X linked inheritance. X-linked recessive diseases

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 a 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. In the literature there is an abbreviation XR to denote X-linked recessive inheritance.

It is typical for X-linked recessive diseases that men are usually affected; for rare X-linked diseases this is almost always true. All of 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 characteristics of fathers appear in daughters, and the characteristics of mothers in sons. This type of inheritance was named by one of the authors of the chromosomal theory of inheritance, Thomas Hunt Morgan. He first described this type of inheritance for the eye color trait in Drosophila 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 detection of this type of inheritance during segregation analysis 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, like 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 discussed 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 the genes found on the X chromosome. For this reason, in men there are only two possible states of the X-linked recessive trait:

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

Since women have two X chromosomes, they have 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 appear, and when inherited, approximately 50% of the descendants receive this allele along with the X chromosome from it (the other 50% of the descendants will receive another X chromosome) ;
• the allele that determines the trait or disorder is present on both X chromosomes - the trait or disorder is manifested and passed on to offspring in 100% of cases.

Some disorders inherited in an X-linked recessive pattern can be so severe that they lead to fetal death. In this case, there may not be a single known patient among 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. Some diseases with X-linked recessive inheritance still have some clinical manifestations in female carriers due to the mechanism of dosage compensation, due to which one of the X chromosomes is randomly inactivated in somatic cells, and in some cells of the body one X allele is expressed, and in others - another.

Some X-linked recessive diseases in humans

Common

Common X-linked recessive diseases:

• Hereditary color vision disorder (color blindness). In Northern Europe, approximately 8% of men and 0.5% of women suffer from varying degrees of weakness of red-green perception.
• X-linked ichthyosis. Dry, rough patches appear on the skin of patients due to excessive accumulation of sulfonated steroids. 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. Occurs in 1 in 3,600 male newborns.
• Hemophilia A (classical hemophilia). The disease associated with deficiency of blood clotting factor VIII occurs in one in 4000-5000 men.
• Hemophilia B. A disease associated with deficiency of blood 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. Occurs in 3-6 out of 100,000 male newborns.
• Kabuki syndrome - multiple birth defects (heart defects, growth deficiency, hearing loss, urinary tract abnormalities) and mental retardation. Prevalence 1:32000.
• Androgen insensitivity syndrome (Morris syndrome) - an individual with complete syndrome has a feminine appearance, developed breasts 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 karyotype of 46,XY.

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 is a congenital immunodeficiency and thrombocytopenia. Prevalence: 4 cases per 1,000,000 male births.
• Lowe's syndrome (oculocerebrorenal syndrome) - skeletal abnormalities, various renal disorders, glaucoma and cataracts from early childhood. Occurs with a frequency of 1:500,000 male newborns.
• Allan-Herndon-Dudley syndrome is a rare syndrome, found only in males, in which postnatal brain development is impaired. The syndrome is caused by a mutation in the MCT8 gene, which encodes a protein that transports thyroid hormone. First described in 1944.

Genes located on the X chromosome, as in autosomal inheritance, can be dominant or recessive. The main feature of X-linked inheritance is the absence of transmission of the corresponding gene from father to son, because Men, being hemizygous (have only one X chromosome), pass on their X chromosome only to their daughters.

If a dominant gene is localized on the X chromosome, this type of inheritance is called X-linked dominant. It is characterized by the following symptoms:

If the father is sick, then all the daughters will be sick, and all the sons will be healthy;

Sick children appear only if one of the parents is sick;

With healthy parents, all children will be healthy;

The disease can be traced in every generation;

If the mother is sick, then the probability of giving birth to a sick child is 50%, regardless of gender;

Both men and women get sick, but in general there are 2 times more sick women in the family than sick men.

When a recessive gene is localized on the X chromosome, the type of inheritance is called X-linked recessive. Women are almost always phenotypically healthy (carriers), i.e. heterozygotes. The severity of the disease depends on the degree of damage to the reproductive system. This type of inheritance is characterized by:

The disease primarily affects males;

The disease is observed in male relatives of the proband on the maternal side;

A son never inherits his father's disease;

If the proband is a sick woman, her father is necessarily sick, and all her sons are also affected;

In a marriage between sick men and healthy homozygous women, all children will be healthy, but daughters may have sick sons;

In a marriage of a sick man and a woman who is a carrier of a daughter: 50% are patients, 50% are carriers; sons: 50% are sick, 50% are healthy.

In a marriage between a healthy man and a heterozygous woman, the probability of having a sick child will be: 50% for boys and 0% for girls.

Carrier sisters have 50% of affected sons and 50% of carrier daughters.

Pedigree with X-recessive inheritance

Pedigree with X-dominant inheritance

Y-linked type of inheritance

In rare cases, a paternal or holandric type of inheritance is observed, due to the presence of mutations in the genes of the Y chromosome.

