 366 00:29:48,865 --> 00:29:55,885 is that if they present with sudden vomiting when they're little or severe headaches, 367 00:29:56,125 --> 00:29:59,545 they might have compression of the foramen magnum. That's an emergency. 368 00:29:59,825 --> 00:30:03,525 And you really want to monitor the head circumferences because some of these 369 00:30:03,525 --> 00:30:07,645 kids have hydrocephalus. And again, the third pearl is the treatment. 370 00:30:08,345 --> 00:30:14,145 And we would have been able to diagnose, again, her disorder by the 1990s with 371 00:30:14,145 --> 00:30:15,185 our single gene testing. 372 00:30:15,345 --> 00:30:20,465 And you can still use the same single gene testing in those patients or a small panel. 373 00:30:20,525 --> 00:30:24,405 If you think they have Marfan syndrome, you don't have to order an exome. 374 00:30:24,865 --> 00:30:28,025 And now here's another patient. 375 00:30:28,105 --> 00:30:31,325 And I mentioned this already, but just to drag the point home, 376 00:30:31,565 --> 00:30:34,905 so very long face, big ears. 377 00:30:34,985 --> 00:30:37,345 The females tend to be very shy. 378 00:30:37,885 --> 00:30:43,985 They can have autism too. They tend to have more prominent foreheads, joint hypermobility. 379 00:30:44,085 --> 00:30:48,225 In the males, we see the testicular enlargement, but only when they're in puberty. 380 00:30:48,225 --> 00:30:49,965 It's not like you're seeing that on a baby. 381 00:30:51,049 --> 00:30:56,289 And many times now we're diagnosing this when the mothers in certain states 382 00:30:56,289 --> 00:31:00,129 have prenatal screening and are found to be pre-mutation carriers, 383 00:31:00,229 --> 00:31:02,129 and then the babies will actually come. 384 00:31:02,249 --> 00:31:06,869 But otherwise, it's diagnosed very, very late. And when you diagnose one person, 385 00:31:06,929 --> 00:31:08,269 you diagnose a whole family. 386 00:31:08,489 --> 00:31:12,869 We're in the category of repeat disorders, fragile X. 387 00:31:13,009 --> 00:31:17,569 By the late 1990s, early 2000, we could test for these repeat disorders. 388 00:31:17,569 --> 00:31:20,889 Disorders and then now we're 389 00:31:20,889 --> 00:31:25,149 into our methylation and 390 00:31:25,149 --> 00:31:32,549 so we have these kids these babies the first two that baby is adorable laughing 391 00:31:32,549 --> 00:31:38,949 all the time but a horrible sleeper these parents are so tired who come and 392 00:31:38,949 --> 00:31:43,289 as the baby gets older doesn't talk might have seizures and the gait in the 393 00:31:43,329 --> 00:31:46,629 older children is very ataxic. 394 00:31:46,769 --> 00:31:54,389 And so you're thinking about Angelman, which the most best test would be a methylation test. 395 00:31:54,589 --> 00:31:59,849 We won't go into the details. And you could also do methylation tests even as 396 00:31:59,849 --> 00:32:06,669 early as in limited scenarios, as early as the 1990s, 2000s for certain conditions. 397 00:32:11,329 --> 00:32:15,969 And maybe a nevus flammus, maybe you look behind the ears, it railroad tracks, 398 00:32:16,209 --> 00:32:21,129 and this is Beckwith-Wiedemann syndrome, another disorder where methylation 399 00:32:21,129 --> 00:32:23,589 and printing tests would be your category. 400 00:32:24,429 --> 00:32:29,969 But now that we've kind of thought about the decades, thought about our genetic 401 00:32:29,969 --> 00:32:33,689 categories, in the real world. 402 00:32:34,809 --> 00:32:38,249 Things are always a little more complicated. The doctor says, 403 00:32:38,409 --> 00:32:40,649 I'm not sure of the cause. I think it could be due to alcohol. 404 00:32:40,909 --> 00:32:45,729 And the patient says, that's okay. I'll come back when you're sober. 405 00:32:45,909 --> 00:32:50,409 So the idea is that in the real world, we all have these feelings. 406 00:32:50,569 --> 00:32:53,849 Many of us, of course, it's not alcohol. It's sleep deprivation. 407 00:32:54,149 --> 00:32:59,869 It's too many sources where we are overwhelmed with our EHRs, 408 00:32:59,869 --> 00:33:04,829 our pagers, our phones, our our emails, and we have time for everything but thinking. 409 00:33:05,169 --> 00:33:10,249 And so we really need to remind everybody, look, 410 00:33:10,429 --> 00:33:15,629 we need our time to think, to sit there for five minutes with the patient and 411 00:33:15,629 --> 00:33:18,449 forget everything else and do, as I mentioned, 412 00:33:18,629 --> 00:33:24,569 that detailed clinical analysis to use our resources and consider where were 413 00:33:24,569 --> 00:33:28,849 we in the past with all this testing and what can the future bring to use the 414 00:33:28,849 --> 00:33:32,049 best of the past for this patient again. 415 00:33:32,169 --> 00:33:37,169 And that is a daily struggle for all of us in practice with this so many paper 416 00:33:37,169 --> 00:33:39,149 reality demands of us today. 417 00:33:39,269 --> 00:33:44,189 But I encourage everybody and I try to make a commitment to that every day. 418 00:33:44,309 --> 00:33:48,889 I'm going to, just like I take time to

