They are inherited in an autosomal recessive manner. Types of inheritance of diseases

Most often, the pathology is transmitted by the autosomal dominant type of inheritance. This is monogenic inheritance of one of the traits. In addition, diseases can be transmitted to children by autosomal recessive and autosomal dominant inheritance, as well as by mitochondrial inheritance.

Types of inheritance

Monogenic inheritance of a gene can be recessive or dominant, mitochondrial, autosomal or linked to sex chromosomes. When crossed, offspring can be obtained with a variety of types of traits:

• autosomal recessive;
• autosomal dominant;
• mitochondrial;
• X-dominant linkage;
• X-recessive linkage;
• Y-clutch.

Different types of inheritance of traits - autosomal dominant, autosomal recessive and others - are capable of transmitting mutant genes to different generations.

Features of autosomal dominant inheritance

The autosomal dominant type of inheritance of the disease is characterized by the transmission of the mutant gene in a heterozygous state. The offspring that receive the mutant allele may develop a gene disease. At the same time, the probability of manifestation of the altered gene in men and women is the same.

When manifested in heterozygotes, the inheritance trait does not have a serious impact on health and reproductive function. Homozygotes with a mutant gene that conveys an autosomal dominant type of inheritance are, as a rule, not viable.

In parents, the mutant gene is located in the reproductive gamete together with healthy cells, and the probability of receiving it in children will be 50%. If the dominant allele is not completely changed, then the children of such parents will be completely healthy at the gene level. At a low level of penentrance, the mutant gene may not appear in every generation.

Most often, the type of inheritance is autosomal dominant, which transmits diseases from generation to generation. With this type of inheritance in a sick child, one of the parents suffers from the same disease. However, if only one parent in a family is sick, and the other has healthy genes, then the children may not inherit the mutant gene.

An example of autosomal dominant inheritance

The autosomal dominant type of inheritance can transmit more than 500 different pathologies, among them: Marfan syndrome, Ehlers-Danlos syndrome, dystrophy, Recklinghuysen's disease, Huntington's disease.

When studying the pedigree, one can trace the autosomal dominant type of inheritance. There may be different examples of this, but the most striking is Huntington's disease. It is characterized by pathological changes in nerve cells in the structures of the forebrain. The disease manifests itself as forgetfulness, dementia, and involuntary body movements. Most often, this disease manifests itself after 50 years.

When tracing the pedigree, you can find out that at least one of the parents suffered from the same pathology and passed it on in an autosomal dominant manner. If the patient has a half-brother or sister, but they do not show any manifestation of the disease, it means that the parents passed on the pathology for the heterozygous trait Aa, in which gene disorders occur in 50% of children. Consequently, the patient’s offspring may also give birth to 50% of children with the modified Aa gene.

Autosomal recessive type

In autosomal recessive inheritance, the father and mother are carriers of the pathogen. To such parents, 50% of children are born carriers, 25% are born healthy and the same number are born sick. The probability of transmitting a pathological trait to girls and boys is the same. However, diseases of an autosomal recessive nature may not be transmitted to every generation, but may appear after one or two generations of offspring.

An example of diseases transmitted by an autosomal recessive type can be:

• Toy-Sachs disease;
• metabolic disorders;
• cystic fibrosis, etc.

When children with an autosomal recessive type of gene pathology are detected, it turns out that the parents are related. This is often observed in gated communities, as well as in places where consanguineous marriages are allowed.

X chromosome inheritance

The X-chromosomal type of inheritance manifests itself differently in girls and boys. This is due to the presence of two X chromosomes in a woman and one in a man. Females receive their chromosomes one at a time from each parent, while boys receive their chromosomes only from their mother.

According to this type of inheritance, pathogenic material is most often transmitted to women, since they are more likely to receive pathogens from their father or mother. If the father is the carrier of the dominant gene in the family, then all boys will be healthy, but girls will show pathology.

With the recessive type of X-linkage of chromosomes, diseases appear in boys with the hemizygous type. Women will always be carriers of the diseased gene, since they are heterozygous (in most cases), but if a female has a homozygous trait, then she can get the disease.

Examples of pathologies with a recessive X chromosome can be: color blindness, dystrophy, Hunter's disease, hemophilia.

Mitochondrial type

This type of inheritance is relatively new. Mitochondria are transferred with the cytoplasm of the egg, which contains more than 20,000 mitochondria. Each of them contains a chromosome. With this type of inheritance, pathologies are transmitted only through the maternal line. From such mothers all children are born sick.

When the mitochondrial trait of heredity manifests itself, healthy children are born to men, since this gene cannot be transmitted from father to child, since there are no mitochondria in sperm.

AUTOSOMAL DOMINANT TYPE OF INHERITANCE

Examples of diseases: Marfan syndrome, hemoglobinopathy M, Huntington's chorea, colon polyposis, familial hypercholesterolemia, neurofibromatosis, polydactyly.

Autosomal dominant type of inheritance characterized by the following signs:

· Equal frequency of pathology in males and females.

· The presence of patients in each generation of the pedigree, i.e. regular transmission of the disease from generation to generation (the so-called vertical distribution of the disease).

· The probability of having a sick child is 50% (regardless of the gender of the child and the number of births).

· Unaffected family members, as a rule, have healthy offspring (since they do not have the mutant gene).

The listed characteristics are realized under the condition complete dominance(the presence of one dominant gene is sufficient for the development of a specific clinical picture of the disease). This is how freckles, curly hair, brown eye color, etc. are inherited in humans. With incomplete dominance, hybrids will exhibit an intermediate form of inheritance. If the gene has incomplete penetrance, there may not be patients in every generation.

AUTOSOMAL RECESSIVE TYPE OF INHERITANCE

Examples of diseases: phenylketonuria, ocular-cutaneous albinism, sickle cell anemia, adrenogenital syndrome, galactosemia, glycogenosis, hyperlipoproteinemia, cystic fibrosis.

Autosomal recessive mode of inheritance characterized by the following signs:

· Equal frequency of pathology in males and females.

· Manifestation of pathology in the pedigree “horizontally”, often in sibs.

· Absence of the disease in half-blooded (children of the same father from different mothers) and half-brothers (children of the same mother from different fathers).

· The patient's parents are usually healthy. The same disease can be detected in other relatives, for example, in cousins ​​or second cousins ​​of the patient.

The appearance of autosomal recessive pathology is more likely in consanguineous marriages due to the greater likelihood of meeting two spouses who are heterozygous for the same pathological allele received from their common ancestor. The greater the degree of relationship between the spouses, the higher this probability. Most often, the probability of inheriting a disease of an autosomal recessive type is 25%, since due to the severity of the disease, such patients either do not live to childbearing age or do not marry.

CHROMOSOME-LINKED X-DOMINANT INHERITANCE

Examples of diseases: one form of hypophosphatemia is vitamin D-resistant rickets; Charcot-Marie-Tooth disease - linked dominant; Orofacial-digital syndrome type I.

Signs of the disease:

· Males and females are affected, but women are 2 times more likely.

· Transfer of a pathological allele by a sick man to all daughters and only to daughters, but not to sons. Sons receive the Y chromosome from their father.

· Transmission of the disease by a sick woman to both sons and daughters is equally likely.

· The disease is more severe in men than in women.

CHROMOSOME-LINKED X-RECESSIVE INHERITANCE

Examples of diseases: hemophilia A, hemophilia B; X-linked recessive Charcot-Marie-Tooth disease; color blindness; Duchenne-Becker muscular dystrophy; Kallmann syndrome; Hunter's disease (mucopolysaccharidosis type II); hypogammaglobulinemia of Brutonian type.

Signs of the disease:

· Patients are born to phenotypically healthy parents.

· The disease occurs almost exclusively in males. Mothers of patients are obligate carriers of the pathological gene.

· A son never inherits a disease from his father.

· A carrier of a mutant gene has a 25% chance of having a sick child (regardless of the sex of the newborn); the probability of having a sick boy is 50%.

HOLANDRIC, OR LINKED TO CHROMOSOME Y,

TYPE OF INHERITANCE

Examples of signs: ichthyosis of the skin, hypertrichosis of the ears, excess hair growth on the middle phalanges of the fingers, azoospermia.

Signs:

· Transfer of a trait from the father to all sons and only sons.

· Daughters never inherit a trait from their father.

· “Vertical” nature of inheritance of a trait.

· The probability of inheritance for males is 100%.

MITOCHONDRIAL INHERITANCE

Examples of diseases(mitochondrial diseases): Leber optic atrophy, Leigh syndrome (mitochondrial myoencephalopathy), MERRF (myoclonic epilepsy), familial dilated cardiomyopathy.

Signs of the disease:

· The presence of pathology in all children of a sick mother.

· The birth of healthy children from a sick father and a healthy mother.

These features are explained by the fact that mitochondria are inherited from the mother. The portion of the paternal mitochondrial genome in the zygote is DNA from 0 to 4 mitochondria, and the maternal genome is DNA from approximately 2500 mitochondria. In addition, it appears that after fertilization, paternal DNA replication is blocked.

With all the diversity of gene diseases in their pathogenesis there is general pattern: the beginning of the pathogenesis of any gene disease is associated with primary effect of the mutant allele- a pathological primary product (qualitatively or quantitatively), which is included in the chain of biochemical processes and leads to the formation of defects in the cellular, organ And organismal levels.

Pathogenesis of the disease at the molecular level unfolds depending on the nature of the mutant gene product in the form of the following disorders:

Abnormal protein synthesis;

Lack of primary product production (most common);

Production of a reduced amount of normal primary product (in this case, the pathogenesis is highly variable);

Production of an excess amount of product (this option is only assumed, but has not yet been discovered in specific forms of hereditary diseases).

