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From Screen to Newborn: Making Sense of Prenatal Genetics in Primary Care · Pediatrics in Practice: A CME Podcast

• 0:03
  Dr Bob Underwood (Host): Welcome to Pediatrics in Practice, A CME podcast.
• 0:06
  I'm your host, Dr.
• 0:07
  Bob Underwood.
• 0:08
  Before we introduce our guests, I'd like to remind you to claim your CME credits
• 0:13
  after listening to today's episode.
• 0:15
  You can do so by visiting cm kc.link/.
• 0:20
  CME podcast and click the claim CME button.
• 0:26
  Now, today we have an expert in prenatal genetic testing from Children's Mercy, Dr.
• 0:33
  Lilac Heisler Cohen.
• 0:36
  We're discussing prenatal genetic testing and how pediatricians
• 0:40
  can use genetic testing while caring for patient's and families.
• 0:46
  Dr.
• 0:46
  Heisler Cohen, welcome to Pediatrics and Practice.
• 0:50
  Dr Lylach Haizler-Cohen: Hi.
• 0:51
  Thank you for having me today.
• 0:53
  It's a pleasure to be here.
• 0:54
  Dr Bob Underwood (Host): Yeah, so This is really advanced and exciting
• 0:58
  stuff that we're talking about.
• 0:59
  So why don't you start us off with just telling us what are some of the most
• 1:05
  common types of prenatal genetic tests, like cell-free, DNA, microarray and exome,
• 1:12
  and, what should pediatricians understand about what these tests can and cannot
• 1:19
  tell us when we're caring for patient's.
• 1:22
  Dr Lylach Haizler-Cohen: Sure.
• 1:23
  So prenatal genetic testing can be divided into two main categories.
• 1:29
  The first one is genetic screening, And this tests for the baby's
• 1:34
  risk of having genetic condition, whether it is high-risk or low risk.
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  The second category is diagnostic testing, And this evaluates
• 1:43
  whether the baby is actually affected with a genetic condition.
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  The most common type of prenatal genetic screening test that we use is NIPT.
• 1:53
  Or non-invasive prenatal testing.
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  This looks for the cell-free DNA That is circulating in the maternal blood.
• 2:02
  We know that most of this circulating, cell-free DNA is from maternal
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  origin, but there is a small portion That is of fetal origin.
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  So starting 10 weeks of pregnancy, there is enough fetal fraction for
• 2:15
  us to be able to evaluate the baby.
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  The standard NIPT looks for a limited number of common genetic conditions
• 2:23
  like Down Syndrome, which is trisomy 21, trisomy 18, trisomy 13, And the
• 2:29
  sex chromosome aloes like Turner Syndrome or Klinefelter Syndrome.
• 2:34
  There are other NIPT platforms that can look for other genetic
• 2:39
  conditions like micro deletions.
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  An example would be 22 q, 11.2
• 2:44
  deletion syndrome or Dior.
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  Other's look for single gene disorders like cystic fibrosis or sickle cell
• 2:52
  disease, And then other platforms look for larger deletions or duplications genome
• 2:58
  wide that are more than seven megabases.
• 3:01
  To understand what is the difference between the different, types of genetic
• 3:05
  testing that we can do prenatally?
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  I like to think of the DNA as a library of the instructions in our bodies.
• 3:13
  If you go to the library, you can see books around you.
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  And in the books there are chapters and those chapters have sentences.
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  So for a archetype, we're looking around the library and we're looking
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  to see if there's any extra books, missing books or something obvious
• 3:30
  like a book That is missing a cover.
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  A microarray goes into more details.
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  Looking at the chapters of each book, so this can find more subtle
• 3:39
  deletions or duplications in the DNA.
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  And finally, exome sequencing looks at the spelling of the sentences in the
• 3:46
  book and can find any typo in the DNA.
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  This makes it pretty clear why cardio type is gonna miss many of
• 3:54
  the genetic differences that may be underlying congenital anomalies.
• 3:58
  So cardio type and microarray are looking at the amount of DNA and
• 4:03
  exome sequencing is looking at the spelling of DNA for sequencing.