eat or answer emails, 419 00:33:49,129 --> 00:33:52,849 I'm going to take at least five minutes with this patient and sit there and 420 00:33:52,849 --> 00:33:55,229 think. And I try to tell the fellows. 421 00:33:55,769 --> 00:34:00,749 So this was a 12-year-old. Previously, this is a true story, 422 00:34:00,929 --> 00:34:06,709 my patient, previously healthy boy who presented with increased clumsiness. 423 00:34:07,129 --> 00:34:09,849 The dad said he acted drunk sometimes. 424 00:34:10,569 --> 00:34:14,649 He had grades and concentration. His handwriting was getting worse. 425 00:34:14,849 --> 00:34:19,129 He wrestled as a sport and had some decreased performance and shortness of breath. 426 00:34:19,369 --> 00:34:24,609 And the cardiology evaluation showed some question of cardiac hypertrophy. 427 00:34:25,049 --> 00:34:30,349 And so the question was, what was the best genetic test? How do we diagnose 428 00:34:30,349 --> 00:34:32,949 them? And he went to neuromuscular clinic. 429 00:34:33,509 --> 00:34:37,569 And the question is, what would you have done? A neuromuscular panel, 430 00:34:37,769 --> 00:34:43,409 an exome, repeat disorder testing, chromosomal microarray, or methylation study? 431 00:34:43,629 --> 00:34:46,389 I can't see the chat, but I can tell you what 432 00:34:46,389 --> 00:34:51,189 the neuromuscular guess what the neuromuscular specialist did a neuromuscular 433 00:34:51,189 --> 00:34:56,969 panel right so it was negative then he came to genetics six months later with 434 00:34:56,969 --> 00:35:02,709 worsening symptoms sometimes requiring a walker so what do we do now we do our 435 00:35:02,709 --> 00:35:05,969 handy dandy approach we fill out the table. 436 00:35:07,073 --> 00:35:12,253 So we do the clinical work. He's had some ataxia, some slurred speech. 437 00:35:12,393 --> 00:35:15,473 He was falling while playing lacrosse and also in wrestling. 438 00:35:15,733 --> 00:35:21,253 He was 10, previously healthy. The exam showed decreased reflexive and a murmur. 439 00:35:21,273 --> 00:35:25,573 His echo, there was that concern about hypertrophic cardiomyopathy. 440 00:35:25,793 --> 00:35:28,533 People say never to use Google. I disagree. 441 00:35:28,773 --> 00:35:35,533 If you know what to Google, what to put in your chat GPT, these things can be useful. 442 00:35:35,533 --> 00:35:39,913 And a simple Google search would reveal that there is nothing else that causes 443 00:35:39,913 --> 00:35:46,433 ataxia, progressive degeneration, and hypertrophic cardiomyopathy except Friedrich's ataxia. 444 00:35:46,513 --> 00:35:50,933 But that's not on a neuromuscular panel. That is a repeat disorder. 445 00:35:51,313 --> 00:35:55,893 And that is what he had. So this table, just doing the table, 446 00:35:56,073 --> 00:36:00,273 could have prevented six months of an extra diagnostic odyssey. 447 00:36:00,313 --> 00:36:02,293 It's an autosomal recessive disorder. 448 00:36:02,673 --> 00:36:06,913 Each parent was a carrier. It's

on two different alleles. It's Friedreich's 449 00:36:06,913 --> 00:36:09,333 ataxia. And time is of the essence. 450 00:36:09,453 --> 00:36:14,233 So you want to do the tables and the right testing because now there's a new 451 00:36:14,233 --> 00:36:21,053 FDA-approved treatment that we are getting him on, which is an activator of nuclear factor. 452 00:36:21,373 --> 00:36:25,153 So the excitement of the Genome Project is all these new treatments. 453 00:36:25,233 --> 00:36:30,053 But if you miscategorize them and do the wrong thing, you waste time. 454 00:36:30,193 --> 00:36:38,093 And that is time away from treatment. So now, case two, to test or not to test. 455 00:36:39,121 --> 00:36:43,341 So because of my work in the Ray Helfer Society, it's a nonprofit for child 456 00:36:43,341 --> 00:36:46,481 protection, it's academic, and that's a whole saga in my life. 457 00:36:46,581 --> 00:36:51,501 But because of it, I do always like to present the other side of cases where 458 00:36:51,501 --> 00:36:55,861 we might think about, do we need to test this baby with genetic testing? 459 00:36:56,301 --> 00:37:01,781 So we have a two-month baby, also a true case of mine, reported apnea. 460 00:37:02,141 --> 00:37:05,761 Parents report previous difficult feeding and colic, otherwise healthy. 461 00:37:06,121 --> 00:37:07,401 Parents are first cousins. 462 00:37:08,161 --> 00:37:12,801 Ophthalmological exam reveals bilateral retinal hemorrhages diffusely located. 463 00:37:13,101 --> 00:37:19,081 The imaging shows subdural hematoma, many rib fractures, and the parents are 464 00:37:19,081 --> 00:37:22,561 described as very caring and nice by the bedside. 465 00:37:23,201 --> 00:37:26,561 So he's not supporting the head while on exam. 466 00:37:26,841 --> 00:37:31,881 We don't see bruising. There's hypotonia. The head is on the large side, 467 00:37:32,041 --> 00:37:35,261 and the pediatric resident who does take a history said, oh, 468 00:37:35,261 --> 00:37:36,421 oh, there's consanguinity. 469 00:37:37,161 --> 00:37:42,861 Consanguinity says this must be metabolic. And when you re-go take the history, 470 00:37:42,981 --> 00:37:46,201 the parents say, oh, maybe there was a little delay in motor skills. 471 00:37:46,361 --> 00:37:49,121 This is a tiny baby. Maybe he wasn't rolling over that well. 472 00:37:49,401 --> 00:37:51,741 He wasn't smiling that much. 473 00:37:52,041 --> 00:37:57,341 And so what do you do next? Do you follow up on the newborn screen results? 474 00:37:57,821 --> 00:38:04,621 Do you send metabolic testing, including something called a urine for C5DC. 475 00:38:04,881 --> 00:38:10,401 I'll explain what that is. Do you do a personalized sequencing panel for every metabolic disorder? 476 00:38:10,781 --> 00:38:14,321 Do you do exome testing or do you do genome testing? 477 00:38:15,635 --> 00:38:22,075 So the disorder that the resident was rightfully concerned about was glutaric acidemia type 1. 478 00:38:22,155 --> 00:38:26,635 It has an incidence of 1 in 30,000. This family was not Amish, 479 00:38:26,635 --> 00:38:28,535 by the way, where the incidence is higher. 480 00:38:28,675 --> 00:38:33,115 And it often presents with dystonia after viral illnesses. 481 00:38:33,995 --> 00:38:39,075 In this disorder, we see retinal hemorrhages in the posterior pole, not diffuse. use. 482 00:38:39,495 --> 00:38:46,055 And macrocephaly is defined as 98%, but this baby's head circumference is 90%. 483 00:38:46,055 --> 00:38:50,575 So it does have a generous head, but so do the parents when you measure their 484 00:38:50,575 --> 00:38:53,195 heads and not true macrocephaly. 485 00:38:53,995 --> 00:38:57,995 And the MRI in this disorder shows widening of the sylvan fissures, 486 00:38:58,035 --> 00:39:05,235 expansion of the CSF spaces, but this baby's MRI only shows the subdural, no other issues. 487 00:39:05,595 --> 00:39:17,355 So actually in doing the deep probe, This child's findings do not match glutaric acidemia type 1 at all. 488 00:39:17,475 --> 00:39:19,575 The retinal hemorrhages are different 489 00:39:19,575 --> 00:39:22,735 once you compare in your clinical synopsis and your gene reviews. 490 00:39:23,235 --> 00:39:26,015 The MRI findings are different. 491 00:39:27,095 --> 00:39:31,655 And in glutaric acidemia, babies don't fracture. So unfortunately, 492 00:39:32,015 --> 00:39:37,795 the multidisciplinary team believes that this is child abuse. 493 00:39:38,915 --> 00:39:44,235 But we send the testing, and the testing shows in glutaric acidemia, 494 00:39:44,315 --> 00:39:52,075 almost 100% of patients, even the low excretors, have abnormal elevated C5DC. 495 00:39:53,075 --> 00:40:00,435 And in this patient, that lab comes back normal, ruling out biochemically glutaric 496 00:40:00,435 --> 00:40:02,875 acidemia, and it is repeated three times. 497 00:40:03,055 --> 00:40:06,755 So should genetic testing be indicated in the first place? 498 00:40:07,758 --> 00:40:10,598 If you're going to do the genetic testing and variants return, 499 00:40:10,958 --> 00:40:12,938 that might be difficult to interpret. 500 00:40:13,958 --> 00:40:17,638 And there is when there's yet another handy dandy table. 501 00:40:17,818 --> 00:40:22,558 And I ask people as an exercise, let's think about the benefits versus the risks 502 00:40:22,558 --> 00:40:27,438 of genetic testing if we're testing for disorders where we have clinically and 503 00:40:27,438 --> 00:40:31,278 biochemically, for example, no suspicion whatsoever. 504 00:40:32,178 --> 00:40:37,098 And so on the one hand, if there's a diagnosis present, that's wonderful. 505 00:40:37,098 --> 00:40:37,978 Fault. That's knowledge. 506 00:40:38,198 --> 00:40:43,038 But on the other hand, if there's a misdiagnosis based on a variant or confusion, 507 00:40:43,338 --> 00:40:45,378 that can cause a lot of anxiety. 508 00:40:46,138 --> 00:40:50,758 And it can cause us to focus on the wrong things. 509 00:40:51,278 --> 00:40:56,038 If there's

a real diagnosis, there's potential for early and improved treatment. That's wonderful. 510 00:40:56,338 --> 00:41:01,258 But if there's misdiagnosis, we might blame everything on the misdiagnosis. 511 00:41:01,398 --> 00:41:07,058 Or if there's a genetic disorder like Down syndrome, we might do diagnostic 512 00:41:07,058 --> 00:41:10,578 overshadowing where every single symptom, they have fractures, 513 00:41:10,598 --> 00:41:14,118 which we don't see in Down syndrome, but we say it must be their Down syndrome. 514 00:41:14,278 --> 00:41:15,798 We don't want to do that either. 515 00:41:16,238 --> 00:41:20,838 For relatives, it can give them prenatal risk counseling, but when a diagnosis, 516 00:41:20,978 --> 00:41:25,858 a misdiagnosis is believed, there could be fear of sudden catastrophic events, 517 00:41:26,178 --> 00:41:30,578 metabolic episodes like dystonia that aren't going to actually happen in this baby. 518 00:41:30,778 --> 00:41:35,038 We want the potential to confirm a genetic diagnosis and as an explanation, 519 00:41:35,298 --> 00:41:40,418 but on the other hand, we don't wanna use an erroneous diagnosis if it's not true. 520 00:41:40,818 --> 00:41:46,898 We wanna advocate for patients using these diagnoses, but if they have a diagnosis 521 00:41:46,898 --> 00:41:49,878 that's not real, they may be considered more medically fragile, 522 00:41:50,038 --> 00:41:54,518 which could affect their adoption, home placement, future life insurance. 523 00:41:55,758 --> 00:42:00,158 Incidental finding can lead to medically actionable plans later in life. 524 00:42:00,458 --> 00:42:05,938 But again, if you find a BRCA mutation in a baby, what is the implication or 525 00:42:05,938 --> 00:42:09,438 a cardiac arrhythmia gene for their future military service? 526 00:42:09,838 --> 00:42:13,998 So we want to provide all of our latest technology and resources, 527 00:42:14,238 --> 00:42:19,278 but we also don't want to erroneously deprive vulnerable or any other children 528 00:42:19,278 --> 00:42:22,138 of their choices in genetic testing. 529 00:42:22,318 --> 00:42:27,018 So it's a hard balance. There's no easy solution, but at least let's think before 530 00:42:27,018 --> 00:42:30,538 we reflexively order exome and genome on everybody. 531 00:42:30,898 --> 00:42:36,158 So in this particular case, biochemical testing over and over again, 532 00:42:36,278 --> 00:42:42,038 the clinical findings ruled out glutaric acidemia, but another colleague before 533 00:42:42,038 --> 00:42:44,818 I arrived to this case had ordered an exome. 534 00:42:45,138 --> 00:42:51,318 And it came back with a likely pathogenic variant in glutaric acidemia, 535 00:42:51,318 --> 00:42:53,598 as well as a variant of unknown significance. 536 00:42:54,098 --> 00:42:58,618 So now she said, I was correct. I ordered the exome. I'm very good friends with 537 00:42:58,618 --> 00:43:00,958 this colleague, which has had a different of opinion. 538 00:43:02,038 --> 00:43:07,278 Then there was a likely pathogenic change in an osteogenesis imperfecta gene. 539 00:43:07,578 --> 00:43:11,918 And there was an incidental finding of hereditary hemochromatosis. 540 00:43:12,478 --> 00:43:17,358 So what do we do? We have to think about the pretest probability, 541 00:43:17,818 --> 00:43:20,838 the database and literature review, the inheritance pattern. 542 00:43:21,038 --> 00:43:25,398 We do not have to think so much about paternity and consanguinity, 543 00:43:25,398 --> 00:43:28,218 and we have to think about the phasing with these variants. 544 00:43:29,400 --> 00:43:35,880 And so what we do is we do a very simple process, just like we do simple clinical work. 545 00:43:36,060 --> 00:43:41,300 We do the same thing with variants every time. The biggest thing is our pretest 546 00:43:41,300 --> 00:43:43,860 probability, the clinical work that came first. 547 00:43:44,000 --> 00:43:46,060 Do we think this is glutaric acidemia? 548 00:43:46,260 --> 00:43:52,020 As I've told you, we do not. Then we search our databases like ClinVar, 549 00:43:52,020 --> 00:43:55,660 Franklin, Decipher for variants that have been reported. 550 00:43:56,480 --> 00:44:01,220 And how likely is this variant to be real? We think about our inheritance pattern. 551 00:44:01,380 --> 00:44:05,520 If there is one variant in an autosomal recessive disorder, that is not enough 552 00:44:05,520 --> 00:44:07,740 to call it a disorder. You need two. 553 00:44:08,000 --> 00:44:12,860 We classified the variants after that using the American College of Medical 554 00:44:12,860 --> 00:44:18,740 Genetics guidelines and pathogenic, it really causes it, likely pathogenic, 555 00:44:18,940 --> 00:44:21,960 a variant benign or likely benign. 556 00:44:22,000 --> 00:44:28,440 So we use that same genetic approach that we used for clinical approaches every 557 00:44:28,440 --> 00:44:30,320 single case, we get a variant. 558 00:44:30,740 --> 00:44:36,000 So like I said, if you have an autosomal recessive disorder, 559 00:44:36,360 --> 00:44:39,600 you need two variants, one on each allele. 560 00:44:39,720 --> 00:44:45,940 But if you look at this, there could be a situation where somebody has two variants on the same allele. 561 00:44:46,160 --> 00:44:51,760 So one gene is affected, but in autosomal recessive disorders, 562 00:44:52,060 --> 00:44:55,500 usually if you have one gene that's working, you don't have the disorder. 563 00:44:55,760 --> 00:45:01,060 So you could also be very confused and see two variants and assume the patient has a disease. 564 00:45:01,280 --> 00:45:06,240 And unless you've done phasing and you know that the variants are on opposite 565 00:45:06,240 --> 00:45:08,660 alleles, they may not have that disease. 566 00:45:08,940 --> 00:45:12,600 And so, again, I know all of this seems kind of overwhelming, 567 00:45:12,800 --> 00:45:15,380 but that's why we don't want to order genetic tests. 568 00:45:16,194 --> 00:45:19,954 And risk variants if we're