Options for implementing the action of an abnormal gene:

1) abnormal gene → cessation of mRNA synthesis → cessation of protein synthesis → hereditary disease;

2) abnormal gene → cessation of mRNA synthesis → hereditary disease;

3) an abnormal gene with a pathological code → synthesis of pathological mRNA → synthesis of pathological protein → hereditary disease;

4) disruption of switching genes on and off (repression and depression of genes);

5) abnormal gene → lack of hormone receptor synthesis → hereditary hormonal pathology.

Examples of the 1st variant of gene pathology: hypoalbuminemia, afibrinogenemia, hemophilia A (factor VIII), hemophilia B (IX - Christmas factor), hemophilia C (XI factor - Rosenthal), agammaglobulinemia.

Examples of the 2nd option: albinism (enzyme deficiency - tyrosinase → depigmentation); phenylketonuria (phenylalanine hydroxylase deficiency → phenylalanine accumulates → its metabolic product, phenylpyruvate, is toxic to the central nervous system → mental retardation develops); alkaptonuria (deficiency of homogentisic acid oxidase → homogentisic acid accumulates in the blood, urine, tissues → coloring of tissues, cartilage); enzymopathic methemoglobinemia (methemoglobin reductase deficiency → methemoglobin accumulates → hypoxia develops); adrenogenital syndrome (one of the most common hereditary human diseases: frequency in Europe 1:5000, among Eskimos of Alaska 1:400 - 1:150; 21-hydroxylase defect → cortisol deficiency, accumulation of androgens → in men - accelerated sexual development, in women - virilization).

Example of the 3rd variant of gene pathology: M - hemoglobinosis (abnormal M-hemoglobin is synthesized, which differs from normal A-hemoglobin in that at position 58 of the α-chain (or at position 63 of the β-chain) histidine is replaced by tyrosine → M-hemoglobin enters into a strong bond with oxygen, not giving it to the tissues, it forms methemoglobin → hypoxia develops).

Example of option 4: Thalassemia. It is known that fetal red blood cells contain special fetal hemoglobin, the synthesis of which is controlled by two genes. After birth, the action of one of these genes is inhibited and another gene is turned on, providing the synthesis of Hb A (95-98% of hemoglobin in healthy people). In pathology, persistence of fetal hemoglobin synthesis may be observed (its amount in healthy people is 1-2%). Hb S is less stable than Hb A - therefore hemolytic anemia develops.

Example of option 5: testicular feminization. It has been revealed that individuals with this disease do not have testosterone receptors. Therefore, the male embryo acquires features characteristic of the female body.

Pathogenesis of any hereditary disease in different individuals, although similar in primary mechanisms and stages, is formed strictly individually– the pathological process, launched by the primary effect of the mutant allele, acquires integrity with natural individual variations depending on the genotype of the organism and environmental conditions.

Characteristics clinical picture gene diseases are caused by the principles expression, repression and gene interaction.

The following are distinguished: main characteristics of gene diseases:features of the clinical picture; clinical polymorphism; genetic heterogeneity. At the same time, it is impossible to fully observe all the common features in one disease. Knowledge of the general features of gene diseases will allow the doctor to suspect a hereditary disease even in a sporadic case.

Features of the clinical picture:

variety of manifestations- the pathological process affects several organs already at the initial stages of the formation of the disease;

different ages of onset of the disease;

progression of the clinical picture and chronic course;

Conditioned disability since childhood and shortened life expectancy.

The variety of manifestations and the involvement of many organs and tissues in the pathological process for this group of diseases is due to the fact that the primary defect is localized in the cellular and intercellular structures of many organs. For example, in hereditary connective tissue diseases, the synthesis of a protein of one or another fibrous structure specific to each disease is disrupted. Since connective tissue is present in all organs and tissues, the variety of clinical symptoms in these diseases is a consequence of connective tissue abnormalities in various organs.

Age of onset for this group of diseases practically unlimited: from the early stages of embryonic development (congenital defects) – to old age ( Alzheimer's disease). The biological basis of different ages of onset of gene diseases lies in the strictly temporal patterns of ontogenetic regulation of gene expression. The reasons for different ages of onset of the same disease may be the individual characteristics of the patient’s genome. The effect of other genes on the manifestation of the effect of the mutant gene may change the time of development of the disease. The time of onset of the action of pathological genes and environmental conditions are also important, especially in the prenatal period. Generalized data on the timing of clinical manifestation of gene diseases indicate that 25% of all gene diseases develop in utero, and almost 50% of gene diseases manifest themselves in the first three years of life.

Most gene diseases are characterized by progression of the clinical picture And chronic protracted course with relapses. The severity of the disease “increases” as the pathological process develops. Primary biological basis This characteristic is the continuity of functioning of the pathological gene (or the absence of its product). This is accompanied by enhancing the pathological process secondary processes: inflammation; dystrophy; metabolic disorders; hyperplasia.

Most gene diseases are severe and lead to disability in childhood And shortens life expectancy. The more important a monogenically determined process is in ensuring life activity, the more clinically severe the manifestation of the mutation.

Concept "clinical polymorphism" unite:

Variability: timing of the onset of the disease; severity of symptoms; duration of the same illness;

Tolerance to therapy.

