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Hello, my name is Doctor Mary Norton, and I am a professor of OBGYN at UCSF.

So, my practice is primarily in prenatal genetic testing.

And I'm going to be talking today about some of

the advances in prenatal genetic testing, past, present, and future.

So, you heard a bit earlier from Doctor Nussbaum

about newborn screening, and now we're going to move into

the prenatal genetic carrier screening arena and talk about

screening for genetic disorders in the prenatal and preconception setting.

And I'm going to talk about current practice recommendations, because that

is interesting and important, and what those current recommendations are.

And then talk about some of the advances and controversies in

carrier screening including testing for fragile

X syndrome and spinal muscular atrophy.

And then talk about universal or expanded carrier screening,

which is also an exciting new development but somewhat controversial.

And I will talk about some of these

disorders in a little bit of detail, because some

of the details of why the testing is controversial

have application more broadly for all of genetic testing.

There is some common themes and patterns that are interesting and important.

So, there are two different approaches to screening for genetic disease.

And one, again, you heard about in newborn screening, where the screening is done

really to look for affected infants such

that treatment can be instituted right after birth.

What we talk about in care, in prenatal screening

is really screening the mother or the parents to determine

if they are carriers and at increased risk for

having a child with a, affected with a genetic disorder.

>> And prenatal screening can be done really anytime in the prenatal period.

Typically, we do it before 20 weeks of

gestation, so in the first half of of pregnancy.

And there are practice guidelines that are published

by the American College of Obstetrics and Gynecologist

and the American College of Medical Genetics that

provide guidelines for prenatal screening for specific genetic diseases.

And in some situations, actually those two organizations diverge

and have different recommendations, which makes practicing this a

little bit complicated for providers when there are different

different recommendations and different standards of care if you will.

So, the goal of carrier screening is to identify

asymptomatic carriers who have no family history of a disease.

And again, as I mentioned, as there

are increasing numbers of tests, the questions that

arise are really, which of these tests should

we offer and who should make that decision?

Who should pay for the testing, because it can become expensive.

And, again, with some of these decisions and with some

of these divergent guidelines, what is our medical, legal responsibility?

And what is our ethical responsibility to patients in telling them what testing is

is available when they could be tested for really thousands of different diseases?

So, just to give a little bit of background when we talk about

carrier screening, we're generally talking about so-called

heterozygote screening usually for autosomal recessive disorders.

So, with these disorders, the carriers are usually asymptomatic.

There's typically no family history, and they affect males and females equally.

And if both parents are found to be carriers, then the chance

to have an affective, affected child is one in four for each pregnancy.

And the, much of our screening historically

has been based on race and ethnicity.

So, the frequency of many of these disorders varies among ethnic

groups, and the genes that are present also varies by, by ethnicity.

So, the effectiveness of the screening, because it generally involves

testing for individual gene mutations, also varies by by ethnicity.

And so, testing has historically targeted the commonly affected

groups, because it is less effective in non-target populations.

And I'll give some examples of that.

So, the current recommendations are that testing, again, be based on ethnicity, and

patients that are of different backgrounds

then be offered testing for different disorders.

And you can see on this slide what the current recommendations are.

There are several disorders in Jewish patients

Tay Sachs disease and a number of others.

In African-American patients they are at higher risk for some of the

hemoglobinopathies, as are patients that are

Southeast Asian and of Mediterranean ancestry.

But increasingly it is recognized that ethnicity-based

screening is problematic for, for many different reasons.

Partly because it presents some barriers.

It requires providers to know who to screen for which disorders.

It does perpetuate some categorizing of patients by

race and ethnicity, which can be seen as stigmatizing.

And it's something that generally we try to move away from.

And as there is increasing multiculturalism, patients are less able

to identify as being of one racial or ethnic group.

So, it's less clear who should be screened for what in our current society.

So, that being said, I'm going to talk about a couple of

different disorders and sort of how the genetics the genetics work.

And then talk a little bit about universal carrier screening.

So, Tay Sachs disease is a disorder that most people have heard of.

It is what's called a lysosomal storage disease, or metabolic disease,

that's caused by a deficiency of an enzyme called hexosaminidase A.

When there is a lack of that enzyme, there are substances called gangliosides

that accumulate in the brain and cause

progressive neuro-degeneration and death in early childhood.

And, at the present time, there's no

treatment or cure for this really devastating disorder.

And this Tay Sachs disease can be screened

for by measuring the levels of hexosaminidase A.

And you can see on this graph, patients that are affected over here will

have very, very low levels of enzyme and that can be very accurately measured.

Patients that are carriers here will have mid level ranges of enzyme.

They are, have enough that they are asymptomatic and healthy, but you can

tell by measuring it that they have only about half of what they should.

And then people that are not carriers have these high normal levels.

So, quite a good test for for Tay Sachs

disease, and this is what has been done historically.

It was one of the first public health

genetic screening programs and has resulted in dramatic

decrease in the frequency of Tay Sachs disease

in patients that are of Ashkenazi Jewish background.

More recently, there's DNA testing now for for Tay Sachs disease.

And there was a move towards moving towards genetic testing.

It has quite good sensitivity and specificity, although

neither enzyme nor DNA testing is is perfect.

And because the genes for Tay Sachs disease in non-Jewish people are less

well- known, enzyme testing is really is really preferable.

And this raises one of the complexities of doing doing carrier

screening is that in some groups enzyme testing may be better,

and in other groups DNA testing may be better, and sometimes

one may need actually to do a combination of, of both.

Moving on, cystic fibrosis is another disorder, genetic disorder, for

which carrier screening is recommended now in in all patients.

It is the most common autosomal recessive disorder in Caucasians.

In one in 25 Caucasian patients with no

family history is a carrier of, of cystic fibrosis.

And 80% of children who have CF are born

to parents with no known history of the disease.

So, this is why we do carrier testing to identify people who have

no family history, and whom they don't realize that they are, are at risk.

CF is caused by a mutation in something called

the CFTR gene, and that gene directs chloride transport.

And when you have a defect in in the gene,

it allows mucus buildup in the lungs and in the pancreas.

And these individuals have severe pulmonary

disease and pancreatic insufficiency and malabsorption.

And there, though there is a range of

severity still most people die of pulmonary disease,

and the mean age is somewhere in their late 30's as of the, the most recent data.

So, although treatment has gotten better, this

is still something that it shortens life expectancy.

So, there are nearly 2,000 gene mutations

for cystic fibrosis that have been identified.

But the standard recommendation is for a 23 mutation panel

that detects most most cases in Ashkenazi Jewish and Caucasian carriers.

And in other ethnic groups the detection rate as

well as the prevalence of disease, is is somewhat lower.

And so, if you look at different racial and ethnic groups, you can see that the

carrier risk is highest in, again, Ashkenazi and

Caucasian patients lower in people of other ethnic backgrounds.

And because the gene mutations, again, aren't as well known,

the detection rate is also lower in the different ethnic groups.

So, what this means is if you do a carrier test in someone, say, is who, who

is of Asian background, their risk to start with is fairly low, 1 in 94.

But the detection rate is only about 50%.

So, if someone has a negative carrier test, you can only cut their risk in half.

You can't lower their risk as much as if the detection rate was better

as it is in some of the other some of the other ethnic groups.

So, again, the the original recommendation was for a 25 mutation panel.

It was realized that some of those

mutations actually probably didn't really cause disease.

So, now the, the standard recommendation is to test for 23 different mutations.

There are laboratories that will that have many more mutations that they test for.

And they often make a big deal about this, oh we test for 100 different mutations.

But each of these additional mutations is typically very rare.

And when you have a rare mutation, you

often don't really know what that might mean.

Does that mean that it's going to cause severe disease?

Or does that just something that may cause much more mild symptoms?

So, adding these rare mutations is often of

pretty uncertain clinical significance and uncertain clinical benefit.

You may end up with, finding things that you are not certain exactly what

that means, which is one of the

problems with many of these genetic genetic advances.

So again, many of these mutations are rare.

They may cause mild or atypical cystic

fibrosis, which may just mean chronic sinusitis.

And definitely 100 mutations is not 4 times better than

23 mutations and that is an important, an important point.