not ready to do the work when they return. 569 00:45:20,554 --> 00:45:25,394 So the true outcome was that the child was a carrier for the disorder, 570 00:45:25,594 --> 00:45:27,754 but not affected for GA1. 571 00:45:27,914 --> 00:45:34,014 Both of these variants, when the parental testing was done, were found on one allele. 572 00:45:34,114 --> 00:45:37,834 Yes, it's a coincidence that the child was a carrier for glutaric acidemia, 573 00:45:37,974 --> 00:45:41,994 but the child was unaffected. It came from one parent. 574 00:45:42,954 --> 00:45:49,054 The C5DC, like I'm saying, was normal. The serpent app was autosomal recessive, 575 00:45:49,054 --> 00:45:54,254 and there was only one variant, and you need two in this rare form of autosomal 576 00:45:54,254 --> 00:45:57,234 recessive osteogenesis imperfecta. 577 00:45:57,254 --> 00:46:02,674 So the child did not have osteogenesis imperfecta as an explanation for the rib fractures. 578 00:46:02,954 --> 00:46:06,934 And the child was affected with hereditary hemochromatosis, 579 00:46:07,114 --> 00:46:11,514 a mild form, where later in life, if you're male, you might want to give blood 580 00:46:11,514 --> 00:46:17,034 transfusion, donate blood so that your blood does not, your iron is not too 581 00:46:17,034 --> 00:46:21,214 high in your liver and so forth, but really didn't cause a problem for this baby. 582 00:46:21,414 --> 00:46:25,694 But because of this genetic testing in the civil proceedings, 583 00:46:25,874 --> 00:46:33,314 the diagnosis was made of glutaric acidemia type 1, osteogenesis type 6. 584 00:46:33,614 --> 00:46:37,834 They said that the hereditary hemochromatosis caused the child's liver injury, 585 00:46:38,054 --> 00:46:43,774 which we we believe was unfortunately from abuse and the criminal proceedings 586 00:46:43,774 --> 00:46:48,614 were dropped and the child was returned to the home. So again. 587 00:46:49,574 --> 00:46:55,174 I have kind of hoped to show you through that kind of sad case that we really 588 00:46:55,174 --> 00:46:59,954 want to think before we just reflexively send genetic testing for everybody, 589 00:47:00,014 --> 00:47:02,494 because particularly in vulnerable children, 590 00:47:02,634 --> 00:47:05,714 genetic testing is not always of benefit. 591 00:47:06,594 --> 00:47:10,754 Now on to kind of our last case in the real world. 592 00:47:10,794 --> 00:47:15,374 And this is, again, just to practice using our handy dandy tables and systematic process. 593 00:47:15,374 --> 00:47:20,434 So, this is a case that I think is a little bit more uplifting than the one 594 00:47:20,434 --> 00:47:25,254 I presented a minute ago, where there's an otherwise healthy boy with appropriate 595 00:47:25,254 --> 00:47:29,494 development and first evaluated for gait abnormalities at 11. 596 00:47:29,714 --> 00:47:34,634 He reportedly always carried his right arm at an abnormal angle when running 597 00:47:34,634 --> 00:47:39,794 and increased his gait disturbance over

the right side in the preceding two years. 598 00:47:39,794 --> 00:47:44,614 And initially, orthopedic evaluation raised concern for a tethered cord, 599 00:47:44,794 --> 00:47:51,274 but a neurological concern raised concern for right hemiparesis with a gait 600 00:47:51,274 --> 00:47:57,694 characterized by kind of the circumduction of his elbow when walking. It was really unusual. 601 00:47:58,334 --> 00:48:01,914 And so we did the clinical work. 602 00:48:02,134 --> 00:48:07,254 This was my colleague, Dr. Seth Berger, who did this case. And the child had 603 00:48:07,254 --> 00:48:09,634 an atypical gait. It was getting worse over time. 604 00:48:09,974 --> 00:48:15,254 Otherwise, a completely unremarkable examination. He was smart, doing well in school. 605 00:48:15,614 --> 00:48:20,874 And the clinical conclusion, there wasn't a lot of laboratory data, was we just don't know. 606 00:48:21,074 --> 00:48:27,774 And this is where, because exome does have, with these really neuroatypical 607 00:48:27,774 --> 00:48:33,154 disorders, a 30% to 40% diagnostic yield, he sent the testing. Okay. 608 00:48:33,848 --> 00:48:40,588 And when the testing came back, there were two variants in a gene called GCH1, 609 00:48:40,748 --> 00:48:43,488 guanosine triphosphate cyclohydroxylase. 610 00:48:43,768 --> 00:48:48,028 And because he had a really good clinical picture of an unusual gait, 611 00:48:48,128 --> 00:48:50,548 he went back and looked at those variants. 612 00:48:50,668 --> 00:48:55,748 And it turns out that they've been reported with hyperphenylalanemia in some cases. 613 00:48:55,788 --> 00:48:59,988 But in rare cases, they don't lead to what we call hyperfi. 614 00:48:59,988 --> 00:49:06,788 But rather there's a central tetrahydrobioptrin deficiency, decreasing tyrosine 615 00:49:06,788 --> 00:49:13,308 hydroxylase, and that tetrahydrobioptrin deficiency is responsible for dopamine. 616 00:49:13,568 --> 00:49:17,488 And when he looked through the literature, even though the lab had classified 617 00:49:17,488 --> 00:49:21,888 these variants as variants of uncertain significance, there were two of them. 618 00:49:21,948 --> 00:49:23,428 He did parental phasing. 619 00:49:23,548 --> 00:49:28,408 It was on opposite alleles, and it fit with the potential clinical. 620 00:49:28,728 --> 00:49:34,648 So he did more testing and he hadn't ordered a chromosomal test. 621 00:49:34,728 --> 00:49:36,028 This patient didn't have Down syndrome. 622 00:49:36,228 --> 00:49:39,768 He didn't look like a microdeletion syndrome. He didn't look like Fragile X or anything. 623 00:49:40,548 --> 00:49:44,808 The neuromuscular panel at that point was not gonna be any higher yield than 624 00:49:44,808 --> 00:49:48,928 the exome because if you have a differential of more than 25 genes, 625 00:49:49,108 --> 00:49:50,788 they're encouraging exome right now. 626 00:49:50,828 --> 00:49:55,748 Again, not on everybody, but on cases where you think that something neuroatypical

627 00:49:55,748 --> 00:50:00,128 and truly unusual is going on, it might be a reasonable approach. 628 00:50:01,108 --> 00:50:06,888 And so this is the outcome of his walk before and after. 629 00:50:07,348 --> 00:50:13,128 So you can see that before dopamine treatment, and let me play it again, 630 00:50:13,428 --> 00:50:21,468 it's much more of a subtle circular gait and his walk is a a lot better after dopamine treatment. 631 00:50:21,928 --> 00:50:26,848 So this is just to show that when you follow a clinical approach, 632 00:50:27,128 --> 00:50:31,288 even if you don't know, but you've tried your best to kind of categorize the 633 00:50:31,288 --> 00:50:37,128 patient, and then you do order a broader test like Exome because you've carefully 634 00:50:37,128 --> 00:50:41,328 thought about its use, its implications, the risks versus benefits, 635 00:50:41,608 --> 00:50:46,028 and you get variants of unknown significance back when you've really thought 636 00:50:46,028 --> 00:50:50,308 about your clinical, you can then spend some time interpreting those variants 637 00:50:50,308 --> 00:50:52,828 and you can make a difference. 638 00:50:53,028 --> 00:50:57,988 And about out of all the people that get exomes, maybe three to 5% will come 639 00:50:57,988 --> 00:51:01,308 back with something actually treatable, like in this case. 640 00:51:01,428 --> 00:51:04,988 And that's why we're really there for these patients to interact, 641 00:51:05,128 --> 00:51:09,948 engage, and always think, are we ordering something where we will identify a 642 00:51:09,948 --> 00:51:12,188 treatable condition that will have impact? 643 00:51:16,128 --> 00:51:22,148 And So just to summarize, let's all encourage a phenotype first approach. 644 00:51:22,448 --> 00:51:26,728 It's a lot more fun to engage with these beautiful patients and try to make 645 00:51:26,728 --> 00:51:30,168 a guess, even if we fail forward, even if we're wrong. 646 00:51:31,318 --> 00:51:36,258 We're really, Dr. Kamat and I were talking about how it's still better to make 647 00:51:36,258 --> 00:51:41,438 a guess of your top three because that distinguishes you as a doctor from any 648 00:51:41,438 --> 00:51:45,018 other service professional or nurse practitioner, 649 00:51:45,318 --> 00:51:49,978 physician assistant, whatever you are that brings so much joy and care for kids. 650 00:51:50,158 --> 00:51:52,958 It distinguishes you as an expert in your field. 651 00:51:53,158 --> 00:51:57,318 Then after we've named our category, thought about what decade could we have 652 00:51:57,318 --> 00:52:02,818 diagnosed them? And if we could have diagnosed them in the 1990s or year 2000s 653 00:52:02,818 --> 00:52:07,098 with a more simple test, maybe we should still use that simple test approach. 654 00:52:07,238 --> 00:52:12,218 We don't need all these extra layers of variants and a more modern approach. 655 00:52:12,398 --> 00:52:17,038 The simple test and solution works and is faster and cheaper. 656

00:52:17,278 --> 00:52:21,698 We're going to consider the benefits versus risks of ordering our tests. 657 00:52:21,958 --> 00:52:25,838 And we're going to be with our patients. And my daughter, who's about to go 658 00:52:25,838 --> 00:52:30,238 to college, was so funny. She does a lot with Best Buddies and Special Olympics. 659 00:52:30,318 --> 00:52:33,018 She's considering being a special education teacher. 660 00:52:33,218 --> 00:52:36,298 It's kind of cute. And she lectured me the other day and said. 661 00:52:36,958 --> 00:52:41,338 Mom, I bet you're not talking directly enough to your nonverbal patients because 662 00:52:41,338 --> 00:52:45,098 nonverbal patients can interact and talk too. 663 00:52:45,218 --> 00:52:47,358 They may not speak, but they can still engage. 664 00:52:47,698 --> 00:52:52,918 So following my daughter's advice, I made extra special care in my clinic last 665 00:52:52,918 --> 00:52:55,218 week to really talk to these kids. 666 00:52:55,218 --> 00:53:01,478 And it was so rewarding because they did talk back to me in their own ways, 667 00:53:01,618 --> 00:53:03,278 whether pointing or engaging. 668 00:53:03,978 --> 00:53:09,198 And that was just such a joy. So let's be with our patients and take time to think about them. 669 00:53:09,318 --> 00:53:13,298 Every patient will have a lot more fun, despite all the pressures of medicine. 670 00:53:13,878 --> 00:53:18,958 And I want to thank Dr. Kamat, who is just such a star and amazing contributor 671 00:53:18,958 --> 00:53:23,758 to the pediatric field, and all of you, my colleagues, both in the Rare Disease 672 00:53:23,758 --> 00:53:25,698 Institute and Child Protection colleagues. 673 00:53:25,778 --> 00:53:29,558 And please come visit us in D.C. 674 00:53:29,918 --> 00:53:32,478 Thank you. And I would love to take any questions. 675 00:53:33,058 --> 00:53:34,638 Yeah, I'm just... 676 00:53:35,693 --> 00:53:40,193 Curious, you mentioned things in your presentation. 