At the same time, only men get sick and pass on their disease to their sons through the Y chromosome. Unlike autosomes and the X chromosome, Y chromosome carries relatively few genes (according to the latest data from the international gene catalog OMIM, only about 40).

A small part of these genes are homologous to the genes of the X chromosome; the rest, present only in men, are involved in the control of sex determination and spermatogenesis. Thus, on the Y chromosome there are the SRY and AZF genes, which are responsible for the sexual differentiation program.

Mutations in any of these genes lead to impaired testicular development and block of spermatogenesis, which is expressed in azoospermia. Such men suffer from infertility, and therefore their disease is not inherited. Men with complaints of infertility should be examined for the presence of mutations in these genes. Mutations in one of the genes located on the Y chromosome cause some forms of ichthyosis (fish skin), and a completely harmless symptom is hair growth of the auricle.

The trait is transmitted through the male line. The Y chromosome contains genes responsible for ear hair growth, spermatogenesis (azoospermia), and the rate of growth of the body, limbs, and teeth.

Pedigree with Y-linked inheritance

Inherent in few forms of pathology, for example, vitamin

D-rickets. Both homozygotes and heterozygotes will have a phenotypic manifestation of the disease. Different marriages are genetically possible, but those in which the father is sick are informative. In a marriage with a healthy woman, the following features of inheritance of pathologies are observed:

1) all sons and their children will be healthy, since only the Y chromosome can be passed on to them from their father;

2) all daughters will be heterozygotes, and phenotypically sick.

These two features distinguish this type from the autosomal dominant type, in which the ratio of sick and healthy siblings is 1:1 and are equally indistinguishable for children from those with an autosomal dominant inheritance pattern (1:1), and there should also be no gender differences. There is a stronger manifestation of the disease in men, since they do not have the compensating effect of the normal alley. The literature describes pedigrees for some diseases with this type of transmission, which do not have male siblings, since the severe degree of damage causes their intrauterine death. This pedigree looks peculiar: the offspring are only female, about half of them are sick, and the anamnesis may include spontaneous abortions and stillbirths of male fetuses.

The listed types of inheritance involve mainly monogenic diseases (determined by a mutation of one gene). However, the pathological condition may depend on two or more mutant genes. A number of pathological genes have reduced penetrance. Moreover, their presence in the genome, even in a homozygous state, is necessary, but not sufficient for the development of the disease. Thus, not all types of inheritance of human diseases fit into the three schemes listed above.

METHODS FOR DETERMINING PRIMARY BIOCHEMICAL DEFECT.

When considering the history of the discovery of monogenic nosological forms, it is clearly seen that its longest period, approximately until the mid-50s, is associated with the identification of such forms on the basis of a clinical and genealogical examination of families. This period, however, is not very productive. For example, the currently identified 18 genetic forms of hereditary mucopolysaccharidoses, caused by mutations of 11-12 different genes, clinically form only two slightly different phenotypes, and based on the clinical picture and type of inheritance, only two nosological units have been discovered - Hurler syndrome and Hunter syndrome. The same situation has developed with other classes of hereditary metabolic defects. The discovery and description of hereditary diseases should not be considered complete. Currently, about two thousand Mendelian pathological conditions are known. Theoretically, based on the total number of structural genes of the order of 50-100 thousand, one could assume that most of the pathological mutant alleles have not yet been discovered. Even if we admit that many such mutations are lethal, while others, on the contrary, do not affect serious functions and go clinically unrecognized, then we should expect the continued discovery of more and more new forms of hereditary pathology. But we can say with confidence that the most common diseases that give a clear clinical picture have already been described. Newly discovered forms are the result of rare mutations. In addition, from a genetic point of view, mutations of the same gene will result, but affecting new structures or being different in their molecular nature (for example, mutations in the regulatory rather than structural part of the gene). That is why the discovery of new mutant alleles and the fragmentation of known diseases into genetically different forms are inseparable from the connection to traditional clinical genetic analysis of new genetic approaches that make it possible to reach more discrete and approaching elementary traits.

The first place is occupied by biochemical methods. The biochemical approach was first applied and turned out to be very fruitful at the beginning of this century in the clinical and genetic study of alcaptunuria. It was as a result of this study that a biochemical mendelian trait was found for one of the hereditary diseases, in the form of excessive excretion of homogentisic acid in the urine, and it was suggested that there are similar congenital metabolic diseases with their own specific biochemical defect. Currently, more than 300 hereditary metabolic diseases with studied anomalies have been described in biochemical genetics. In clinical practice, for the biochemical diagnosis of known metabolic diseases, a system of qualitative and semi-quantitative tests is used, with the help of which it is possible to detect the disturbed content of metabolic products (for example, excessive urinary excretion of phenylpyruvic acid in phenylketonuria or homocystine in homocystinuria). The use of various types of electrophoresis and chromatography separately and in combination, as well as other methods, makes it possible to determine which metabolic link is disturbed. To find out which enzyme or other protein is involved in the metabolic effect and what the change in protein is, as a rule, not only biological fluids are used, but also the patient’s cells, and complex methods are used to determine the content of the enzyme, its catalytic activity and molecular structure.

