Expressivity: not the same manifestation of a trait in individuals who exhibit this trait; the degree of phenotypic manifestation of the mutation. An example is the manifestation of the Lobe mutation, which alters the eyes in Drosophila. The mutation is dominant, but if we compare heterozygous individuals, then, despite the same genotype, its manifestation is very different - from the complete absence of eyes to almost wild-type large eyes. In between there are individuals with all possible eye variations. This is a case of variable expressivity. In the simplest case, one can speak of a strong and weak manifestation of a trait if the allele encoding this trait is penetrant. