Hereditary diseases

Hereditary diseases include a large group of diseases that are transmitted from generation to generation, they are those that “run in the family”, and have a genetic origin, that is, the cause of the inheritance of these diseases is genetic inheritance. Therefore, to understand what this group of diseases are all about, it is necessary to understand how genetic inheritance works and, for this, we invite you to read our blog on genetic inheritance and ancestry, where you will find useful information such as the organization of DNA and the different types of mutations that we can find. It is important to understand that not all genetic diseases are inherited, since a genetic mutation that leads to a disease can occur spontaneously or be enhanced by environmental factors. 

Once we know what genetic inheritance is all about, we can classify it into two types: Mendelian inheritance and polygenic inheritance, depending on whether it is the consequence of a single gene or of several genes. Both types of inheritance are associated with the nuclear genome, but beyond this we find mitochondrial inheritance, which as its name suggests, is linked to the mitochondria. 

Types of genetic inheritance

Mendelian inheritance

Mendelian inheritance is explained as a consequence of a single gene. It owes its name to the Austrian monk Gregor Mendel, who defined the patterns of this type of inheritance in the 19th century thanks to thousands of experiments carried out with pea plants [1]. 

Within Mendelian inheritance, a second classification can be made according to the chromosomal location of the gene involved, thus distinguishing autosomal inheritance and sex-linked inheritance. 

Autosomal inheritance

Autosomal inheritance is inheritance linked to one of the 22 autosomal chromosomes. Since the inheritance of these chromosomes is independent of sex, this type of genetic inheritance affects males and females equally. Autosomal inheritance, in turn, can be classified into autosomal recessive and autosomal dominant inheritance. 

For Autosomal recessive inheritance to occur, the person must have two copies of the mutated gene, while people with a single copy are called carriers and do not have features of the disease [2]. An example of a hereditary disease with autosomal recessive inheritance is cystic fibrosis.  

Cystic fibrosis causes severe damage primarily to the lungs and digestive tract, though it can affect other organs of the body. At the cellular level, it affects the cells that produce mucus, sweat and digestive juices, i.e. the cells that secrete internal fluids. These fluids, because of cystic fibrosis, become sticky and thick, so that they clog internal tubes and ducts, especially in the lungs and pancreas [3]. 

The gene involved in this hereditary disease is the cystic fibrosis transmembrane conductance regulator gene (CFTR), which codes for a protein of the same name. The CFTR protein is found in cell membranes and plays a key role in controlling the secretion of sodium, chloride, water and bicarbonate. The result of alterations in this protein is thick, sticky mucus in the respiratory, digestive and reproductive systems, as well as increased salt in sweat [4]. 

Many mutations in the CFTR gene have been described and the specific disease-causing mutation determines the severity of the disease. 

For a person to have cystic fibrosis, since inheritance is autosomal recessive, they must have two copies of the mutated gene, so their parents must have at least one copy of the mutated gene each. However, the parents do not necessarily have to have the disease, since both can only be carriers of the disease. 

Autosomal dominant inheritance is characterized by the presence of a single copy of the mutated gene being sufficient for the disease to develop. 

There are multiple diseases that are inherited like this, including some types of osteogenesis imperfecta, for example, osteogenesis imperfecta type 3, also known as severe osteogenesis imperfecta, which is a rare disease, i.e. it affects less than 5 out of 10,000 people. It is characterized by increased bone fragility, leading to frequent fractures, and deformation of the long tubular bones. Other symptoms that may occur are short stature, lax ligaments and osteopenia (decreased bone mineral density). 

Osteogenesis imperfecta is caused by a congenital defect in collagen production, which in the case of type 3 is caused by a mutation in the gene coding for the collagen proteins COL1A1 or COL1A2 [5]. 

Sex-linked inheritance

Sex-linked inheritance is transmitted through the sex chromosomes, either X or Y. Biological females have two copies of the X chromosome and none of the Y chromosome, whereas biological males have one copy of the X chromosome and one copy of the Y chromosome.

