Monogenic diseases, what are they and how are they inherited?

Monogenic diseases are caused by alterations in genes, which are structural units that code for proteins and other necessary molecules to make our organism function. Most of our genes are found in the nucleus of our cells organized in the form of chromosomes. People have 23 pairs of chromosomes, 22 autosomal (identical in both genders) and 1 pair of sex chromosomes (which vary according to gender, XX in females and XY in males). Each chromosome from a pair is inherited from a parent. In addition to nuclear DNA, our cells also have DNA within organelles called mitochondria. Mitochondria are inherited exclusively from the mother, so all the genetic material within them also comes from the mother.

Broadly speaking, monogenic diseases can be divided according to the type of inheritance. Thus, there are different types depending on whether the causative gene is located on an autosome chromosome, on a sex chromosome or in the mitochondrial DNA.

Autosomal recessive diseases are those in which in order to show symptoms of the disease it is necessary for the person to inherit both copies of an altered gene. In these cases, both parents must have a normal copy of the gene on one chromosome and an altered copy on the other. They are usually “hidden” diseases, with no family history, since carriers of a healthy copy, such as the parents mentioned above, do not usually show symptoms of the disease as the normal copy maintains the function of the gene. One of the best-known diseases with this type of inheritance is Cystic Fibrosis.

Within the autosomal recessive diseases there is a subtype of inheritance called digenic inheritance: in this case, in order to show the disease, it is not necessary for the person to have both copies of the same gene altered, but it is sufficient to have an altered copy of each of the genes that make up the digenic pair. For example, in the case of the CDH23 and PCDH15 genes, related to Usher syndrome and deafness, a person who is a carrier of only one altered copy of each of these genes may show symptoms of the disease, even if he also has a healthy copy of the CDH23 gene and a healthy copy of the PCDH15 gene.

In the case of autosomal dominant diseases, it is sufficient to inherit a single altered copy of the gene to show symptoms. This copy can come from either parent, who is usually also affected. If one parent is affected by a disease with an autosomal dominant inheritance, 50% of his offspring will inherit the altered copy of the gene and, consequently, will be affected by the same disease. Due to their severity, this type of disease is not usually inherited from the parents; as they are normally caused by de novo alterations, namely they are generated in the gametes or in the embryo in the early stages of its development. One of the best-known diseases with this type of inheritance is achondroplasia (dwarfism).

As for the genes packed in the sex chromosomes, the most common diseases are recessive X-linked inheritance diseases. In this type of diseases, it is necessary for the person to inherit all of his or her altered X chromosome copies. In the case of males, who have only one copy of the X chromosome, they will show symptoms if they inherit one copy of the X chromosome with the altered gene. This altered copy will be inherited from the mother as the father will contribute with the Y chromosome. For this same reason affected males cannot transmit these diseases to their sons. In the case of females, unlike males, since they have two X chromosomes, it is generally necessary for them to inherit an altered copy from both parents in order to show symptoms. However, since there is a phenomenon of inactivation of the X chromosome that does not occur in autosomes, some females may show symptoms with only one altered copy. Depending on the degree of inactivation of the healthy X chromosome, the symptoms tend to be more or less severe, but usually milder than the symptoms presented by males. One of the best-known diseases with this type of inheritance is Haemophilia A and B.

X-linked diseases can also have X-linked dominant inheritance. In these diseases, for the person to show symptoms of the disease, it is sufficient for him to have one copy of the X chromosome with the altered gene. As in the case of autosomal dominant diseases, this type of disease is often caused by a de novo alteration. However, they can also be transmitted between generations. Affected females will transmit the disease to 50% of their offspring. This type of disease is often lethal in men, as they do not have any healthy copies of the affected gene and the symptoms are significantly aggravated. Incontinentia pigmentosa would be a disease with this type of inheritance.

Finally, there are diseases with mitochondrial inheritance, caused by gene alterations found in the DNA of the mitochondria. Since mitochondria are exclusively inherited from the mothers, these diseases are only transmitted from mother to child. It should be noted that within each cell we have many mitochondria and not all of them are carriers of the disease, so depending on the proportion of altered mitochondria that are inherited, the descendants will show symptoms of the disease with more or less severity or may not even show symptoms. One of the best-known diseases with this type of inheritance is Leber’s hereditary optic neuropathy.

Finally, there are also alterations that may imply that the person has a predisposition to develop a disease, although the fact of being a carrier of an altered copy of the gene does not imply that the patient is affected. This would be the case of some genes related to cancer, such as BRCA1, in which between 55% and 72% of women carrying a pathogenic variant in this gene develop breast cancer during their lifetime. In other words, being carriers of a variant in this gene makes it much more likely that they will develop the disease, although not all of them will develop it. Since being a carrier of variants in these genes confers predisposition, but not a certainty of suffering the disease, these diseases can be transmitted from carrier parents without symptoms to affected children. Symptoms usually appear in adulthood, so the influence of environmental factors cannot be ruled out.

There are other types of inheritance of diseases due to genetic causes such as inheritance linked to the Y chromosome or pseudoautosomal inheritance, which are extremely rare.