The genetic causes of clinical polymorphism can be determined not only by the pathological gene, but also by the genotype as a whole, that is, the genotypic environment in the form of modifier genes. The genome as a whole functions as a well-coordinated system. Together with the pathological gene, the individual inherits from his parents combinations of other genes that can enhance or weaken the effect of the pathological gene. In addition, in the development of a gene disease, like any hereditary trait, not only the genotype matters, but also the external environment. There is a lot of evidence for this position from clinical practice. For example, the symptoms of phenylketonuria in a child are more severe if during its prenatal development the mother’s diet included a lot of foods rich in phenylalanine.

There is a concept genetic heterogeneity masquerading as clinical polymorphism.

Genetic heterogeneity means that the clinical form of a gene disease can be caused by:

mutations in different genes, encoding enzymes of one metabolic pathway;

different mutations in the same gene, leading to the emergence of different alleles (multiple alleles).

In fact, in these cases we are talking about different nosological forms, from an etiological point of view, combined into one form due to the clinical similarity of the phenotype. The phenomenon of genetic heterogeneity is general; it can be called a rule, since it applies to all proteins of the body, including not only pathological, but also normal variants.

Deciphering the heterogeneity of gene diseases continues intensively in two directions:

clinical- the more accurately studied phenotype(analysis of the clinical picture of the disease), the more opportunities there are in the discovery of new forms of diseases, in the division of the studied form into several nosological units;

genetic- provides the most complete information about the heterogeneity of the clinical form of the disease DNA probe method(a modern method for analyzing human genes). The assignment of a gene to one or different linkage groups, the localization of the gene, its structure, the essence of the mutation - all this makes it possible to identify nosological forms.

Concept genetic heterogeneity of gene diseases opens up many opportunities in understanding the essence of individual forms and causes of clinical polymorphism, which is extremely important for practical medicine and provides the following opportunities: correct diagnosis; choice of treatment method; medical and genetic counseling.

Understanding epidemiology of gene diseases necessary for a doctor of any specialty, since in his practice he may encounter manifestations of a rare hereditary disease within the area or population he serves. Knowledge of the patterns and mechanism of spread of gene diseases will help the doctor timely develop preventive measures: examination for heterogeneity; genetic counseling.

Epidemiology of gene diseases includes the following information:

About the prevalence of these diseases;

About the frequencies of heterozygous carriage and the factors that determine them.

Prevalence of the disease(or number of patients) in the population determined by population patterns: the intensity of the mutation process; selection pressure, which determines the fertility of mutants and heterozygotes under specific environmental conditions; population migration; isolation; genetic drift. Data on the prevalence of hereditary diseases are still fragmentary due to the following reasons: a large number of nosological forms of genetic diseases; their rarity; incomplete clinical and pathological diagnosis of hereditary pathology. The most objective assessment of the prevalence of these diseases in different populations is to determine their number among newborns, including stillborns. The overall frequency of newborns with genetic diseases in populations as a whole is approximately 1%, of which:

With an autosomal dominant type of inheritance - 0.5%;

With autosomal recessive - 0.25%;

X-linked - 0.25%;

Y-linked and mitochondrial diseases are extremely rare.

The prevalence of individual forms of disease ranges from 1:500 (primary hemochromatosis) up to 1:100000 and below (hepatolenticular degeneration, phenylketonuria).

The prevalence of a gene disease is considered:

High – if 1 patient occurs per 10,000 newborns or more often;

Average – from 10,000 to 40,000;

Low – very rare cases.

To the group common includes no more than 15 gene diseases, but they account for almost 50% of the total frequency of patients with hereditary pathology.

Prevalence of many dominant diseases determined mainly by new mutations. Reproductive function in such patients is reduced for biological and social reasons. Almost all dominant diseases lead to decreased fertility. Exceptions are late-onset diseases (Alzheimer's disease, Huntington's chorea); by the time of their clinical manifestation (35-40 years), childbearing is already over.

Prevalence recessive diseases determined by the frequency of heterozygotes in the population, which is many times higher than the frequency of homozygotes for the mutant allele. The accumulation of heterozygotes in populations is due to their reproductive advantage compared to homozygotes for normal and pathological alleles. Populations of all living beings, not just humans, are burdened with recessive mutations. This general biological pattern was discovered by the Russian geneticist S.S. Chetverikov.

Selection in any population is determined by differential mortality and fertility of individuals with different genotypes, which leads, after a certain number of generations, to different concentrations of alleles in populations. Since selection is closely related to environmental conditions, on this basis different concentrations of alleles arise in different populations. Elimination or preferential reproduction can be observed depending on the adaptability of heterozygotes, normal or mutant homozygotes to environmental conditions. At the same time, it is necessary to pay attention to reduction of selection pressure in human populations, which goes two ways:

· improvement of medical and social care for patients(especially the treatment of hereditary diseases) - leads to the fact that homozygotes (for example, patients with phenylketonuria), who previously did not survive to the reproductive period, now not only live up to 30-50 years or more, but also get married and have children. Consequently, populations are replenished with heterozygotes for pathological genes;

· family planning(reducing the birth rate to arbitrary values, most often 1-2 children) - changes the effect of selection in connection with reproductive compensation. The essence of this phenomenon is that hereditarily burdened couples, in whom the mortality rate of children due to hereditary diseases is increased, due to a greater number of pregnancies compared to hereditarily unburdened couples, have the same number of children. Pathological alleles in these cases will be more likely to persist and increase in frequency than in the natural implementation of the reproductive abilities of individuals with different genotypes.

