In X-linked disorders, the abnormal gene is located on the X chromosome. X-linked diseases differ significantly from autosomal diseases.

Because females inherit two copies of the X chromosome, they can be heterozygous and sometimes homozygous for any allele at a particular locus. Therefore, in women, X-linked genes appear in the same way as autosomal genes. As a result of the inactivation of the X chromosome (this process is random and occurs in the early stages of embryogenesis in females), only one X chromosome is active in each cell of the body. This means that in women heterozygous for the mutant X-linked allele, the normal gene product is produced in an amount of 50% of the normal one, which also occurs in heterozygotes in autosomal recessive conditions. Usually this amount of gene product is sufficient for normal phenotypic manifestations. Since the male inherits only one X chromosome, he is hemizygous for all X chromosome genes and all genes are expressed. In the case of hereditary transmission of an X-linked mutant gene, phenotypic manifestations of the disease develop, since the Y chromosome does not contain normal alleles that can compensate for the function of the mutant gene.

X-linked recessive inheritance

For X-linked inheritance of the recessive type, the following features are characteristic:

• the incidence of the disease is significantly higher in men;
• in heterozygous female carriers, the phenotypic manifestations of the disease are usually absent;
• the gene is passed from a sick man to all his daughters, and the son of any of his daughters has a 50% risk of inheriting the gene;
• the mutant gene is not passed from father to son;
• the mutant gene can be transmitted through a series of female carriers, then the connection between all sick men is established through female carriers;
• a significant proportion of sporadic cases of the disease is the result of a new mutation.

There are situations in which the development of phenotypic manifestations of X-linked inheritance in females is possible. If both parents are carriers of an X-linked recessive gene, the girl may get the mutant gene in the homozygous state. But due to the fact that X-linked inheritance of the recessive type is rare, this situation is unlikely (with the exception of closely related marriages). Girls with Turner syndrome, which is characterized by a set of chromosomes 45,X, are hemizygous for all genes contained on the X chromosome; in this case, all genes contained in all loci of the X chromosome are expressed, as in men. Finally, since the inactivation of the X chromosome is random, in the fetus it obeys the law of normal distribution. Therefore, in a small proportion of women, almost complete inactivation of one X chromosome is possible. This pathological (asymmetric) pattern of X-chromosome inactivation is often observed in women with phenotypic manifestations of X-linked recessive diseases.

Hemophilia A: a typical example of X-linked recessive inheritance. Hemophilia A (classic hemophilia) is characterized by clotting factor VIII deficiency, which leads to prolonged bleeding after trauma, tooth loss, surgical failure, rebleeding after primary bleeding has stopped, and delayed bleeding. The onset of clinical manifestations and the frequency of bleeding episodes depend on the coagulating activity of factor VIII; There are severe and mild forms of the disease. Severe cases are usually diagnosed in infancy, mild cases may not be recognized until adolescence or adulthood. As a result of asymmetric X-chromosome inactivation, 10% of female carriers may experience mild bleeding.

The diagnosis of hemophilia A is established by determining the low coagulating activity of factor VIII, provided that the level of von Willebrand factor is normal. Molecular genetic testing identifies mutations responsible for the development of the disease in approximately 90% of patients. It is not necessary to conduct this study in all cases, but it is quite accessible. Molecular genetic testing is used for genetic counseling of family members at risk and sometimes for the diagnosis of cases of the disease with mild clinical manifestations.

Hemophilia A has an X-linked recessive inheritance pattern. The risk of developing the disease in proband siblings depends on whether the mother is a carrier of the mutant gene. The risk of transmitting a mutant B8 gene from a carrier woman is 50% with each pregnancy. If the mutation is passed on to sons, they develop the phenotypic manifestations of the disease; daughters to whom the mutation is passed on become carriers of the mutation. Affected males pass the mutation on to all daughters, not sons.

X-linked inheritance of dominant type

X-linked diseases are considered dominant if the disease regularly occurs in heterozygous female carriers. Characteristic features of the X-linked dominant:

• the disease is phenotypically manifested in all daughters and does not develop in the sons of a sick man;
• in the sons and daughters of sick women, the risk of inheriting the disease is 50%;
• rare X-linked dominant diseases are more common in women, but the disease in women is characterized by milder (albeit variable) phenotypic manifestations.

Only a few diseases with X-linked dominant inheritance are known. One of them is hypophosphatemic rickets. Although both sexes are affected, the disease is more severe in men. Some rare X-linked diseases occur almost exclusively in women, as hemizygous for this gene in male fetuses leads to death. These include pigment incontinence, which manifests itself in the form of damage to the skin, hair, teeth and nails. The skin lesion goes through characteristic stages, starting from the formation of blisters on the skin in infancy, then warty rashes appear (and persist for several months), eventually giving way to areas of hyper- and hypopigmentation. Alopecia, hypodontia, abnormal shape of teeth and dystrophic changes in nails are observed. Some patients present with retinal vascular anomalies that predispose them to early retinal detachment, psychomotor retardation, or mental retardation. The diagnosis of pigment incontinence disease is established clinically and in some cases confirmed by skin biopsy. Affected females have a 50% risk of passing the mutant IKBKG allele to offspring. The affected male fetus is not viable. The estimated percentage of live births is 33% of unaffected girls, 33% of affected girls, and 33% of healthy boys.

X-linked recessive inheritance(English) X-linked recessive inheritance ) is one of the types of sex-linked inheritance. Such inheritance is typical for traits whose genes are located on the X chromosome and which appear only in the homozygous or hemizygous state. This type of inheritance has a number of congenital hereditary diseases in humans, these diseases are associated with a defect in any of the genes located on the sex X chromosome, and appear if there is no other X chromosome with a normal copy of the same gene. There is an abbreviation in the literature XR to denote X-linked recessive inheritance.

For X-linked recessive diseases, it is typical that males are usually affected; for rare X-linked diseases, this is almost always true. All their phenotypically healthy daughters are heterozygous carriers. Among the sons of heterozygous mothers, the ratio of sick to healthy is 1 to 1.

A special case of X-linked recessive inheritance is criss-cross inheritance (English) criss-cross inheritance, also criss-cross inheritance), as a result of which the signs of fathers appear in daughters, and the signs of mothers in sons. The name of this type of inheritance was given by one of the authors of the chromosome theory of inheritance, Thomas Hunt Morgan. He first described this type of inheritance for the Drosophila eye color trait in 1911. Criss-cross inheritance occurs when the mother is homozygous for a recessive trait localized on the X chromosome, and the father has a dominant allele of this gene on the only X chromosome. The identification of this type of inheritance in the analysis of cleavage is one of the proofs of the localization of the corresponding gene on the X chromosome.

Peculiarities of inheritance of sex-linked recessive traits in humans

In humans, as in all mammals, the male sex is heterogametic (XY) and the female sex is homogametic (XX). This means that men have only one X and one Y chromosome, while women have two X chromosomes. The X chromosomes and Y chromosomes have small homologous regions (pseudoautosomal regions). The inheritance of traits whose genes are located in these regions is similar to the inheritance of autosomal genes, and is not considered in this article.

Traits linked to the X chromosome can be recessive or dominant. Recessive traits do not appear in heterozygous individuals in the presence of a dominant trait. Since males have only one X chromosome, males cannot be heterozygous for those genes that are on the X chromosome. For this reason, only two states of an X-linked recessive trait are possible in men:

• if there is an allele on the only X chromosome that determines the trait or disorder, the man manifests such a trait or disorder, and all his daughters receive this allele from him along with the X chromosome (sons will receive the Y chromosome);
• if there is no such allele in the only X chromosome, then this trait or disorder does not manifest itself in a man and is not transmitted to offspring.

Since women have two X chromosomes, there are three possible conditions for X-linked recessive traits:

• the allele that determines this trait or disorder is absent on both X chromosomes - the trait or disorder does not manifest itself and is not transmitted to offspring;
• the allele that determines the trait or disorder is present on only one X chromosome - the trait or disorder usually does not manifest itself, and when inherited, approximately 50% of the offspring receive this allele from it along with the X chromosome (the other 50% of the offspring will receive another X chromosome) ;
• the allele that determines the trait or disorder is present on both X chromosomes - the trait or disorder manifests itself and is transmitted to offspring in 100% of cases.

Some X-linked recessive inherited disorders can be so severe as to result in fetal death. In this case, there may not be a single known patient among the family members and among their ancestors.

Women who have only one copy of the mutation are called carriers. Typically, such a mutation is not expressed in the phenotype, that is, it does not manifest itself in any way. Certain diseases with X-linked recessive inheritance still have some clinical manifestations in female carriers due to the dose compensation mechanism, due to which one of the X chromosomes is accidentally inactivated in somatic cells, and one X allele is expressed in some cells of the body, and in others - another.

Some X-linked recessive human diseases

Common

Common X-linked recessive diseases:

• Hereditary violation of color vision (color blindness). About 8% of men and 0.5% of women suffer from varying degrees of weakness in red-green perception in Northern Europe.
• X-linked ichthyosis. Dry rough patches appear on the skin of patients due to excessive accumulation of sulfonated steroids. It occurs in 1 in 2000-6000 men.
• Duchenne muscular dystrophy. A disease accompanied by degeneration of muscle tissue and leading to death at a young age. It occurs in 1 in 3600 male newborns.
• Hemophilia A (classic hemophilia). The disease associated with insufficiency of factor VIII blood clotting occurs in one in 4000-5000 men.
• Hemophilia B. The disease associated with insufficiency of clotting factor IX, occurs in one in 20,000-25,000 men.
• Becker muscular dystrophy. The disease is similar to Duchenne muscular dystrophy, but is somewhat milder. It occurs in 3-6 out of 100,000 male newborns.
• Kabuki syndrome - multiple birth defects (heart defects, growth deficiency, hearing loss, urinary tract anomalies) and mental retardation. The prevalence is 1:32000.
• Androgen insensitivity syndrome (Morris syndrome) - an individual with a complete syndrome has a female appearance, a developed breast and vagina, despite a 46XY karyotype and undescended testicles. The frequency of occurrence is from 1:20,400 to 1:130,000 newborns with a 46,XY karyotype.

Rare

• Bruton's disease (congenital agammaglobulinemia). Primary humoral immunodeficiency. It occurs among boys with a frequency of 1:100,000 - 1:250,000.
• Wiskott-Aldrich syndrome - congenital immunodeficiency and thrombocytopenia. Prevalence: 4 cases per 1,000,000 male births.
• Lowe's syndrome (oculocerebrorenal syndrome) - skeletal anomalies, various renal disorders, glaucoma and cataracts from early childhood. It occurs with a frequency of 1:500,000 male newborns.
• Allan-Herndon-Dudley syndrome is a rare syndrome, found only in men, in which the postnatal development of the brain is impaired. The syndrome is caused by a mutation in the MCT8 gene, which codes for a protein that transports thyroid hormone. First described in 1944.

Classification of hereditary diseases (working).

Classification of hereditary diseases

Before talking about the classification of hereditary diseases, it should be emphasized that, along with hereditary diseases, there are also congenital diseases, familial and sporadic diseases.

Congenital are diseases with which a child is born, they can be hereditary and non-hereditary. Some of them arise purely under the influence of environmental factors on the body of a pregnant woman and fetus - a teratogenic effect (these are drugs and harmful chemicals, ionizing radiation, infection, etc.).

family diseases- may occur in all or several family members, but this may not be due to a genetic factor, but to the general living environment, living conditions, nutrition, etc. (for example, a family of miners, a family of pigeon breeders, etc.)

sporadic diseases- are associated with the primary occurrence of a mutation.

1. Genetic diseases
2. Multifactorial diseases (diseases with hereditary predisposition)
3. Chromosomal diseases
4. Genetic diseases of somatic cells
5. Diseases with an unconventional type of inheritance (mitochondrial diseases, trinucleotide repeat expansion diseases, genomic imprinting diseases, uniparental disomies).

Genetic diseases (about 4.5 thousand)

The reason is gene mutations. The patterns of their inheritance correspond to Mendeleev's rules of splitting in offspring. At the same time, it is assumed that we are talking about the full form of hereditary pathology, i.e. pathological genes are present in all cells of the body.

Schematically, the general pathogenesis of gene mutations can be represented as follows:

Mutation → mutant gene → pathological primary product (qualitative or quantitative) → a chain of subsequent biochemical processes → changes at the level of a cell → an organ → an organism.

The primary effects of gene mutations at the molecular level can manifest themselves in 4 variants (for example, metabolism) (described in detail in the textbook - p. 115):

1. Lack of protein synthesis. Example: phenylketonuria (absence of the enzyme phenylalanine hydroxylase - phenylalanine accumulates)

2. Synthesis of an abnormal protein. Example: sickle cell anemia (hydrophilic glutamine → to hydrophobic valine, it does not perform an oxygen-acceptor function, it crystallizes with a lack of oxygen - red blood cells have a crescent shape)

3. Insufficient protein synthesis. Example: β-thalassemia (hemoglobinopathy) - inhibition of the synthesis of the ß-chain Hb, the à chain is synthesized normally, while the synthesis of normal Hb A decreases, but the synthesis of HbA2 and HbF increases.

4. Excess protein synthesis. Example: primary hemochromatosis (excessive synthesis of globin, overload of erythrocytes with hemoglobin and, accordingly, iron, → hemosiderosis of parenchymal organs).

This is the same principle of pathogenesis (i.e. mutant gene → pathological primary product) for morphogenetic control genes, mutations in which lead to the occurrence of congenital malformations (polydactyly (additional fingers or toes), etc.).

Molecular changes manifest themselves at the cellular level. The cell, as it were, takes the blow from the primary pathological effect of the gene. In this case, the target is cellular structures (cell membranes, lysosomes, etc.).

Example: glycogenoses (storage diseases). They are characterized by the accumulation of glycogen polymers in the cells of the liver and muscles. The mechanism is associated with a violation of the processes of glycogenolysis due to the lack of glycogen cleavage enzymes.

Another example where the target is the cell membrane: a violation of the synthesis of androgen receptors leads, in the presence of a male (XY) genotype, to the development of a female phenotype (this is testicular feminization syndrome).

The next level of pathogenesis of gene diseases is organ level. It is derived from the molecular and cellular levels of pathological changes.

Example: alkaptonuria. The mechanism of development is determined by the deposition of homogentisic acid accumulating in the blood in the articular cartilage and heart valves, which leads to joint stiffness and heart defects.

Classification of gene diseases:

1. autosomal - dominant and recessive.

2. sex-linked - dominant and recessive.

Autosomal dominant gene diseases In dominant autosomal diseases, the pathological gene is located in the autosome and manifests itself even in the heterozygous state.

Features of the transmission of dominant autosomal diseases:

2. The transmission of a pathological trait is possible from any of the parents.

3. The frequency of individual lesions among the descendants of the patient - 50%.

4. Occur in every generation (assuming 100% penetrance).

Penetrance is the probability of phenotypic manifestations of a pathological gene, the ability of a gene to break into a trait. It shows what% of the carriers of the pathological gene reveals the corresponding phenotype. With high penetrance, all people who receive an abnormal gene will develop a disease, i.e. the number of carriers of this gene will be equal to the number of patients. With weak penetrance, the number of carriers of the pathological gene will exceed the number of patients. However, a clinically healthy carrier of a pathological gene can pass it on to their descendants. This is how diseases jump across generations.

Incomplete penetrance is determined by the genotypic environment of the gene, i.e. a person may be a carrier of a pathological gene, but the gene may not manifest itself due to the modifying influence of other genes of the genotype on it. In this case, one speaks of incomplete penetrance and varying expressivity.

expressiveness is the degree of expression of the pathological gene. Example: six-fingered, but the sixth finger is a short, weak manifestation of an inherited trait.

Examples of autosomal dominant diseases: short-fingered, multi-fingered, multiple intestinal polyposis, congenital ptosis of the eyelids, achondroplasia, congenital night blindness (which cannot be treated with vitamin A, because there is night blindness that is treated with vitamin A), Marfan's disease (Lincoln's portrait, arachnodactyly - spider fingers, lens subluxation ), Huntington's chorea (manifested at 35-40 years old, has 2 main syndromes: chorea - hyperkinetic twitching of the trunk, face, shuffling gait, a symptom of speech impairment due to twitching of the tongue and palate; dementia - dementia), etc. Expressiveness in Huntington's chorea can vary from nystagmus to complete dementia - this indicates a clinical polymorphism of hereditary diseases.

Autosomal recessive gene diseases. They appear only in the homozygous state.

Features of the transmission of recessive autosomal diseases:

1. Males and females are equally affected.

2. The parents of the patient are phenotypically healthy, are heterozygotes, carriers of the pathological gene, which is detected only in the case of the birth of a sick child.

3. At the same time, the risk of having a sick child is 25%.

4. If one of the parents is sick, the children are usually healthy.

5. Often the parents of a sick child are relatives (more likely to be carriers of the same recessive gene). According to WHO, today millions of people on the planet enter into consanguineous marriages. In our country, this phenomenon is widespread in Asia, where 20% of all marriages are related. In every 60th such family, a child is born with a hereditary pathology. In the West, intra-family marriages are also common and the frequency of hereditary diseases is high, for example, in the farming regions of Finland.

Examples: enzymopathies - hereditary defects in the metabolism of carbohydrates (for example, galactosemia), lipids (for example, sphingolipidoses), amino acids (for example, phenylketonuria, albinism); vitamins, erythrocyte enzymes, hormone biosynthesis defects, collagen diseases.

Another example: channelopathy - cystic fibrosis - pulmonary and intestinal form. (characterized by the formation of a thick secret in the glands, which clogs the glandular ducts, resulting in the formation of cysts).

X-linked dominant diseases.

Features of the transmission of dominant diseases linked to sex:

1. Both men and women are affected. But sick women are 2 times more than sick men.

2. All the daughters of a sick father will be sick, the sons will be healthy.

3. If the mother is homozygous for this trait, then all the offspring will be sick, if heterozygous, 50% of sons and daughters will be sick, i.e. 50% of children.

4. On average, heterozygous women are less severely ill than hemizygous men.

Examples: defect of tooth enamel, anomaly of hair follicles (follicular hyperkeratosis, it leads to complete or partial loss of eyelashes, eyebrows, head hair - severe forms only in men), etc.

Transmission Features:

1. The transmission of the pathological gene comes from the father of the daughter, all the daughters of the sick father are phenotypically healthy carriers.

2. A carrier woman will pass on the abnormal gene to 50% of her children.

3. A sick man can only get a pathological gene from his mother.

4. A carrier woman can receive a pathological gene from both her mother and father.

5. Women rarely get sick. Why? The birth of a sick daughter is possible only in the case of a marriage of a hemizygous father and a heterozygous mother, homozygosation occurs - the disease is severe, some of the fetuses are aborted, some of the newborns die in the 1st year of life.

6. In a homozygous sick mother, only sons will be sick, daughters will be carriers.

Examples: hemophilia A, B; color blindness, sex-linked ichthyosis agammaglobulinemia -Brutton's disease, lack of G-6-PD, Lesch-Nyhan syndrome - a rare anomaly of purine metabolism associated with a deficiency of the enzyme hypoxanthine-guanine-phosphoribosyltransferase (severe hyperuricemia, neurological disorders, gouty nodes, idiocy, indomitable the desire for self-harm - biting off the finger phalanges, the tip of the tongue).

four . Forms of interaction of allelic genes. Pleiotropic action of the gene. Multiple allelism.

5 . Interaction of non-allelic genes, their types.

6. Patterns of inheritance of traits according to Mendel. Mendelian signs in humans.

7. Types of trait inheritance, their characteristics. expressiveness and penetrance.

X-linked inheritance

9. Inheritance of blood groups of the ab0 system in humans

10. Rh factor. Rhesus conflict. Rhesus - incompatibility.

Rh blood incompatibility

11. Modern methods of genetic research.

12. Chromosomal diseases. Their classification, diagnosis.

All chromosomal diseases can be divided into 3 large groups:

13. Genetic diseases in humans. Their classification, diagnosis.

Classification

14. Cytogenetic method in the genetic analysis of the human hereditary apparatus

15. Cytogenetic and phenotypic characteristics of patients with Down syndrome. Diagnostics.

16. Cytogenetic and phenotypic characteristics of patients with Shereshevsky-Turner syndrome. Diagnostics. Shereshevsky-Turner syndrome (x-chromosome monosomy).

17. Cytogenetic and phenotypic characteristics of patients with Klinefelter's syndrome. Diagnostics. Klinefelter's syndrome is a genetic disorder.

Symptoms of Klinefelter's Syndrome

Diagnosis of Klinefelter's syndrome

18. Human populations, factors of their subdivision. population gene pool.

19. Biological factors of population gene pool dynamics.

20. Socio-demographic factors of the dynamics of the gene pool of populations.

21. Genetic load of populations, determination of its value using the Hardy-Weinberg equation.

22. Clinical and genealogical method, its use in

23. Biochemical method, its essence, possibilities of application in medical genetic counseling.

24. Twins in humans, criteria for determining the identity of twins. Twin method in genetic analysis.

25. Dermatoglyphic method, its essence and possibilities of use in genetic analysis.

26. Molecular genetic method, its modern possibilities and prospects for use in medicine.

27. Hybridological analysis, its use in genetic research.

28. Sexual dimorphism in humans, its genetic and phenotypic characteristics.

29. Medical genetic counseling, its tasks, organization. Medical genetic counseling

30. Inbreeding (random, non-random, total), its role as a factor in changing the gene pool of a population.

31. Natural selection, determination of its magnitude in the human population.

32. Chromosomal mosaicism, its formation, phenotypic manifestation in humans. Phenocopies, their essence.

8. The concept of "linkage" of genes. X-linked inheritance of traits in humans.

A phenomenon based on the localization of genes on one chromosome. Linkage of genes was first discovered in 1906 by W. Batson and R. Pennet in experiments on crossing sweet peas. Later, the linkage of genes was studied in detail by T. Morgan et al. in experiments with Drosophila. Linkage of genes is expressed in the fact that alleles of linked genes that are in the same linkage group tend to be inherited together. This leads to the formation of gametes in the hybrid preim. with "parental" combinations of alleles. To indicate the linkage of genes, the symbols AB / av or AB / Ab linkage of dominant (or recessive) alleles with each other AB / av are used. the linkage phase, and the linkage of dominant alleles with recessive AB / AB - the repulsion phase. In both cases, gene linkage results in a lower frequency of individuals with "non-parental", recombinant combinations of traits than would be expected from independent inheritance of traits. With complete linkage of genes, only two types of gametes are formed (with initial combinations of linked genes), with incomplete linkage, new combinations of alleles of linked genes are formed. Incomplete linkage of genes is the result of crossing over between linked genes, therefore, complete linkage of genes is possible in organisms in whose cells crossing over does not normally occur (for example, germ cells of Drosophila males). Thus, complete linkage of genes is rather an exception to the rule of incomplete linkage of genes. In addition, full linkage of genes can be mimicked by the phenomenon of pleiotropy. In some cases, non-random divergence of non-homologous chromosomes to one pole regularly occurs in meiosis, which leads to the formation of gametes predominantly. with certain combinations of alleles of unlinked genes. Different pairs of genes within the same linkage group are characterized by different degrees of linkage depending on the distance between them. The greater the distance between the genes in the chromosome, the less the adhesion force between them and the more often recombinant types of gametes are formed. The study of gene linkage and linked inheritance of traits served as one of the confirmations of the chromosome theory of heredity and the initial impetus for the analysis and development of the theory of crossing over.