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  There's also different types of tests that can be ordered.
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  Gene panels.
• 4:12
  Look at the specific spelling of genes that are related for a specific
• 4:16
  fetal condition, like a skeletal dysplasia or nunan syndrome or horo.
• 4:23
  Cephalic, exome and genome sequencing are more comprehensive.
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  Genomic tests.
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  Exome sequencing looks at one to 2% of DNA.
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  That is coding for protein and genome sequencing looks at the entire
• 4:37
  DNA, also, the non-coding region.
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  When we're ordering exome or genome sequencing, the ideal
• 4:44
  situation is to have a trio sample.
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  So to have a sample from both the baby And the parents.
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  If we know that the parents are healthy And we find a genetic change
• 4:54
  in the baby And in one of the parents, we wouldn't expect that genetic
• 4:58
  change to be the reason for the differences we're seeing in the baby.
• 5:02
  In prenatal diagnosis, we consider exome and genome sequencing
• 5:06
  the most comprehensive testing That is available today.
• 5:11
  Dr Bob Underwood (Host): So, one of the things that I think we talked about
• 5:14
  earlier is just how Ansys has gotten and how fast it's getting advanced.
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  So when a family comes in for their first newborn visit, with prenatal
• 5:26
  results in hand, what are the key questions that a pediatrician should
• 5:31
  ask to quickly assess what follow-up might be needed for this newborn?
• 5:37
  Dr Lylach Haizler-Cohen: So there are a few important questions
• 5:40
  that a pediatrician can ask.
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  First, it's important to clarify whether these results come from
• 5:46
  a screening or a diagnostic test.
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  If the findings are from a screening test, like NIPT, the pediatrician should
• 5:53
  ask whether diagnostic confirmation was performed and if it wasn't performed.
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  Postnatal confirmation is necessary.
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  Next, it's important to understand what is the prenatal testing that was done.
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  For example, was it done for advanced maternal age for abnormal ultrasound
• 6:11
  findings, or was it done for a family history of a genetic condition?
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  The pediatrician should try to review the specific result, and if possible,
• 6:20
  the actual testing report specifically for microarray or exome sequencing.
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  It's also helpful to determine whether the variant was pathogenic or likely
• 6:30
  pathogenic, or was it a variant of uncertain significance, because we
• 6:34
  look at those results very differently.
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  It's also important to assess what counseling the family has received so far.
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  Have they been informed on the natural history?
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  The prognosis, the treatment options, the surveillance recommendations, And the
• 6:49
  recurrence risk for future pregnancies.
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  And finally, based on the results and clinical context, the pediatrician should
• 6:56
  also help coordinate the referrals with specialist follow-up as needed to ensure
• 7:02
  that the family has a clear plan of care.
• 7:05
  Dr Bob Underwood (Host): Now you just mentioned variants of
• 7:07
  uncertain significance, and Those are increasingly common, so.
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  Should a primary care clinician explain a variant of uncertain, significant
• 7:20
  or VUS to a family in any particular way, and what's the appropriate
• 7:26
  approach to follow-up on a referral?
• 7:30
  Dr Lylach Haizler-Cohen: So variants of uncertain significance are
• 7:32
  very difficult to navigate both for providers And for patient's.
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  A variant of uncertain significance or a VOUS is a genetic change for where there
• 7:42
  isn't really enough evidence to classify it as either pathogenic or benign.
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  In other words, we just don't know whether these genetic changes are
• 7:51
  just normal human variations from one person to another, or are
• 7:54
  they actually disease causing?
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  Over time.
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  Interestingly, most of the VUSs are actually reclassified as benign,
• 8:02
  so it's important to emphasize that the medical management And the
• 8:05
  surveillance for the baby should actually not be altered solely based
• 8:09
  on a variant of uncertain significance.
• 8:11
  And many laboratories don't even report VUSs prenatally because of the
• 8:16
  difficulties with interpretation And the confusion it can cause for parent.
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  After birth, a vose can be reported by the lab if it is requested by the provider.