The epidemiology of gene diseases is also reflected population migration- an inevitable companion of many social processes. It reduces or increases the frequency of carriers of pathological genes in “donor” and “recipient” populations.

Consanguineous marriages are especially important in the prevalence of recessive gene diseases. Such marriages in various ethnic groups can range from 1 to 20 and even 30% (at the level of first and second cousins). The biological significance of the consequences of consanguineous marriages is that they significantly increase the likelihood of having offspring homozygous for recessive pathological genes. Rare recessive gene diseases occur mainly in children from such marriages.

EXAMPLES OF GENE DISEASES

A.Monogenic inheritance. A trait encoded by one gene is inherited in accordance with Mendel's laws and is called Mendelian. The totality of all the genes of an organism is called the genotype. A phenotype is the realization of a genotype (in morphological and biochemical terms) under specific environmental conditions.

1. One of the possible structural states of a gene is called an allele. Alleles arise as a result of mutations. The potential number of alleles for each gene is practically unlimited. In diploid organisms, a gene can be represented by only two alleles, localized on identical sections of homologous chromosomes. The condition when homologous chromosomes carry different alleles of the same gene is called heterozygous.

2. Inheritance of monogenic diseases - autosomal or X-linked - can be determined by studying the pedigree. According to the nature of the manifestation of the trait in a heterozygous organism, inheritance is divided into dominant and recessive. With dominant inheritance, the disease manifests itself if at least one of the homologous chromosomes carries a pathological allele, with recessive inheritance - only if both homologous chromosomes carry the pathological allele.

A.Autosomal dominant inheritance. Diseases with an autosomal dominant pattern of inheritance include Huntington's disease, achondroplasia (chondrodystrophy) and neurofibromatosis type I (Recklinghausen's disease).

1) Today, about 5,000 monogenic diseases are known. More than half of them are inherited in an autosomal dominant manner.

2) Autosomal dominant diseases are passed on from generation to generation. A sick child must have one of his parents who is sick.

3) If one parent is sick, the proportion of children affected is approximately 50%. Healthy family members give birth to healthy children.

4) Autosomal dominant diseases are always inherited, regardless of the sex of the child and the sex of the affected parent. Exceptions occur in cases of new mutations and incomplete gene penetrance.

b.Autosomal recessive inheritance. Diseases with an autosomal recessive pattern of inheritance include Tay-Sachs disease, cystic fibrosis, and most inherited metabolic disorders. Autosomal recessive diseases are usually more severe than autosomal dominant diseases.

1) If both parents are healthy but are carriers of a pathological gene, the risk of having an affected child is 25%.

2) A healthy child in 2/3 of cases turns out to be a heterozygous carrier of the pathological gene.

3) In a child with an autosomal recessive disease, especially a rare one, the parents often turn out to be blood relatives.

4) Males and females get sick equally often.

V.X-linked inheritance. Diseases with this type of inheritance include hemophilia A and B, as well as Duchenne myopathy. X-linked dominant inheritance is rare. Diseases inherited in this pattern include X-linked hypophosphatemic rickets (vitamin D-resistant rickets) and ornithine carbamoyltransferase deficiency.

1) Mostly men are affected.

2) With a recessive type of inheritance, all the sons of the patient are healthy. In daughters, the disease does not manifest itself (heterozygous carriage), but the risk of the disease in their sons is 50%.

3) With a dominant type of inheritance, all the sons of the patient are healthy, all the daughters are sick. The risk of the disease in children born to daughters of the patient is 50%, regardless of gender.

G.Gene manifestation. The quantitative characteristics of the phenotypic manifestation of the gene are as follows.

1) Penetrance— frequency of manifestation of a gene in the phenotype of its carriers. If some individuals carrying a given gene do not manifest it phenotypically, they speak of incomplete penetrance.

2) Expressiveness- the degree of phenotypic manifestation of the same gene in different individuals. Differences in the same trait among blood relatives are explained by different expressivity of the gene that controls this trait. Different expressivity occurs in most monogenic diseases.

3) Beginning of clinical manifestations. Not all hereditary diseases appear immediately after birth. For example, Huntington's disease usually appears after age 30 to 40. Phenylketonuria does not manifest itself in utero; the first signs of the disease appear only after the baby begins to be fed.

