Cystic Fibrosis — A Story of Human Genetics

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From the course by Novosibirsk State University

From Disease to Genes and Back

30 ratings

Novosibirsk State University

From Disease to Genes and Back

30 ratings

Human genetics explores the genetically determined similarities and differences between human beings. This scientific discipline encompasses a variety of related fields such as molecular genetics, genomics, population genetics and medical genetics. Study of human genetics can help to find answers to questions regarding the inheritance and development of different human phenotypes. The field of medical genetics is quickly growing and dynamically developing thanks to the new technologies such as the next-generation sequencing. Most human diseases have a genetic component. This genetic component varies by disease. Some rare diseases appear to be completely determined by the genome, whereas more common diseases arise from a complex interplay of many genes, the environment and chance. The understanding of how our genomes contribute to disease susceptibility offers the prospect of large gains: it may guide disease diagnostics and prognostics and help in developing new therapies. The overall goal of this course is to describe how the researchers find genes responsible for different diseases and how this information is used to better understand and fight these diseases. You will learn about current approaches for finding single genetic variants underlying monogenic (Mendelian) diseases and sets of variants responsible for more complex, multifactorial ones. Furthermore, you will learn how the identification of these genetic variants makes it possible to understand how the affected biological pathways lead to disease development. During the final week of the course, we will talk more about clinical applications of the genetic findings. Upon completing the course, you will be able to: - give examples of monogenic and complex disorders - recognise patterns of Mendelian inheritance of monogenic diseases; - understand and describe principles and methods of gene mapping ; - describe the main steps and principles of genome-wide association studies (GWAS); - give examples of modern technologies that are currently used to find variants underlying human diseases; - discuss the approaches to finding causative variants underlying complex disorders; - discuss the possibilities and areas of application of genetic findings.

From the lesson

From variant to function. Application of the genomic findings

During the last two weeks, we have been discussing the approaches to finding variants and genomic regions underlying the development of human disorders or predisposition to them. The question is – what are the next steps that should be taken in order to prove the causality of the identified variants? Moreover, we are eager to understand if these findings can be translated into the clinics. Can these variants provide predictive or prognostic information and do they have any important pharmacological implications? Will the answers be the same for variants underlying Mendelian and complex disorders? Gert Matthijs, Yurii Aulchenko and Michel Georges will tell you more this week.

Cystic Fibrosis — A Story of Human Genetics10:59

Meet the Instructors

Marianna Bevova
PhD, Director of GIGA Doctoral School
University of Liège (GIGA)
Michel Georges
PhD, Professor, GIGA Research Director
University of Liège
Gert Matthijs
PhD, Professor
Center for Human Genetics, University of Leuven
Lennart Karssen
PhD, Owner and Chief Computational Scientist
PolyOmica
Natalia Aulchenko
M.Sc., Project manager
Theoretical and Applied Functional Genomics Laboratory
Yakov Tsepilov
PhD, Senior Researcher
Theoretical and Applied Functional Genomics Laboratory
Sodbo Sharapov
M.Sc, Junior Researcher
Theoretical and Applied Functional Genomics Laboratory
Alexander Tashkeev
Skolkovo Institute of Science and Technology (Skoltech), Junior Researcher
Laboratory of Computational and Structural Transcriptomics
Yurii Aulchenko
PhD, Professor, Head of Theoretical and Applied Functional Genomics Laboratory
Theoretical and Applied Functional Genomics Laboratory

In this lecture,

we will take you from the basic science into the clinic,

and I will give you an example of how the rules of monogenic diseases apply

to a clinical case which I will present as the one on cystic fibrosis.

But let me first rehearse the basic principles of autosomal recessive diseases.

First, autosomal recessive diseases strike like lightning.

So, the parents are carrier but have

no clue that they are a carrier of this rare disease and

then find themselves with a boy or a girl that has this rare recessive disease.

So, it means that the parents are not at risk of developing

the disease but the siblings or the patients are.

And there is a one in four chance that the siblings will be affected,

and both of the sexes are affected equally.

So, boys and girls are at risk of having these diseases.

Now, the example is cystic fibrosis because it's a more frequent rare disease,

recessively inherited in the western population,

and it has a frequency of about one in 1/2500-1/3300.

The gene is called the cystic fibrosis transmembrane conductance

regulator which is a name that was given to the gene when it was identified.

And actually, the cystic fibrosis gene was

cloned by positional cloning about 30 years ago.

So, it's one of the prime examples of referred genetics where

people had no clue what gene they were looking for and then eventually

identified it by linkage analysis.

It's a relatively big gene and it encodes a chloride channel.

So now that we know the gene,

we can offer diagnostic testing but we can also offer carrier testing in the family

and we could even offer carrier testing to the whole population if that were an option.

Now, cystic fibrosis, to give you a little clinical insight,

it's a chronic disease of the lungs, so, eventually,

the lungs will be destroyed by recurrent infections.

It also affects the pancreas.

So, also the pancreas needs a lot of secretion and if that secretion is not normal,

the pancreatic function is not normal either.

Newborns will be born often with what is called

Meconium ileus which is actually an obstruction of the small bowel,

and also the males will be infertile because they are born

with the absence of the Vas Deferens.

There's also a few presentations which are more mild than

this classical cystic fibrosis and they are called cystic fibrosis-related diseases.

Now, cystic fibrosis as I said is the most common lethal genetic diseases among

the western population and it has differences in

the frequency depending on the ethnic and the geographical region of the patient.