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  after the baby is born, there could be additional clinical information
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  about the baby's phenotype that sometimes can help the lab clarify
• 8:36
  the significance of the variant.
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  So I would say important for pediatricians.
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  When a vose is identified on prenatal testing, it's recommended
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  to refer to the family to a medical geneticist for expert interpretation.
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  And also to ensure that appropriate phenotyping has
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  been completed for the baby.
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  The follow-up for VUS generally involves just periodic reanalysis by the laboratory
• 8:59
  because as new research and clinical data become available, sometimes it
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  does help the lab reclassify these variants of uncertain significance.
• 9:09
  Dr Bob Underwood (Host): It really is kind of amazing how much information
• 9:11
  we can get from genetics and we're still learning, what is avu And
• 9:16
  what may not be in the long run.
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  And so you're right, a lot of that will just.
• 9:22
  Add uncertainty or confusion to parents if they don't know whether
• 9:26
  or not it's significant or not.
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  And I think that that's really important.
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  And even to pediatricians who may be unfamiliar with pre genetic
• 9:34
  testing or prenatal genetic testing.
• 9:37
  for the kids that they're taking care of.
• 9:39
  So with that being said, how should pediatricians prioritize which
• 9:46
  prenatal findings require immediate postnatal testing, like confirmatory
• 9:50
  labs, imaging, specialty referral, things like that versus results
• 9:55
  that can be monitored over time?
• 9:58
  how should a pediatrician prioritize that?
• 10:01
  Dr Lylach Haizler-Cohen: So prioritizing really depends on whether the suspected
• 10:05
  genetic condition in question actually poses an immediate risk for the newborn.
• 10:10
  And many of these severe conditions are actually included
• 10:14
  in the newborn screening.
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  So a classic example is a newborn with atypical genitalia where we are
• 10:19
  suspecting congenital adrenal hyperplasia.
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  We all know that with the classic form there is impaired production of cortisol
• 10:27
  and aldosterone, And that could lead to life-threatening salt wasting crisis.
• 10:32
  So these infants, traditionally need very emergent evaluation
• 10:37
  of the electrolytes after birth.
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  And if adrenal hyperplasia is suspected, they need replacement
• 10:42
  therapy with glucocorticoids to avoid that adrenal crisis.
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  Another example of a high priority category with, genetic conditions
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  are disorders of metabolism.
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  We know that many of these conditions place newborns at-risk for rapid
• 10:57
  decompensation after birth, even with brief fasting or physiologic stress.
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  And early signs can be, immediately noticeable.
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  infants showing up with hypoglycemia or acidosis or altered mental status.
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  So when a prenatal diagnosis, of an inherited disorder of metabolism
• 11:16
  is present, or a strong clinical suspicion, exists, the infant
• 11:20
  should be evaluated immediately by a biochemical geneticist, and their
• 11:24
  input is helpful for many things.
• 11:26
  To guide laboratory testing, fetal feeding plans, and emergency management protocols.
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  In contrast to those situation, there are other findings that
• 11:36
  don't necessarily pose an immediate physiologic risk to the newborns.
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  So things like carrier status or variants of uncertain significance or
• 11:46
  mild structural differences without functional compromise, and those
• 11:50
  can usually be monitored over time with close follow-up and appropriate
• 11:54
  specialty referral as needed.
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  Ultimately the guiding principle is not how significant a diagnosis sounds, but
• 12:03
  rather whether an early intervention can prevent acute harm in the neonatal period.
• 12:08
  Dr Bob Underwood (Host): when we started our questions.
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  you mentioned a couple of high impact scenarios.
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  For example, positive cell-free DNA screening for Trisomy 21,
• 12:19
  or a microarray finding of a.
• 12:23
  22 Q1 two deletion.
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  Can you explain some of the first steps that a primary care
• 12:31
  provider should take after birth?
• 12:34
  If these are the high impact scenarios that they're running into?
• 12:39
  Dr Lylach Haizler-Cohen: Absolutely.
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  And these are exactly the situations where a primary care pediatrician
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  can actually make a huge difference in those first days of life.
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  So a cell-free DNA, that was high-risk for Trisomy 21 in a pregnancy.
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  And did not have confirmatory testing during pregnancy needs
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  to first of all be confirmed postnatally, and This is typically
• 13:01
  done with a fish in a cardio type.
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  A fish can actually give us a very quick preliminary result within 48 to 72 hours.
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  the baby should also be thoroughly examined after birth for the
• 13:13
  common dysmorphology that we would expect with Trisomy 21.
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  The exam should also include evaluation for things like
• 13:20
  hypotonia, feeding difficulties.
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  If a murmur is present, that could suggest a congenital heart disease,
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  And then any respiratory concern.
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  Specifically for Trisomy 21, we should also order an echocardiogram because
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  we know that 50% of those babies can have congenital heart disease.
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  Also important to check is third screening, hearing evaluation,
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  and feeding and tone assessment.
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  And then for the baby that presents with 22 Q1 1.2
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  deletion syndrome or known as Dior syndrome.
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  So there are other important clinical evaluations that should take place.
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  those include immune function, evaluation, checking calcium levels.
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  Because these babies can have high hypocalcemia, it's important to take
• 14:05
  a look in the mouth and to evaluate whether there is a cleft palate because
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  those babies are at increased risk.
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  For these cleft palates, And that could lead to feeding difficulties.
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  And then also these babies should have a echocardiogram because
• 14:19
  of the association with Conal, truncal congenital heart disease.
• 14:23
  Dr Bob Underwood (Host): So a lot of This is really new and parents are
• 14:27
  likely to be worried, confused, or misunderstanding even the meaning
• 14:33
  of some of these genetic testing.
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  So what are some communication strategies that help pediatricians navigate
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  conversations with parents, when they come in, not really understanding
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  the full meaning of these results.
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  Dr Lylach Haizler-Cohen: So there are several communication strategies
• 14:52
  that I typically use, and I also see commonly used by genetic counselors.
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  And I think those can be very helpful for pediatricians who are navigating
• 15:00
  these sensitive conversations.
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  So first of all, it's essential to assess the parents'
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  understanding of what's going on.
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  So using open-ended questions like, can you share with me what
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  you were told about these results?
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  Or What are you most worried about right now?
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  Questions like that can help uncover misunderstandings and
• 15:20
  parents, And also provide insight as to their emotional state.
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  Families often arrive to us with partial information or assumptions
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  that need gentle clarification.
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  If applicable.
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  It's also important to clearly distinguish between screening and diagnostic testing,
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  as we said, because many parents don't realize the difference between the two
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  types of tests and clarifying, this can immediately reduce confusion and anxiety.
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  It can also be helpful to organize the discussion and to
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  kind of three simple categories.
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  What do we know about the condition?
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  What don't we know about the condition, And what are we going to do next?
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  This structure provides clarity to parents, sets expectations, and
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  reassures families that we actually have a plan in place for them.
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  Parents frequently experience, guilt, fear, self-blame when hearing about, a
• 16:12
  possible or confirmed genetic condition, and using statements like, nothing you
• 16:18
  did caused this, or it's completely understandable to feel overwhelmed.
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  This can significantly reduce the distress and build trust with parents.
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  Delivering the information in small, manageable pieces while
• 16:32
  pausing to check, understanding with phrases like, does that make sense?
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  Can also really improve retention and engagement.
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  Repetition can be helpful, especially in high stress moments.
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  And finally, ending the conversation with the clear plan, And that includes
• 16:47
  the specific next steps, the timeline, and a schedule for follow-up.
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  All of those can greatly reduce the anxiety and help families
• 16:55
  leave feeling supported.
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  Dr Bob Underwood (Host): Yeah, I think that that's really, really, really
• 17:00
  important because This is gonna be a stressful time for parents when they
• 17:04
  have these kind of results and they really don't understand them, and
• 17:08
  your mind for new parents is already.
• 17:12
  at a position of worry.
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  And so I, really think it's up to the clinician, to the pediatrician
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  to help settle a lot of that concern that they may be having.