4) Pleiotropy. A mutation of one gene leads to structural and functional disorders of only one protein. However, if this protein is involved in several physiological processes, then its damage will manifest itself in several forms simultaneously. An example is Marfan syndrome, a disease with an autosomal dominant pattern of inheritance. The mutation of the gene encoding the synthesis of the fibrillin protein is accompanied by numerous clinical manifestations: lens subluxation, aneurysm of the ascending aorta, mitral valve prolapse, etc.

B.Polygenic inheritance does not obey Mendel's laws and does not correspond to the classical types of autosomal dominant, autosomal recessive inheritance and X-linked inheritance.

1. A trait (disease) is controlled by several genes at once. The manifestation of the trait largely depends on exogenous factors.

2. Polygenic diseases include cleft lip (isolated or with cleft palate), isolated cleft palate, congenital hip dislocation, pyloric stenosis, neural tube defects (anencephaly, spina bifida), and congenital heart defects.

3. The genetic risk of polygenic diseases largely depends on family predisposition and the severity of the disease in the parents.

4. Genetic risk decreases significantly with decreasing degree of consanguinity.

5. The genetic risk of polygenic diseases is assessed using empirical risk tables. Determining the prognosis is often difficult.

IN. Recently, thanks to advances in molecular genetics, other types of inheritance other than monogenic and polygenic have been studied.

1. Mosaicism- the presence in the body of two or more clones of cells with different chromosome sets. Such cells are formed as a result of chromosomal mutations. Mosaicism is observed in many chromosomal diseases. It is believed that somatic mutations and mosaicism play an important role in the etiology of many types of malignant neoplasms. Mosaicism also occurs among germ cells. During oogenesis, 28-30 mitotic divisions occur, and during spermatogenesis - up to several hundred. In this regard, with non-somatic mosaicism, the frequency of manifestation of the mutation and the risk of its transmission to next generations increase. Nonsomatic mosaicism is observed in osteogenesis imperfecta and some diseases inherited linked to the X chromosome.

2. Mitochondrial diseases. Mitochondria have their own DNA; mtDNA is located in the matrix of the organelle and is represented by a circular chromosome. It is believed that during cell division, mitochondria are randomly distributed between daughter cells. Mitochondrial diseases are characterized by different expressivity, since the phenotypic manifestation of the pathological gene depends on the ratio of normal and mutant mitochondria. Among mitochondrial diseases, Leber syndrome is the best studied. The disease is manifested by the rapid development of optic nerve atrophy, which leads to blindness. Mitochondrial diseases are inherited only through the maternal line.

3. Genomic imprinting. According to Mendel, the manifestation of a trait should not depend on whether the gene is received from the mother or from the father. There are exceptions to this rule, such as genomic imprinting.

A. The most famous examples of genomic imprinting are Prader-Willi syndrome and Angelman syndrome. Both diseases are caused by a deletion of the long arm of chromosome 15. However, if a child inherits a mutant chromosome from his father, Prader-Willi syndrome develops. Clinical manifestations include obesity, hypogonadism, small hands and feet, and mental retardation. If the mutant chromosome is received from the mother, Angelman syndrome develops. Clinical manifestations of Angelman syndrome are a characteristic gait (on legs wide apart with arms bent at the elbows) and characteristic facial features (progenia, macrostomia, wide interdental spaces, divergent strabismus).

b. The reasons for genomic imprinting have not yet been established; perhaps it is associated with different types of DNA folding in male and female gametes.

4. Uniparental disomy- transition to the descendant of a pair of homologous chromosomes from one of the parents. Transmission of hemophilia A from father to son may be associated with uniparental disomy. It is not yet clear whether uniparental disomy should be considered a special case of mosaicism or whether it is a separate chromosomal abnormality.

Polygenic diseases include cleft lip (isolated or with cleft palate), isolated cleft palate, congenital hip dislocation, pyloric stenosis, neural tube defects (anencephaly, spina bifida), and congenital heart defects. 3. The genetic risk of polygenic diseases largely depends on family predisposition and the severity of the disease in the parents. 4. Genetic risk decreases significantly with decreasing degree of consanguinity. 5. The genetic risk of polygenic diseases is assessed using empirical risk tables. Determining the prognosis is often difficult. Q. Recently, thanks to advances in molecular genetics, other types of inheritance other than monogenic and polygenic have been studied. 1. Mosaicism - the presence in the body of two or more clones of cells with different chromosome sets. Such cells are formed as a result of chromosomal mutations.

The type of inheritance is autosomal dominant. types of inheritance of traits in humans

X-linked recessive diseases One of the most common and severe forms of hereditary diseases with X-linked inheritance is pseudohypertrophic Duchenne muscular dystrophy, which belongs to the group of neuromuscular diseases. It was first described in 1868. Its frequency is 1:3000 -5000 boys. The disease is caused by a violation of the synthesis of the protein dystrophin, the gene of which is localized in the short arm of the X chromosome.
The main symptomatology of the disease is a progressive increase in dystrophic changes in the muscles with gradual immobilization of the patient. In children under three years of age, diagnosing the disease is quite difficult. It is known that these children are somewhat behind in motor development in the first year of life and begin to sit and walk later than normal.