Biochemical methods are complemented by molecular genetic methods, which are of independent importance for deciphering the nature of mutations directly in DNA. Traditionally, their use is possible after identifying a defect in the corresponding gene product, but so far it is realistic for a few cases of pathology, for example, for mutations of globin genes.

The fruitfulness of biochemical research methods is largely due to the fact that the biochemical analysis of biological fluids is complemented by the analysis of body cells. Genetic biochemical analysis on cells turned out to be decisive in the transition to biochemical diagnostics with the analysis of metabolites to the study of enzymes and structural proteins directly, in particular cellular receptors.

This led to the discovery of primary defects in protein molecules and many hereditary diseases. Immunological methods are close in their capabilities to biochemical methods. Diagnostics and in-depth study of the genetic forms of various hereditary immunodeficiency conditions are based on methods for assessing the level of serum immunoglobulins of different classes, as well as the state of cellular immunity. A prominent place in the arsenal of these methods is occupied by classical serological reactions with erythrocytes or leukocytes to determine the status of surface antigens. In recent years, radioimmunochemical methods for determining the defect of hormones and some other biologically active substances have become increasingly used.

All of these methods are used to identify biochemical defects and the molecular nature of mutations with a population-geographical approach. The significance of this approach is that rare defects and mutations can occur predominantly in certain geographic regions due to the specific conditions of the human environment. It is enough to recall the predominant distribution of various genoglobinopathies, especially in areas where malaria is widespread. Isolated populations with a large number of consanguineous marriages often served as a source for the discovery of new mutations due to the more frequent segregation of homozygotes in a recessive state. The population-geographic approach also helps, with large samples of patients, to more quickly differentiate phenotypically similar, but genetically different mutations.

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. A person has thousands of genes. Genes can be compared to instructions that are used to control the growth and coordinated functioning of the entire organism. Genes are responsible for many characteristics 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 cells in the body 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. Thus, we have two sets of 23 chromosomes, or 23 pairs of chromosomes. Because genes are located on chromosomes, we inherit two copies of each gene, one copy from each parent. Chromosomes (and therefore genes) are made 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 sex chromosomes.

The chromosomes (see Figure 2), numbered 1 to 22, are the same in men and women. Such chromosomes are called autosomes. The chromosomes of the 23rd pair are different in women and men and 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 passed on from the mother and the Y chromosome from the father. Thus, Figure 2 shows the chromosomes of a man, 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 functioning of the gene. Such a mutation can lead to the development of a genetic (hereditary) disease, since the altered gene does not transmit the necessary information to the body. X-linked diseases are caused by changes in genes on 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 the organism. The Y chromosome is much smaller and contains fewer genes. As is known, women have two X chromosomes (XX), therefore, if one copy of a 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 the 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 have moderate manifestations of the disease.

Males have one X and one Y chromosome, so when one copy of a 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, this will be enough for the disease to manifest itself. If a man inherits an altered copy of the X chromosome gene, he will develop the disease, since men only have 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 will be healthy.

How are X-linked diseases inherited?

If a carrier woman has a son, then she can pass on to him either an X chromosome with a normal copy of the gene, or an X chromosome with an altered copy of the gene. Thus, each son has a 50% (1 in 2) chance of inheriting an altered copy of the gene and developing the disease. At the same time, there is the same chance - 50% (1 in 2) - 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 (Figure 3).

If a carrier woman has a daughter, she will pass on either 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 an altered copy of the gene, in which case she will be a carrier, like her mother. On the other hand, there is an equal 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 men

If a man with an X-linked disease has a daughter, he will always pass on the altered copy of the gene to her. 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 (Fig. 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, he will never pass on the altered copy of the gene to him. 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 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 be diagnosed with this disease?

Sometimes a child with an X-linked genetic disorder may be the first in the family to be diagnosed with the condition. This may be explained by the fact that a new mutation (change) in the gene has occurred in the sperm or egg from which the child developed. In this case, neither of the child’s parents will be a carrier of the disease. The likelihood of these parents having another child with the same disease is very low. However, a sick child who has an altered gene may pass it on to his children in the future.