X-linked inheritance

Since the X chromosome is present in the karyotype of each person, the traits inherited linked to the X chromosome appear in both sexes. Females receive these genes from both parents and pass them on to their offspring through their gametes. Males receive the X chromosome from their mother and pass it on to their female offspring.

There are X-linked dominant and X-linked recessive inheritance. In humans, an X-linked dominant trait is passed on by the mother to all offspring. A man passes on his X-linked dominant trait only to his daughters. An X-linked recessive trait in women appears only when they receive the corresponding allele from both parents. In men, it develops when receiving a recessive allele from the mother. Women pass the recessive allele to their offspring of both sexes, while men only pass it on to their daughters.

With X-linked inheritance, an intermediate character of the manifestation of the trait in heterozygotes is possible.

Y-linked genes are present in the male genotype only and are passed down from generation to generation from father to son.

This brochure provides information about what X-linked inheritance is and how X-linked diseases are inherited.

What are genes and chromosomes?

Our body is made up of millions of cells. Most cells contain a complete set of genes. Humans have thousands of genes. Genes can be compared to instructions that are used to control growth and coordinate the work of the whole organism. Genes are responsible for many traits of our body, such as eye color, blood type, or height.

Figure 1: Genes, chromosomes and DNA

Genes are located on thread-like structures called chromosomes. Normally, most body cells contain 46 chromosomes. Chromosomes are passed on to us from our parents - 23 from mom and 23 from dad, so we often look like our parents. So we have two sets of 23 chromosomes, or 23 pairs of chromosomes. Since genes are located on chromosomes, we inherit two copies of each gene, one copy from each parent. Chromosomes (hence genes) are made up of a chemical compound called DNA.

Figure 2: 23 pairs of chromosomes distributed by size; chromosome number 1 is the largest. The last two chromosomes are the sex chromosomes.

Chromosomes (see Figure 2), numbered 1 to 22, are the same in males and females. Such chromosomes are called autosomes. Chromosomes of the 23rd pair are different in women and men, and they are called sex chromosomes. There are 2 variants of sex chromosomes: X-chromosome and Y-chromosome. Normally, women have two X chromosomes (XX), one of them is transmitted from the mother, the other from the father. Normally, males have one X chromosome and one Y chromosome (XY), with the X chromosome inherited from the mother and the Y chromosome from the father. So, in Figure 2, the male chromosomes are shown, since the last, 23rd, pair is represented by the XY combination.

Sometimes a change (mutation) occurs in one copy of a gene that disrupts the normal operation of the gene. Such a mutation can lead to the development of a genetic (hereditary) disease, since the altered gene does not convey the necessary information for the body. X-linked diseases are caused by changes in the genes of the X chromosome.

What is X-linked inheritance?

The X chromosome contains many of the genes that are very important for the growth and development of an organism. The Y chromosome is much smaller and contains fewer genes. As you know, women have two X chromosomes (XX), so if one copy of the gene on the X chromosome is changed, then the normal copy on the second X chromosome can compensate for the function of the changed one. In this case, the woman is usually a healthy carrier of an X-linked disease. A carrier is a person who has no signs of the disease, but has an altered copy of the gene. In some cases, women may present moderate manifestations of the disease.

Males have one X and one Y chromosome, so when one copy of the gene on the X chromosome is altered, there is no normal copy of the gene to compensate for the function. This means that such a man will be sick. Diseases that are inherited in the manner described above are called X-linked recessive. Examples of such diseases are hemophilia, Duchenne muscular dystrophy and fragile X syndrome.

X-linked dominant inheritance

Most X-linked diseases are recessive, but in rare cases, X-linked diseases are inherited as dominant. This means that if a woman has one altered and one normal copy of the gene, then this will be enough for the disease to manifest itself. If a man inherits an altered copy of the X chromosome gene, then he will develop the disease, since men have only one X chromosome. Affected women have a 50% (1 in 2) chance of having an affected child, and it is the same for daughters and sons. A sick man will have all his daughters sick and all his sons healthy.

How are X-linked diseases inherited?

If a carrier woman has a son, then she can pass on either the X chromosome with a normal copy of the gene, or the X chromosome with an altered copy of the gene. Thus, each son has a 50% (1 in 2) chance of inheriting the altered copy of the gene and becoming ill. At the same time, there is the same 50% (1 in 2) chance that the son will inherit a normal copy of the gene, in which case he will not have the disease. This probability is the same for each son (Fig. 3).

If a carrier woman has a daughter, she will either pass on an X chromosome with a normal copy of the gene or an X chromosome with an altered copy. Thus, each daughter has a 50% (1 in 2) chance of inheriting the altered copy of the gene, in which case she will be a carrier just like her mother. On the other hand, there is the same 50% (1 in 2) chance that the daughter will inherit a normal copy of the gene, in which case she will be healthy and not a carrier (Figure 3).

Figure 3: How X-linked recessive diseases are transmitted from female carriers

Figure 4: How X-linked recessive diseases are transmitted from affected males

If a man with an X-linked disease has a daughter, he will always give her an altered copy of the gene. This is because men only have one X chromosome and they always pass it on to their daughters. Thus, all his daughters will be carriers (Figure 4). As a rule, daughters are healthy, but they are at risk of having sick sons.

If a man with an X-linked disease has a son, then he will never give him an altered copy of the gene. This is due to the fact that men always pass on the Y chromosome to their sons (if they pass on the X chromosome, they will have a daughter). Thus, all the sons of a man with an X-linked disease will be healthy (Fig. 4).

What happens if the patient is the first in the family to have the disease?

Sometimes a child with an X-linked genetic disorder may be the first in the family to be diagnosed with the disorder. This may be due to the fact that a new mutation (change) in the gene occurred in the sperm or egg from which this child developed. In this case, none of the parents of the child will be a carrier of the disease. The likelihood of these parents having another child with the same disease is very small. However, a sick child who has an altered gene may pass it on to their children in the future.

Carrier test and prenatal diagnosis (test during pregnancy)

For people who have a family history of an X-linked recessive hereditary disorder, there are several options for testing. A carrier test can be done in women to determine if they are carriers of mutations (changes) in a specific gene on the X chromosome. This information may be useful when planning a pregnancy. For some X-linked diseases, prenatal diagnosis (i.e., diagnosis during pregnancy) may be done to determine if the child has inherited the disease (for more information, see the Chorionic Villus Biopsy and Amniocentesis brochures).

Other family members

If someone in your family has an X-linked disease or is a carrier, you may want to discuss this with other members of your family. This will give women in your family the opportunity, if they wish, to be tested (a special blood test) to determine if they are carriers of the disease. This information may also be important for relatives in diagnosing the disease. This may be especially important for those relatives who have or will have children.

Some people may find it difficult to discuss their genetic disorder with other family members. They may be afraid of disturbing family members. In some families, people experience difficulties in communication because of this and lose mutual understanding with relatives.

Geneticists are usually experienced in dealing with such family situations and can help you discuss the problem with other family members.

What is important to remember

• Women who carry an X-linked disease have a 50% chance of passing on the altered copy of the gene to their children. If the son inherits the modified copy from the mother, he will be ill. If the daughter inherits the modified copy from the mother, then she will be a carrier of the disease, like her mother.
• A man with an X-linked recessive disorder always passes on the altered copy of the gene to his daughter, and she will be a carrier. However, if it is an X-linked dominant disorder, then his daughter will be affected. A man never passes on an altered copy of a gene to his son.
• An altered gene cannot be corrected - it remains altered for life.
• The altered gene is not contagious, for example, its carrier may be a blood donor.
• People often feel guilty about having a genetic disorder in their family. It is important to remember that this is not anyone's fault or a consequence of anyone's actions.