Within sex-linked inheritance, a distinction is made between X-linked inheritance and Y-linked inheritance. 

In Y-linked inherited diseases, since biological males are the only ones who have a copy of the Y chromosome, this type of inheritance is exclusive to males, who will present the disease whenever the mutated gene is present. 

In X-linked diseases, since females have two copies of the X chromosome and males have only one, the inheritance patterns change according to sex. In general, those affected are males, since a single copy of the mutated gene is sufficient to cause the disease. In females, both copies of the gene must be mutated for the disease to occur, which is less likely. The presence of one mutated copy of the gene and a second, non-mutated copy may cause milder symptoms, or even no symptoms at all. In the latter case, we speak of female carriers. 

An example of X-linked pathology is X-linked centronuclear myopathy, also known as myotubular myopathy. This is a rare disease that affects skeletal muscle, causing muscle weakness. It is caused by a mutation in the MTM1 gene, located on the human X chromosome, and affects almost exclusively biological males. Female carriers are generally asymptomatic, although on rare occasions women have been described presenting with the disease in heterozygosis [6]. 

Polygenic inheritance

Polygenic inheritance is a pattern of inheritance determined by genetic factors, usually involving several genes, and by environmental factors. It is therefore also referred to as multifactorial. In diseases that follow this type of inheritance, the fact of inheriting one or more pathogenic mutations does not necessarily imply the development of the disease, since the environmental factor plays a very important role, although it does mean an increased risk. 

In these diseases, the susceptibility or genetic predisposition to suffer from them is calculated by means of mathematical models in which the pathogenic polymorphisms are considered to be additive. 

Among the best known diseases that follow this type of inheritance are diabetes, certain cardiovascular diseases, multiple sclerosis and some types of cancer. 

Breast cancer

One of the most studied examples is breast cancer and its relationship to mutations in the BRCA1 and BRCA2 genes. 

Although the etiology of breast cancer is not completely known, hormonal, reproductive and hereditary risk factors have been described. As for the hereditary basis, a subgroup of this type of cancer has been defined, characterized by mutations in BRCA1 and BRCA2. According to the latest epidemiological studies, between 5 and 10% of breast cancers correspond to inherited mutations in these genes. These genes are classified as tumor suppressor genes, since they code for proteins involved in DNA repair. Therefore, mutations in these genes leading to a loss of their function increase the likelihood of developing a tumor [7]. 

Beyond genetics, other risk factors for breast cancer include age, hormone replacement treatments, such as certain oral contraceptives, and alcohol consumption, among others.  

Multiple sclerosis

Another example of a disease that is inherited by a polygenic inheritance pattern is multiple sclerosis. The risk of multiple sclerosis in the general population is 0.1-0.2%, while for a direct relative of a patient with the disease it is 2.5-5% [8]. 

Although in a large number of diagnosed cases there is no family history, there are genetic factors that increase the predisposition to suffer from this disease. These genetic factors may or may not be inherited. In addition, since it is a multifactorial disease, external factors also play an important role in its development. 

Multiple sclerosis is a hereditary autoimmune disease that affects the central nervous system: the immune system mistakenly attacks the protective sheath (myelin) that covers neurons, causing communication problems between the brain and the rest of the body. The majority of multiple sclerosis diagnoses occur in people between 20 and 40 years of age. 

In the case, for example, of identical twins who share their entire genetic makeup, the risk of one of them suffering from multiple sclerosis, if the other has it, is 18.2%. In the case of non-identical twins it is 4.6%, while among non-identical twins the probability decreases to 2.7%. It is believed that in the case of non-identical twins there is a higher probability than in common siblings because they experience very closely the same environmental factors.

Currently, more than 200 mutations have been linked to the risk of developing multiple sclerosis. Affected genes include, for example, genes coding for different interleukins (immune system proteins), such as IL12A, IL12B, and genes coding for interleukin receptors, such as the IL7R gene [9]. 