The diagnosis is mainly based on clinical science.

So actually, we don't need a DNA test to confirm a diagnosis.

What people normally use is what is called the sweat test because there is

this abnormal chloride concentration even at the level of the skin.

Now for diagnostic testing,

what's important to know is that

the cystic fibrosis gene affects about 99% of the cystic fibrosis cases.

So, it means that this disease is not heterogeneous because it's one gene, one disease.

However, at the level of mutations,

we have a significant heterogeneity.

So, there is more than 1500 different ways to inactivate the cystic fibrosis gene.

And this is shown schematically in this slide where we

have this schematic presentation of the cystic fibrosis gene,

and we can see that there is missense mutations,

nonsense mutations, frameshift mutations, splice site mutations

at different positions induce genes and every patient will have two of these mutations.

Now if we look at the list of mutations,

what is apparent is that one of those mutations which is

the F508del mutation is very frequent.

It accounts for approximately 70% of all the mutant alleles.

And then comes a series,

the small series of mutations that are relatively

frequent like five percent in the western population.

And after that you have a long list of rare mutations.

This means that if we would design a test that covers this handful of mutations,

we can already confirm the diagnosis in most of the patients.

If this is not true,

one can move to more comprehensive testing, and in that case,

we would do Sanger sequencing to sequence the entire coding sequence,

or nowadays, we are using massive parallel sequencing to indeed sequence the entire gene.

Now, recessive diseases, what is more important in

the clinic is actually the implications for the family members.

As we've shown before,

if a patient is affected,

both parents will be carriers and they have recurrence

risk of one in four of having another child with cystic fibrosis.

But what is now the risk for cousins?

Well, the first thing which we can easily calculate

is the risk for the siblings of the parents.

So, for the uncles and the aunts,

their risk is one in two of being a carrier,

because they have either inherited the normal or the abnormal allele from their parents.

What's more intriguing is to know

the frequency of the carrier status in the normal population.

And we have no clue how much that frequency would be.

We have only one figure to calculate this frequency.

And here I come back to the Hardy-Weinberg equilibrium

that was explained to you by Yury in one of the previous courses.

And this is a equilibrium,

this is an equation to calculate the frequency of

disease of alleles in a normal population.

So, the only figure we have is the frequency of the disease which is q²,

and let me use 1/2500 because that's an easy figure.

Well, q² is the frequency of the disease,

meaning that q is the frequency of the abnormal allele.

And if we have 2pq,

we have two times the allele frequency,

which means we have 2√q² which would be 1/50.

So, the carrier frequency of the disease would be 1/25.

So, if we use that figure of 1/25 as the carrier frequency in the normal population,

we can calculate that the risk for these cousins would be 1/200

which is 10 times above the frequency of the disease in the general population.

Apart from cystic fibrosis,

there is hundreds of these different autosomal recessive diseases.

There's one that would like to mention which is

the sickle-cell anaemia which is very frequent

in the African population because of the presence of malaria.

And this gives you the first of one of the interesting features of recessive diseases.

One of the features of

recessive diseases is that there is a founder effect in some populations.

So, mutation occurs somewhere in

the population and then stays in that population for different generations.

If you combine this founder effect which is called a selective advantage,

one of the mutations may become very frequent.

And that's exactly the case for this F508del mutation.

It has occurred about 50,000 years ago.

And through all these generations,

it has been selected,

and people believe that it has been selected because of its resistance to cholera.

Another aspect which is very important in the recessive disorders is the consanguinity.

What we know is that in inbred populations,

the risk for cystic fibrosis and the risk for

other rare diseases is remarkably increased.

So, consanguinity is a risk factor for recessive diseases.

And one last thing as a molecular feature is what is called uniparental disomy.

There's a very few cases where the patient would have

homozygous mutations but one of the parents would not be a carrier.

And rather to invoke a known paternity what has happened in

those families is that there is a maternal uniparental disomy,

meaning that chromosome 7 has come

twice from the mother and the mother happens to be a mutation carrier,

so, it means that the boy or girl will be affected.

In this case, the recurrence risk is of course not 1/4,

but it's about 1 / 1 000 000.

Now, what are the treatment options?

The problem with many rare diseases is that we don't have any treatment at all,

partly because there are inborn errors,

and secondly, because there is no interest because they are so rare.

Now, for cystic fibrosis,

people have been looking for treatment for at least 30 years.

There is the symptomatic treatment.

One can treat the infections,

one can try to supplement the pancreatic enzymes.

So basically, one would love to have a fundamental basic treatment.

And there is one example now of a treatment that

has been approved and it's called Ivacaftor

which is a drug that actually modulates the efficiency of one mutant protein.

So, this is a protein that has the G551D mutation.

This aberrant mutant protein makes it to the plasma membrane.

So basically, it sits where it should sit but it doesn't function well.

And the Ivacaftor comes as a potentiator,

comes as a kind of a chaperone,

helps the protein to fold properly and to let the chloride transfer the protein.

So, we do have a treatment for cystic fibrosis but

the main limitation is that this mutation has to be present.

So, this treatment is limited to those patients who have this mutation.

And as you will recognize,

this is not the most frequent mutation.

So, for cystic fibrosis,

we don't have a treatment yet,

for the most frequent mutation,

we only have a treatment for a mutation that

occurs in about five percent of the patients.

This is the study of cystic fibrosis,

and I hope it has been helpful to tell you

one particular case to show how we take basic science to the clinic.

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