The classic picture of the disease manifests itself in children 3 to 5 years old.

Autosomal dominant type of inheritance

IX. 1). An example is achondroplasia - a severe skeletal lesion with pronounced shortening of the limbs and an increased head size (pseudohydrocephalus). Moreover, in 80% of patients, the disease is registered as a sporadic case, resulting from a mutation that arose in the germ cells of one of the parents. It is very important to identify such cases (of a new mutation), since the risk of having the next sick child in a given family does not exceed the population one.
In general, the main signs that allow one to suspect an autosomal dominant type of inheritance of the disease are the following: 1) the disease manifests itself in each generation without gaps.

Autosomal recessive mode of inheritance

Attention

Most often, the pathology is transmitted by the autosomal dominant type of inheritance. This is monogenic inheritance of one of the traits. In addition, diseases can be transmitted to children by autosomal recessive and autosomal dominant inheritance, as well as by mitochondrial inheritance. Types of inheritance Monogenic inheritance of a gene can be recessive or dominant, mitochondrial, autosomal or linked to sex chromosomes.

• autosomal recessive;
• autosomal dominant;
• mitochondrial;
• X-dominant linkage;
• X-recessive linkage;
• Y-clutch.

Different types of inheritance of traits - autosomal dominant, autosomal recessive and others - are capable of transmitting mutant genes to different generations.

Autosomal recessive type of inheritance of the disease

Info

Thus, new mutations cause 80-90% of all cases of achondroplasia, 30-50% of cases of neurofibromatosis-1. An exception to this rule are late-onset diseases, when childbearing has already ended at the onset of the disease. For parents of a child with a new mutation that has arisen in the reproductive cell of one of them, the risk of having a sick child again does not exceed the population one, and for the child himself it is equal to 50%.

However, if only one parent in a family is sick, and the other has healthy genes, then the children may not inherit the mutant gene. An example of inheritance according to an autosomal dominant type. The type of autosomal dominant inheritance can transmit more than 500 different pathologies, among them: Marfan syndrome, Ehlers-Danlos syndrome, dystrophy, Recklinghuisen disease, Huntington disease. When studying the pedigree, one can trace the autosomal dominant type of inheritance.

There may be different examples of this, but the most striking is Huntington’s disease. It is characterized by pathological changes in nerve cells in the structures of the forebrain.

Autosomal dominant and autosomal recessive mode of inheritance

All the characteristic features of our body are manifested under the influence of genes. Sometimes only one gene is responsible for this, but more often it happens that several units of heredity are responsible for the manifestation of a particular trait. It has already been scientifically proven that for a person, the manifestation of such characteristics as skin color, hair, eyes, and the degree of mental development depends on the activity of many genes at once.
This inheritance does not exactly obey Mendel’s laws, but goes far beyond it. The study of human genetics is not only interesting, but also important from the point of view of understanding the inheritance of various hereditary diseases. Nowadays, it is becoming quite relevant for young couples to seek genetic counseling so that, after analyzing the pedigree of each spouse, one can confidently say that the child will be born healthy.

Introduction

Important

A disease with an autosomal recessive type of inheritance is clinically expressed only when both autosomes are defective for a given gene. The prevalence of diseases inherited in an autosomal recessive manner depends on the frequency of occurrence of the recessive allele in the population. Most often, recessive hereditary diseases occur in isolated ethnic groups, as well as among populations with a high percentage of consanguineous marriages.

• Medical genetics

1. Tarantula V.Z.

Types of inheritance of diseases

The vast majority of hereditary metabolic diseases (enzymopathies) are inherited in an autosomal recessive manner. The most common and clinically significant diseases are diseases with an autosomal recessive type of inheritance, such as cystic fibrosis (cystic fibrosis of the pancreas), phenylketonuria, adrenogenital syndrome, many forms of hearing or vision impairment, and storage diseases. To date, more than 1,600 autosomal recessive diseases are known. The main methods of their prevention are medical and genetic counseling of families and prenatal diagnostics (in the case of diseases for which intrauterine diagnostic methods have been developed). Autosomal recessive diseases form a significant part of the segregation genetic load due to the high frequency of the pathological allele in the population.

Autosomal dominant and autosomal recessive mode of inheritance

The most common in clinical practice are the following monogenic diseases with an autosomal dominant type of inheritance: familial hypercholesterolemia, hemochromatosis, Marfan syndrome, neurofibromatosis type 1 (Recklinghausen disease), Ehlers-Danlos syndrome, myotonic dystrophy, achondroplasia, osteogenesis imperfecta and others. In Fig. IX.6 shows a pedigree characteristic of an autosomal dominant type of inheritance. p A typical example of an autosomal dominant disease is Marfan syndrome, a generalized connective tissue disorder. Patients with Marfan syndrome are tall, have long limbs and fingers, and characteristic skeletal changes in the form of scoliosis, kyphosis, and curvature of the limbs. The heart is often affected; a characteristic sign is subluxation of the lens of the eye. The intelligence of such patients is usually preserved.

The main feature of a recessive gene is that it manifests its effect only in homozygous

Rice. 6. Pedigree of a family with an autosomal recessive disease. See text for explanation.

nom condition. Therefore, in a heterozygous state, it can exist for many generations without manifesting itself phenotypically. As a result, the first patient with a recessive disease appears many generations after the mutation occurs (Fig. 6), since the birth of an affected child is possible only if both parents carry the recessive gene for the disease. There are three options for such marriages:
\)aa X aa - all children are sick;

1. AaX aa - 50% of children will be sick (genotype aa), 50% will be phenotypically healthy (genotype Aa), but will be carriers of the mutant gene;
2. Aa X Aa - 25% of children will be sick (genotype aa), 75% will be phenotypically healthy (genotypes AA and La), but 50% of them (genotype Aa) will be carriers of the pathological gene.

Rice. 7. Pedigree of a family with consanguineous marriages.
See text for explanation.

but some of them have a mutant gene, then the probability of having a child with a pathology will be 1/3200 ("/oo frequency of the gene in populations '/in common genes 'D probability of having a sick child with an autosomal recessive type of inheritance).
Based on the fact that the commonality of genes among parents and children, brothers and sisters (except for monozygotic twins), i.e., among relatives of the first degree of kinship, is equal to 50% (V2), it is possible to calculate the indicators of gene commonality among relatives of different degrees of kinship (Table . 1).
Table 1. Indicators of gene commonality among relatives of different degrees of kinship

Thus, the probability of having a sick homozygous child in families with consanguineous marriages that have a recessive gene is much higher than in unrelated marriages, since the “concentration” of heterozygous carriage in them is higher than in the general population. The lower the prevalence of a recessive gene, the more common the corresponding recessive disease
occurs among children from consanguineous marriages. The negative impact of such marriages on offspring is also evidenced by the fact that mental retardation among children from these marriages is 4 times higher than in families with unrelated marriages, and amounts to 16%.
So, autosomal recessive inheritance has the following distinctive features. 1. Sick children are born from healthy parents. The most common type of marriage is a marriage between heterozygous carriers (Aa X Aa), when both parents are phenotypically healthy, but they may have children with a homozygous genotype. 2. Healthy children are born from a sick parent. When a patient with a recessive disease marries a healthy person (the type of marriage is usually AA X aa), all children will be healthy. 3. Mostly sibs (brothers, sisters) get sick, and not parents - children, as with the dominant type of inheritance.

1. The pedigree shows a higher percentage of consanguineous marriages. 5. All parents of sick children are heterozygous carriers of the pathological gene. 6. Men and women get sick equally often. 7. In heterozygous carriers, the ratio of sick and healthy children is 1:3. The probability of having a sick person is 25% for each subsequent child. As with the dominant mode of inheritance, this ratio applies to families with a large number of children or to the sum of children from many families with the same recessive disease. Theoretically, in a marriage between two heterozygous carriers, 75% of families with one child will have that child healthy, 56% of families with two children will have both children healthy, but only 32% of families with 4 children will have all healthy children.

Rice. 8. Pedigree of a family with alkaptonuria. See text for explanation.

Rice. 9. Pedigree of a family with albinism. See text for explanation.

only healthy children and does not come into the doctor’s field of vision. If this is not taken into account, the incidence of patients will significantly exceed the expected 25% (Table 2).
As already noted, the most common type of marriage with an autosomal recessive type of inheritance is a marriage between heterozygous carriers. Then all the specified features will be observed in the pedigrees. However, in some cases, if there is an autosomal recessive disease in the family, the pedigree may “take on the appearance” of a pseudo-dominant type of inheritance. This can happen in two cases: 1) the disease is often caused
an occurring recessive gene; 2) the disease is caused by a rare recessive gene, but the family has a high percentage of consanguineous marriages (Fig. 8).
If the pathology caused by the recessive gene does not affect the viability of the organism and is quite common in the population, then marriages between two individuals with an autosomal recessive disease are possible. From a marriage of this type (aa X aa), all children will have this pathological phenotype. For example, from the marriage of two albinos, all children will be albinos (Fig. 9). On the pedigree fig. Figure 8 shows the inheritance of alkaptonuria, an autosomal recessive disease. Due to the high frequency of consanguineous marriages in the family, the type of pedigree resembles that of the dominant type of inheritance (pseudo-dominant type).
With an autosomal recessive type of inheritance, as with an autosomal dominant one, different degrees of expressiveness of the trait and frequency of penetrance are possible.
Most often, recessive diseases occur sporadically in families. In this case, the appearance of a sick child can either be the result of the first marriage in the family between heterozygous parents, or it can occur in the marriage of a heterozygous carrier with a healthy one, in whose germ cell the primary mutation has occurred. In order to correctly assess a sporadic case of a recessive disease in order to establish the degree of risk of having other sick children, it is necessary to determine heterozygous carriage. Tests have now been developed that can detect subtle phenotypic differences between heterozygous carriers and healthy individuals.