Fragile X syndrome, another relatively common

genetic disorder that can be screened for.

Although Down's syndrome is a more common form of intellectual

disability, fragile X syndrome is the most common inherited form.

And it causes a number of typical phenotypic features, but the main feature

is really quite significant intellectual disability

and behavioral behavioral problems including, including autism.

And it effects about 1 in 4,000 males and about half

as many females will have typical features of, of fragile X.

And the carrier frequency is one and somewhere around 150 to 200 people

will be, women will be a carrier for fragile X, fragile X syndrome.

And again, it can be associated with a broad range of other clinical features and

carriers sometimes can have premature ovarian failure or or infertility.

At present population screening for fragile x syndrome, although it

is possible, is not recommended, but it is really hotly debated.

Because it is relatively common, there is a

test available, and it has quite a severe phenotype.

But the genetic counseling is complicated, and that's really the reason that

it's not recommended that all women be offered be offered this screening.

So, it is caused by a so-called premutation, which is an enlargement

of the gene that doesn't cause symptons usually by itself, but in the

process of passing that gene on to the next generation, it can expand

to what's called a full mutation that then causes the the symptom.

And in males those symptoms are quite predictable,

but in females the outcome is quite unpredictable.

And some females that carry this can be completely

asymptomatic, while some can have typical severe fragile X syndrome.

And then finally I'm going to talk a

little bit about multiplex panel testing, or

universal carrier screening, which now can allow

testing for hundreds of disorders, all at once.

This is relatively inexpensive.

It's actually less expensive when you consider

just the direct testing than doing gene by

gene testing, and it raises the issue of

should we just be offering this to everybody?

Where we test for many, many, many genetic diseases with one single blood draw.

And some of the laboratories are offering this.

This is you know, from the website of one of these

labs, they'll offer testing for over a hundred different genetic diseases.

Again, at a price that is comparable to testing for a single genetic disease.

The pros are that if you only include the direct cost of

testing, it's actually very cost-effective, it's

much more efficient, and it allows

universal screening without regard to ethnicity which is, I discussed, is a

little bit problematic when you gear your screening to racial and ethnic groups.

But fully a third of patients who are tested this

way will be found to have some kind of genetic disorder.

That then means testing their partner, and their partner is not always available.

And again, the costs become increased when you have to

start screening all of the partners for many of these.

Many of these disorders are rare in the history, and the

exact outcome is not always well-known and can be complicated to explain.

So, it becomes a a complicated implementation issue, if you will.

But as we advance in genetics and genomic medicine, I

think really the the theme is that the paradigm for

this kind of carrier testing is going to have to change

from our methodical single gene disorder approach to really broader screening.

Where rather than saying let's test for fragile x

screening, fragile x disease, this is what it is.

Where we say, you know, do you

want testing for birth defects and genetic disorders?

The outcomes of these may vary, but generally

most of these have are not desirable outcomes.

They may have adverse outcomes.

And not everything can be detected, but we can certainly decrease your risks.

So, a different way of approaching screening if you will.

So, I think that finally, you know, I, I think one of the important themes

of all genetic testing, especially in the

prenatal arena, is that really the purpose, I

think this is a nice quote, the purpose of prenatal screening is really not to

decrease the incidence of genetic disease, but it

is really to fulfill the couple's reproductive goals.

This is about what does this family want and

what if, what does this patient and her partner want

for testing, thinking about their children, and their family, and

their their goals in, in, reproducing and creating a family.

>> So, with that in mind, I have a

question, thinking back on this module and this topic.

So, if a patient has no family history of cystic fibrosis, what

is the chance she'll be found to be a carrier of the disorder?

Is the chance extremely low?

Is it dependent on her racial and ethnic background?

Is it dependent on her age?

Or is it much higher if she has an expanded panel or more mutations tested?

So, which of these is the, is the right answer?

And hopefully you knew that the answer is

it depends upon her racial and ethnic background.

So, today we have talked about screening and

diagnostic testing for Mendelian and other genetic disorders.

And next week you will hear about next

gen sequencing in the resolution of diagnostic dilemmas.

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Week 2 - Module 4: Carrier Testing

Genomic and Precision Medicine

Meet the Instructors