677 00:53:40,773 --> 00:53:44,713 Anyway, thanks for a wonderful presentation and a joyous one. 678 00:53:45,773 --> 00:53:53,933 Where we're having to deal with relatively common tetradogenic events that occur 679 00:53:53,933 --> 00:53:56,493 as prenatal exposures but are not genetics. 680 00:53:56,593 --> 00:54:05,493 And about the sort of total ecology of running every possible genetic test and the cost of doing that. 681 00:54:05,693 --> 00:54:12,213 Financial cost as well as the clinical and emotional cost of doing all of that. 682 00:54:12,373 --> 00:54:19,913 When the child was gestated and born in a toxic environment, 683 00:54:21,253 --> 00:54:28,493 on the peninsula, organic toxins for agriculture are the most obvious one, 684 00:54:28,553 --> 00:54:31,233 which you mentioned, which is prenatal exposure to alcohol. 685 00:54:31,573 --> 00:54:34,393 Or maybe it's the mom who's on phenobarb. 686 00:54:35,693 --> 00:54:38,953 Feature disorder and how far what 687 00:54:38,953 --> 00:54:42,573 exactly how to balance this ecology in terms 688 00:54:42,573 --> 00:54:45,433 of resets the time and assets that 689 00:54:45,433 --> 00:54:48,793 we have available when we're trying to differentiate between 690 00:54:48,793 --> 00:54:52,453 let's say some rare satellite amplification syndrome 691 00:54:52,453 --> 00:54:58,853 versus prenatal exposure to alcohol i mean yeah i know a lot of people for example 692 00:54:58,853 --> 00:55:04,853 that have done a lot of research really high level research on autism and there's 693 00:55:04,853 --> 00:55:10,433 about a third of those kids that have small heads and eventually you start to think. 694 00:55:11,478 --> 00:55:15,258 Maybe this is not genetic. Absolutely. 695 00:55:15,778 --> 00:55:20,138 And it is a hard balance, but I think what you're getting at, 696 00:55:20,818 --> 00:55:24,498 and I completely agree, is that, for example, if you're thinking fetal alcohol 697 00:55:24,498 --> 00:55:26,518 syndrome, there is diagnostic criteria. 698 00:55:27,218 --> 00:55:34,018 And what I do is I just put the checklist, and then I put this patient has microcephaly, 699 00:55:34,098 --> 00:55:38,678 the small help ebrile fissures, the flattening of the bridge, 700 00:55:38,818 --> 00:55:40,718 the hockey hockey stick hand. 701 00:55:40,878 --> 00:55:43,138 This patient has the neurotypical behaviors. 702 00:55:43,438 --> 00:55:48,038 And then I tell the families that it depends on the state, but sometimes having 703 00:55:48,038 --> 00:55:51,958 the diagnosis of fetal alcohol syndrome actually helps with services. 704 00:55:52,238 --> 00:55:58,418 And sometimes that's enough. And so there are times when it might behoove them 705 00:55:58,418 --> 00:56:02,538 to hold off on further testing. 706 00:56:02,698 --> 00:56:07,698 And really instead I say to them, I think we could always do genetic testing, 707 00:56:07,838 --> 00:56:12,078 but maybe we really want to focus on this diagnosis, the services for this right 708 00:56:12,078 --> 00:56:16,418 now, and then see them back, do the developmental evaluation. 709 00:56:17,038 --> 00:56:20,538 Get their early intervention and see them back later. 710 00:56:20,538 --> 00:56:26,558 And so by really, again, spending time and thinking about what would have the 711 00:56:26,558 --> 00:56:28,138 most impact for this child, 712 00:56:28,398 --> 00:56:36,778 many families will avoid testing and are quite reasonable when you refocus them 713 00:56:36,778 --> 00:56:42,498 and say what the benefit might be of holding off and focusing on something else for a while. 714 00:56:42,498 --> 00:56:48,438 And I always tell people, if it is a teratogen, like if it's, 715 00:56:48,438 --> 00:56:56,658 I had a baby with a very, very severe cloacal abnormality and many, many other things. 716 00:56:56,838 --> 00:57:01,078 And they said, oh, this is maternal diabetes. But the mom really only had one. 717 00:57:01,800 --> 00:57:05,660 A little bit of diabetes. It was not enough to

explain the severity of the disease. 718 00:57:05,840 --> 00:57:12,320 So I do think that when there is a teratogen present that has a known disease, 719 00:57:12,620 --> 00:57:17,040 you can also use those clinical, like valproic acetatexase, that you can use 720 00:57:17,040 --> 00:57:20,240 those clinical features to try to categorize them. 721 00:57:20,440 --> 00:57:25,100 And then your discussion can follow based on how suspicious you are that it's 722 00:57:25,100 --> 00:57:26,880 fetal alcohol versus something else. 723 00:57:27,720 --> 00:57:30,820 Thank you, Dr. Natasha. There is a question from Dr. Buesgenwald. 724 00:57:30,820 --> 00:57:35,840 Can you share your favorite website resource again for looking up syndromes? 725 00:57:36,400 --> 00:57:41,440 Yes. So I use two sites. When you go to OMA, which is, you know, 726 00:57:41,440 --> 00:57:45,560 free, it's very overwhelming if you do a disorder like Noonan syndrome, 727 00:57:45,660 --> 00:57:51,200 but you have to go to the clinical synopsis section, touch clinical synopsis. 728 00:57:51,240 --> 00:57:54,540 That gives you all the little things that you want to look for at the bedside. 