Carrier test and prenatal diagnosis (test during pregnancy)

For people who have a family history of an X-linked recessive disorder, there are several options for testing. A carrier test can be performed on women to determine whether 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 testing (that is, testing during pregnancy) can be done to determine whether the baby has inherited the disease (for more information, see the chorionic villus sampling 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 undergo testing (a special blood test) to determine whether they are carriers of the disease. This information may also be important for relatives when 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 condition with other family members. They may be afraid of disturbing family members. In some families, because of this, people experience difficulties in communication and lose mutual understanding with relatives.

Genetic doctors usually have extensive experience in dealing with these types of family situations and can help you discuss the problem with other family members.

What is important to remember

• Women who are carriers of an X-linked disease have a 50% chance of passing on an altered copy of the gene to their children. If a son inherits a modified copy from his mother, he will be sick. If a daughter inherits a modified copy from her mother, she will be a carrier of the disease, like her mother.
• A man with an X-linked recessive disorder will always pass 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 the altered copy of the 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 can 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 the result of anyone else's actions.

Genes located on the sex chromosomes are referred to as sex-linked. They are distributed differently in men and women. Sex-linked genes can be located on both the X and Y chromosomes. However, in clinical genetics, X-linked diseases are of practical importance, i.e. such when the pathological gene is located on the X chromosome.

The distribution of the X-linked trait depends on the distribution of the X chromosome carrying the abnormal gene. Considering that women have two X chromosomes, and men have one, the following genotype options are possible: for a man - XY, XY, for a woman - XHA, XHA, XHa.

Recessive X-linked type

Inheritance of the disease

An X-linked recessive disease (or trait) always appears in men who have the corresponding gene, and in women only in cases of a homozygous state (which is extremely rare). An example of an X-linked recessive disease is hemophilia A, characterized by a blood clotting disorder due to deficiency of factor VIII - antihemophilic globulin A. The pedigree of a patient with hemophilia is shown in Fig. IX.11. Clinically, the disease is manifested by frequent prolonged bleeding, even with a minor wound, and hemorrhages into organs and tissues. The incidence of the disease is 1 in 10,000 newborn boys. Using the above notations, it is possible to determine all possible genotypes in the offspring of a sick man and a healthy woman (Fig. IX. 12).

According to the scheme, all children will be phenotypically healthy, but genotypically all daughters are carriers of the hemophilia gene. If a woman, a carrier of the hemophilia gene, marries a healthy man, the following options for the genotypes of the offspring are possible (Fig. IX. 13).

In 50% of cases, daughters will be carriers of the pathological gene, and for sons there is a 50% risk of being a hemophiliac.

Thus, the main signs of X-linked recessive inheritance are the following:

1) the disease occurs mainly in males;

2) the trait (disease) is transmitted from a sick father through his phenotypically healthy daughters to half of his grandchildren;

3) the disease is never transmitted from father to son;

4) carriers sometimes exhibit subclinical signs of pathology.

Dominant X-linked type of inheritance of the disease

In contrast to diseases with an X-linked recessive type of inheritance, diseases with an X-linked dominant type of inheritance occur 2 times more often in women than in men. The main characteristic of X-linked dominant inheritance is that affected men pass the abnormal gene (or disease) on to all their daughters and do not pass it on to their sons. A sick woman passes on the X-linked dominant gene to half of her children, regardless of gender (Fig. IX.14).

The distribution of patients in the pedigree depends on the gender of the affected parent (Fig. IX. 15).

Rice. 1X.14.

Pedigree with X-linked dominant

Type of inheritance of the disease

(vitamin D-resistant rickets)

Rice. IX. 15.:

A - the father is sick (individual II-1 of the pedigree shown in Fig. IX. 14); b - the mother is sick (individual 1-2, Fig. IX. 14) The main signs of the X-linked dominant type of inheritance are the following:

1) the disease occurs in men and women, but in women it is twice as common;

2) a sick man transmits the mutant allele only to his daughters, and not to his sons, since the latter receive the Y chromosome from their father;

3) sick women transmit the mutant allele to half of their children, regardless of gender;

4) women suffer less severely in case of illness (they are heterozygotes) than men (who are hemizygotes).

Normally, genes localized on the sex chromosomes of the heterogametic sex are hemizygous, i.e. sex, which forms different types of germ cells. Hemizygosity also occurs as a result of aneuploidy or deletion, when only one of a pair of allelic genes is retained in the genotype, which can manifest itself as a recessive mutation.

Diseases characterized by X-linked dominant inheritance include vitamin D-resistant rickets (rickets that cannot be treated with regular doses of vitamin D), orofacial-digital syndrome (multiple hyperplastic frenulum of the tongue, cleft lip and palate, hypoplasia of the nasal alae, asymmetrical shortening of the fingers) and other diseases.