What is a genetic disease?

80% of diseases which are considered as rare have genetic origins. Rare diseases affect fewer than 1 in 2,000 people. Looked at separately, these diseases are very rare, even exceptional, but altogether they affect 35 million people in Europe. In France, nearly 1 in 20 people are affected. A genetic abnormality or a congenital malformation is reported for nearly 3% of births and can lead to many disabilities.

Diseases that originate in our genome

Genetic diseases occur because of an alteration in the cell, base entity which makes up our body, at the level of our genome. The genome represents all the genetic information of an organism: it is made up of the well-known DNA molecule and is present in each one of our cells in the form of chromosomes. The genome contains:

• Coding regions: genes that contain information to produce proteins which are responsible for fulfilling specific functions in the cell, or even in other molecules. The human genome contains about 22,000 genes.
• Non-coding regions, which make up 98% of DNA: these regions do not contain information relevant to protein production. Sometimes called the “dark matter” of DNA, they are increasingly being studied by researchers who wish to understand their role and their possible influence on cell function and, on a larger scale, on the body.

Each of our cells—except for reproductive cells—has 46 chromosomes which correspond to 23 pairs of chromosomes. Each chromosome in a pair is inherited from either the mother or the father. Gametes or reproductive cells only have one version of each chromosome.

Many forms of genetic diseases

There are 3 forms of genetic diseases depending on the type alteration which causes them: chromosomal, monogenic and polygenic diseases.

Nearly 1% of children are born with a chromosomal abnormality: the chromosome, the compressed form of DNA associated with proteins, has either a structural abnormality, or there are too many chromosomes present in the cell. The most common pathology is Down Syndrome (Trisomy 21) which is characterized by 3 copies of chromosome 21 instead of 2, one from the mother and the other from the father.

About 7,000 pathologies are said to be the genetic result of a mutation in a single gene. These are monogenic diseases. Once a gene has been affected, defective proteins or an absence of proteins follows. Yet, these molecules are supposed to fulfill specific functions in the cells. If one single gene is damaged, it affects multiple organs in a more or less harmful way, impacting the lives of the people concerned. One of the most common is sickle cell anemia. This severe anemia is caused by the mutation of a gene that produces beta-globin, one of the components of hemoglobin. The hemoglobin which is produced by the mutated gene tends to polymerize when the oxygen concentration decreases. It is a hereditary disease, which is far from being the case for all monogenic diseases.

Gene mutations can have many other consequences. In 2001, Corinne Antignac's team at Imagine was the first to expose the genetic origins of steroid-resistant nephrotic syndrome. In patients with this syndrome, after a gene has mutated, the kidney no longer plays its role of sorting macromolecules successfully, and proteins which are normally retained in the blood accumulate in the urine.

There are also diseases which involve several genes. This group of diseases, which is by far the most common, includes diabetes, hypertension, etc. Studying the mechanisms involved is incredibly complex.

What is a mutation?

Genetic diseases start with a mutation: a modification of genetic information. Occurring spontaneously, mutations can take highly varied forms: from the change of a single letter in the genetic code, to the existence of too many chromosomes, such as in the case of Down Syndrome.

However, not all variations in the genome systematically lead to a disease. There are many variations between the genomes of two individuals which can be found among the 6 billion nucleotides, or letters of the genetic code, which make it up. Let’s talk about variants. If we compare the genomes of two individuals at random, we might find 3.2 million different “letters,” which only represents a variation of 0.01%.

The challenge for geneticists is to distinguish the mutations which cause a disease from the variations responsible for our individuality.

Genetic diseases are not necessarily hereditary

Another challenge in analyzing monogenic diseases is finding out whether the identified mutation has been inherited or if it has appeared in the patient. In cases where it has appeared in the patient, we call it a de novo mutation.

If a de novo mutation appears in the early stages of fertilization, it can be present in all the cells of an individual and therefore in the germ cells that will be used in reproduction. If this is the case, there is a risk that the mutation can be passed on to descendants. However, this does not necessarily mean that the child will be sick. It all depends on the way the disease is expressed.

• For autosomal recessive diseases such as cystic fibrosis and sickle cell anemia, their onset requires a mutation in both copies of the gene, the one inherited from the mother and the one inherited from the father. Both parents carry the mutation without developing the disease. However, the probability of the parents passing on both mutated genes is 1 in 4.
• For autosomal dominant diseases, the disease occurs when there is a mutation in just one of the two genes. This mutation can be inherited from one parent who is also sick—which is, for example, the case for achondroplasia, the most common form of dwarfism—or can occur spontaneously.

The challenge of genetic diseases: identifying the gene in order to understand and treat the disease

Identifying the gene which has been altered is essential for research to continue in order to better understand the disease. It is only once the gene has been identified that researchers can explore the cellular mechanisms involved and, above all, try to restore them to healthy state. This principle prevailed when Imagine was founded: bring together the expertise of doctors and researchers in one place to advance research on genetic diseases and cure them. Even though there have been significant improvements concerning the French National Rare Diseases Plan, young patients and their family sometimes arrive at Imagine after months, even years, of diagnostic uncertainty.

This is why we make every effort to identify the origins of the disease. Often, families tell us that when they arrive at Imagine, they feel like it is their last chance. Discouraged and filled with doubt, at Imagine they find a place where doctors and researchers will do everything possible in order to give a name to the disease that their child suffers from, and their hope is renewed.

And identifying a disease is not always easy. With more than 7,000 genetic diseases identified to date (and the number continues to increase), these mostly rare diseases are highly variable in their expression and very heterogeneous in their genetic basis. Identifying the gene is often an important and sometimes decisive step in deciphering mechanisms and developing treatments.

Several forms of genetic diseases

There are 3 forms of genetic diseases depending on the alteration at their origin: chromosomal, monogenic and polygenic diseases.

Nearly 1% of children are born with a chromosomal abnormality: the chromosome, the compacted form of DNA associated with proteins, has a structural abnormality, or is too numerous in the cell. The most frequent pathology is trisomy 21, characterized by the presence of 3 chromosomes 21 instead of 2, one from the mother and the other from the father.

Nearly 7,000 so-called genetic diseases result from the presence of a mutation in a single gene. These are monogenic diseases. Once a gene is affected, it results in the production of defective proteins or their absence. These molecules are supposed to perform specific functions in the cells. Damage to a single gene disrupts multiple organs in a more or less harmful way, impacting the lives of the people concerned. One of the most common is sickle cell disease. This severe anemia is caused by the mutation of a gene that produces beta-globin, one of the components of hemoglobin. The hemoglobin produced tends to polymerize when the oxygen concentration decreases. It is an inherited disease, which is far from being the case for all monogenic diseases.

Mutations in a gene can have many other consequences. In 2001, Corinne Antignac's team at Imagine was the first to identify a genetic origin of cortico-resistant nephrotic syndrome. In these patients, following the mutation of a gene, the kidney does not play its role of sorting macromolecules properly, and proteins normally retained in the blood accumulate in the urine.

There are also diseases involving several genes. This group of diseases, by far the most common, includes diabetes, hypertension, etc. The study of the mechanisms involved is extremely complex.

What is a mutation?

The starting point of genetic diseases, a mutation is a change in the genetic information. Occurring spontaneously, the mutation can take many different forms: from a change of a single letter in the genetic code to the existence of extra chromosomes, as in trisomy.

However, not all variations in the genome result in disease. There are many variations between the genome of two individuals among the 6 billion nucleotides, or more simply said, letters forming the genetic code, which compose it. These are called variants. If we compare the genome of two individuals taken at random, we count 3.2 million different "letters", which represents a variation of only 0.01%.

The difficulty for geneticists is to distinguish between the mutations that cause a disease and the variants that mark our individuality.

A genetic disease is not necessarily hereditary

Another challenge in single gene disease analysis is to determine whether the identified mutation is inherited or whether it originated in the diseased individual. The latter is called a de novo mutation.

If a de novo mutation appears in the very first stages of fertilization, it can then be present in all the cells of an individual and thus in the germ cells which will be used for reproduction. At this point, there is a risk of transmission to the descendants. However, this does not necessarily mean that the child will be ill. It all depends on how the disease is expressed.

• Autosomal recessive diseases such as cystic fibrosis and sickle cell anemia: their occurrence requires the mutation of both copies of the gene, the one inherited from the mother and the one inherited from the father. Each parent carries the mutation without developing the disease. On the other hand, the probability that the parents transmit both mutated genes is 1 in 4.
• Autosomal dominant diseases: a mutation in one of the two genes is sufficient for the disease to occur. This mutation can be inherited from one of the two parents who is then himself ill - which is for example the case of achondroplasia, the most common form of dwarfism - or it can occur spontaneously.

The challenge of genetic diseases: identifying the gene to understand and treat

The identification of the altered gene is essential for further research to better understand the disease. Only then can researchers explore the cellular mechanisms involved and, above all, attempt to restore them. This was the principle behind the creation of Imagine: to bring together the expertise of doctors and researchers in the same place to advance research on genetic diseases and to cure them. Even though there have been immense improvements linked to the National Plans for Rare Diseases, young patients and their families sometimes arrive at Imagine after months, even years, of diagnostic wandering.

Every effort is then made to identify the origins of the disease. Often, the families explain to us that their arrival at Imagine is experienced by them as a last chance. Overcome by doubt and often discouragement, they find in Imagine a place where doctors and researchers will do everything possible to give a name to the disease from which their child suffers, and hope is reborn within these families.

And naming the disease is not always easy. With more than 8,000 genetic diseases identified to date (and the number is growing), these mostly rare diseases are extremely variable in their expression and very heterogeneous in their genetic basis. Identifying the gene often represents an important, sometimes decisive, step towards deciphering the mechanisms and developing treatments to cure them.