729 00:57:54,720 --> 00:57:59,740 And then the other one is gene reviews with an S. So if you type Noonan syndrome 730 00:57:59,740 --> 00:58:03,400 gene reviews, it's going to give you everything a geneticist would tell you. 731 00:58:03,480 --> 00:58:08,080 And so, in fact, when I make a diagnosis, I literally pull it up because I like 732 00:58:08,080 --> 00:58:10,160 to be systematic and I don't want to forget things. 733 00:58:10,220 --> 00:58:13,500 And I just go through and then I cut and paste it into my note half the time. 734 00:58:14,000 --> 00:58:18,180 I do the same thing. If there's a variant in somebody for a gene like in a Noonan, 735 00:58:18,260 --> 00:58:22,980 I literally take the clinical synopsis and then I paste it and I highlight in 736 00:58:22,980 --> 00:58:24,380 bold what the patient has. 737 00:58:24,640 --> 00:58:27,300 And if they have the diagnosis, a lot of it is going to be in bold. 738 00:58:27,300 --> 00:58:29,080 Otherwise, it's not it, usually. 739 00:58:30,060 --> 00:58:33,980 There is a comment by Dr. Williams, very helpful approach, and thank you for 740 00:58:33,980 --> 00:58:38,040 reminding us all about the joy and importance of being with the patient. 741 00:58:38,620 --> 00:58:41,520 Thank you, Dr. Williams. And there's a question by Dr. Perlman, 742 00:58:41,700 --> 00:58:47,200 are methylation disorders and repeat disorders included in current microarray panels? 743 00:58:48,720 --> 00:58:54,560 No, they are not. There are rare, so in the SNP array, which has single nucleotide 744 00:58:54,560 --> 00:59:01,060 polymorphisms, they They do not always have the methylation included. 745 00:59:01,220 --> 00:59:06,700 However, in cases, for example, Angelman or Prader-Willi, where it's because 746 00:59:06,700 --> 00:59:09,760 they got two copies from one parent, 747 00:59:09,960 --> 00:59:14,760 then you will see the same single nucleotide polymorphisms and you'll think 748 00:59:14,760 --> 00:59:16,440 that they have two of the same chromosome. 749 00:59:17,360 --> 00:59:22,980 So some of it can inadvertently show it, but not if there's just one methylation 750 00:59:22,980 --> 00:59:24,300 difference or something. thing. 751 00:59:24,340 --> 00:59:28,700 So that is why on your boards and in real life, if you suspect Angelman, 752 00:59:28,800 --> 00:59:32,180 Prader-Willi, Russell-Silver, Beckwith-Wiedemann syndrome, 753 00:59:32,500 --> 00:59:36,900 certain diabetes things, you really want to go for the methylation test because 754 00:59:36,900 --> 00:59:43,280 that will show you every type of methylation abnormality and it won't miss them. 755 00:59:43,460 --> 00:59:47,920 But there are some cases of Angelman or Prader-Willi that are caused by microdeletion. 756 00:59:47,920 --> 00:59:51,980 There are some cases where you would see uniparental diastomy that SNP can detect, 757 00:59:51,980 --> 00:59:55,840 but your highest yield is still the methylation category, methylation test. 758 00:59:56,200 --> 00:59:57,460 That's always on your boards. 759 00:59:58,821 --> 01:00:04,101 Any other questions, comments for Dr. Schur? This is Ryan Van Ramstorst, 760 01:00:04,101 --> 01:00:07,021 Chief Medical Director for Medicaid CHIP Services in Texas. 761 01:00:07,381 --> 01:00:11,281 Dr. Schur, thank you so much. Just a public service announcement for the group. 762 01:00:11,521 --> 01:00:16,041 Because of legislation from the last legislative session, Senate Bill 989, 763 01:00:16,201 --> 01:00:17,961 which is what we call the biomarker legislation, 764 01:00:18,501 --> 01:00:23,701 the draft clinical policy for Texas Medicaid coverage of things such as whole 765 01:00:23,701 --> 01:00:27,901 genome sequencing will soon be posted to our website for public comment. 766 01:00:28,201 --> 01:00:33,621 I highly encourage all of you to take a look at that and submit a comment if you're so interested. 767 01:00:33,941 --> 01:00:39,141 Your comments help us sculpt the policy and make sure it's in line with clinical 768 01:00:39,141 --> 01:00:40,101 best practice guidelines. 769 01:00:40,441 --> 01:00:43,541 And so just wanted to make that announcement. We anticipate it's going to be 770 01:00:43,541 --> 01:00:45,101 posted within the next week or so. 771 01:00:45,281 --> 01:00:48,441 I'll put a link in the chat to the website where it's going to be posted. 772 01:00:48,541 --> 01:00:51,281 So just wanted to make that announcement because of this wonderful presentation 773 01:00:51,281 --> 01:00:52,541 this morning. Thanks, y'all. 774 01:00:53,181 --> 01:00:58,801 I'm so jealous. I wish that our Medicaid would come to some of of our genetics lectures. 775 01:00:58,981 --> 01:01:02,621 I'm so jealous of how things are being done in your area. 776 01:01:03,181 --> 01:01:07,121 That's wonderful that you're working together on this. That's amazing. 777 01:01:07,521 --> 01:01:10,161 See, we can learn from other states. 778 01:01:11,061 --> 01:01:12,361 I'm going to tell them that. 779 01:01:16,080 --> 01:01:21,520 Music. 780 01:01:18,821 --> 01:01:20,661 Thank you for listening to that 781 01:01:20,661 --> 01:01:25,061 wonderful talk. Click on the link in this podcast for free credit. it. 782 01:01:25,601 --> 01:01:30,321 I'm Holly Wayment, and you're listening to Pediatrics Now. I'll see you next time.