Mitochondrial inheritance 

Mitochondrial inheritance encompasses the inheritance of genes included in the mitochondrial genome. Mitochondria are inherited only maternally, so this type of inheritance is exclusive to this pathway. Therefore, in the case of being a carrier of a mutation in the mitochondrial DNA, women will always transmit it to their offspring (both sons and daughters), while men will never do so. 

To better understand this type of inheritance, it is necessary to clarify what a mitochondrion is. Mitochondria are cell organelles found in the cytoplasm of cells (i.e. outside the nucleus). The main function of mitochondria is energy production, and they encode their own proteins as they contain their own DNA. The number of mitochondria per cell varies depending on the cell type, with up to 500 mitochondria per cell. This can cause mitochondria with different genetic material to exist within a cell (due to sporadic mutations). This is called heteroplasmy, and determines the severity of diseases caused by this type of inheritance [10]. 

An example of a disease with mitochondrial inheritance is mitochondrial DNA-associated Leigh syndrome, a subtype of Leigh syndrome clinically characterized by encephalopathy, lactic acidosis, seizures, cardiomyopathy, respiratory disorders and developmental delay, with onset in infancy or early childhood [11]. 

Bibliography

[1] Herencia mendeliana. https://www.genome.gov/es/genetics-glossary/Herencia-mendeliana Accessed: 2022-12-09

[2] Definición de herencia autosómica recesiva – Diccionario de cáncer del NCI – NCI https://www.cancer.gov/espanol/publicaciones/diccionarios/diccionario-cancer/def/herencia-autosomica-recesiva Accessed: 2022-12-09

[3] Cystic fibrosis – Symptoms and causes – Mayo Clinic https://www.mayoclinic.org/diseases-conditions/cystic-fibrosis/symptoms-causes/syc-20353700 Accessed: 2022-12-09

[4] Función del CFTR: más allá de la fibrosis quística. Xavier Molero Richard. Gastroenterología y Hepatología Continuada, 6, 5, 9 2007. doi: 10.1016/S1578-1550(07)75685-1

[5] Enfermedades raras: osteogénesis imperfecta, una revisión bibliográfica. https://revistasanitariadeinvestigacion.com/enfermedades-raras-osteogenesis-imperfecta-una-revision-bibliografica/ Accessed: 2022-12-09

[6] X-Linked Myotubular Myopathy. James J Dowling, Michael W Lawlor et al. GeneReviews®, 8 2018

[7] Cáncer de mama y ovario hereditario: prevención primaria y secundaria en mujeres portadoras de mutación en los genes BRCA1 y BRCA2. Gemma Llort, Mercè Peris et al. Medicina Clínica, 128, 12, 3 2007

[8] Esclerosis Múltiple y Genética – Dra. Mar Mendibe [publicado feb. 2007; revisado junio 2011; consultado nov. 2022] Disponible en: https://www.esclerosismultipleeuskadi.org/esclerosis-multiple-y-genetica/#:~:text=Mar%20Mendibe-,La%20Esclerosis%20M%C3%BAltiple%20(EM)%20NO%20es%20una%20enfermedad%20hereditaria%20aunque,factores%20ambientales%2C%20gen%C3%A9ticos%20e%20inmunol%C3%B3gicos.

[9] La influencia de la genética en Esclerosis Múltiple – Esclerosis Múltiple España. Fuente:Federación Internacional de Esclerosis Múltiple [publicado nov. 2018; consultado nov. 2022] Disponible en: https://esclerosismultiple.com/genetica-en-esclerosis-multiple/ 

[10] Mitochondrial Inheritance – Michigan Genetics Resource Center https://migrc.org/teaching-tools/genetic-inheritance-patterns/mitochondrial/ Accessed: 2022-12-09

[11] Orphanet: Síndrome de Leigh asociado al ADN mitocondrial https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=ES&Expert=255210 Accessed: 2022-12-09