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  So as prenatal testing becomes more sophisticated, what are
• 17:27
  the emerging trends we mentioned earlier it's advancing fast, so.
• 17:32
  what trends should pediatricians be aware of and how might this change what happens
• 17:38
  in the newborn or early infancy period as we see these things come to fruition,
• 17:44
  Dr Lylach Haizler-Cohen: So as the cost of exo and genome sequencing continue to
• 17:48
  decline, we are expecting to use these technologies more frequently, and not
• 17:53
  only in pregnancies with fetal anomalies, but also in pregnancies that are
• 17:58
  uncomplicated just by maternal request.
• 18:00
  And this broader use will inevitably lead us to more findings and
• 18:05
  more complex findings that would be difficult to interpret.
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  One of the major trends will be findings of variance in genes with variable
• 18:14
  expressivity and reduced penetrance.
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  So what I mean is that we can find genetic changes that may or may not
• 18:21
  cause symptoms for the baby, and when they do cause symptoms, the severity
• 18:26
  can also range from mild to severe.
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  We are also likely to see more prenatal findings and genes that are associated
• 18:34
  with neurodevelopmental conditions without findings on ultrasound.
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  And these diagnosis often don't have clear manifestations in the newborn period.
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  So this may place pediatricians in a.
• 18:45
  Spots where there are guiding families through uncertainty, And also focusing
• 18:50
  on developmental milestones and referral for early intervention.
• 18:54
  And then finally, with this expanded use of exome and genome sequencing,
• 18:58
  we will also find more variants of uncertain significance prenatally.
• 19:02
  And these findings, as we said, can hide, heighten the parental stress levels and
• 19:07
  particularly when we don't have a clear answer about the clinical implications.
• 19:11
  Dr Bob Underwood (Host): This is really exciting stuff and just quite
• 19:14
  advanced over a short period of time.
• 19:17
  Anything you'd like to add as we kind of come to a conclusion
• 19:20
  on, some of these thoughts?
• 19:23
  Dr Lylach Haizler-Cohen: So just last thing to say, I am very interested in
• 19:27
  the genetic etiologies of different congenital anomalies, and I feel that
• 19:31
  even when using very comprehensive.
• 19:34
  Genetic testing.
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  We're often left in a situation where we don't find an answer for the
• 19:39
  family, and many of these conditions are thought to be multifactorial.
• 19:44
  So there are genetic and environmental kind of factors that
• 19:48
  play together to cause the anomaly.
• 19:51
  I am, specifically interested in looking at even more
• 19:54
  advanced genomic technologies.
• 19:56
  One of the technologies we're using at Children's Mercy.
• 19:59
  It is called Longer Genome Sequencing, And we are using this under the
• 20:03
  Genomic Answers for Kids program.
• 20:05
  And we're now trying to enroll, pregnant patient's and sending that am myotic
• 20:10
  fluid for this more comprehensive genetic testing to help us cover these variants
• 20:15
  that we're just not picking up with a traditional genetic testing methods.
• 20:20
  So I think we're at a very exciting time and I'm really hopeful
• 20:23
  that we will be able to find.
• 20:26
  More answers for these families that are really struggling, to
• 20:29
  go through these pregnancies.
• 20:32
  Dr Bob Underwood (Host): Absolutely.
• 20:34
  Yeah.
• 20:34
  Thank you Dr.
• 20:35
  Heisler Cohen, thank you for being with us today.
• 20:38
  Really exciting advances.
• 20:40
  we appreciate you being on.
• 20:42
  Dr Lylach Haizler-Cohen: Thank you.
• 20:43
  Dr Bob Underwood (Host): Yeah.
• 20:43
  And as a reminder, claim your CME credits after listening to
• 20:46
  this fascinating episode today.
• 20:49
  You can do so by visiting c kc.link.
• 20:53
  Slash CME podcast and click the claim CME button.
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  And if you enjoyed this podcast, please share it on your social channels and
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  check out the entire podcast library.
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  For topics of interest to you, I'm your host, Dr.
• 21:08
  Bob Underwood, and This is Pediatrics in Practice, A CME Podcast.