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 disorder. 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.
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 incidence rate 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.
As discussed earlier, X-linked phenotype considered dominant if it usually appears in heterozygotes. Dominant inheritance can be easily distinguished from autosomal dominant inheritance by the lack of male-to-male transmission, which is clearly not possible with X-linked inheritance, since males pass on the Y chromosome to their sons, not the X chromosome.
Thus, the distinguishing feature of a completely penetrant X-linked dominant pedigree- all the daughters of sick men are also sick, while none of the sons is sick; if there is at least one healthy daughter or sick son, inheritance must be autosomal and not X-linked. Inheritance through a woman is no different from autosomal dominant inheritance; Because women have a pair of X chromosomes, as well as pairs of autosomes, each child of an affected woman has a 50% chance of inheriting the trait, regardless of gender.
In numerous families with X-linked dominant diseases The clinical picture is usually milder in women, who are almost always heterozygous because the mutant allele in some of their cells is located on the inactive X chromosome. Thus, most X-linked dominant diseases are not completely dominant, as is the case with most autosomal dominant diseases.
TO X-linked dominant diseases There are only a few genetic disorders. One example is X-linked hypophosphatemic rickets (or vitamin D-resistant rickets), which impairs the ability of the renal tubules to reabsorb phosphate. The product of the defective gene belongs to the family of endopeptidases, which activate or degrade a number of peptide hormones.
The pathogenesis due to which the lack of this endopeptidases causes disturbances in phosphate metabolism and rickets, unknown. The disease is classified as X-linked dominant because, although both sexes are affected, in heterozygous women the serum phosphate level is less reduced and the clinical picture of rickets is less severe than in sick men.
Characteristics of X-linked dominant inheritance:
Affected men married to a healthy woman do not have affected sons or healthy daughters.
Both sons and daughters of female carriers have a 50% risk of inheriting the phenotype. The pedigree is similar to autosomal dominant inheritance.
Affected women are almost twice as common as men, but usually have a variable but milder phenotype.
Genes located on chromosome X, as well as in the autosomal mode of inheritance, can be dominant or recessive. The main feature of X-linked inheritance is the absence of transmission of the corresponding father's gene to the son, since men, being hemizygous (have only one X chromosome), pass on their X chromosome only to daughters. If a dominant gene is localized on the X chromosome, this type of inheritance is called X-linked dominant ( rice. 12.1.). It's typical for him.
· if a father is sick, then all his daughters will be sick, and all his sons will be healthy;
· children are sick only if one of the parents is sick;
· healthy parents will have healthy children;
· the disease can be traced in every generation;
· if the mother is sick, then the probability of having a sick child, regardless of gender, is 50%:
· both men and women are sick, but in general there are 2 times more women among sick women.
When a recessive gene is localized on chromosome X, the type of inheritance is called X-linked recessive. It is characterized by:
· predominantly males are affected;
· 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 woman, her father is necessarily sick, and the mother is a heterozygous carrier and all her sons are sick;
· in a marriage of sick men and healthy homozygous women, all children will be healthy, but daughters may have sick sons;
· in a marriage of a healthy man and a heterozygous woman, the probability of having a sick child will be 50% for boys and 0% for girls.
Figure 12.1. Example of a pedigree with X-linked dominant inheritance
Examples of sex-linked inheritance:
X-linked inheritance - hemophilia (Fig. 12.2.), color blindness.
Thanks to a well-known pedigree, it was possible to trace the inheritance of the hemophilia gene from Queen Victoria of England. Victoria and her husband were healthy. It is also known that none of her ancestors suffered from hemophilia. Most likely, a mutation occurred in the gamete of one of Victoria’s parents. As a result, Queen Victoria became a carrier of the hemophilia gene and passed it on to many of her descendants. All male descendants who received an X chromosome with a mutant gene from Victoria suffered from a serious illness - hemophilia.
Y-linked inheritance - hypertrichosis (increased hair growth in the auricle), membranes between the fingers.
X- and Y-linked inheritance - general color blindness.
Figure 12.2. Pedigree of a family with hemophilia (X-linked recessive inheritance)
One of the sex-linked recessive genes causes a special type of muscular dystrophy (Dumain type). This dystrophy manifests itself in early childhood and gradually leads to disability and death before the age of 20. Therefore, men with Dumain's dystrophy do not have offspring, and women who are heterozygous for the gene for this disease are quite normal. Among the dominant traits associated with the X chromosome, one can point to a gene that causes a deficiency of organic phosphorus in the blood. As a result, in the presence of this gene, rickets often develops, resistant to treatment with ordinary doses of vitamin A. In this case, the pattern of sex-linked inheritance differs markedly from the course of transmission over generations that has been described for recessive diseases. In the marriages of nine sick women with healthy men, the children were half sick girls and half boys. Here, in accordance with the nature of inheritance of the dominant gene, splitting occurred in the X chromosomes in a ratio of 1:1:1:1. Another example of a dominant gene localized on the human X chromosome is the gene that causes a dental defect that leads to darkening of tooth enamel.
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 their disease on 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
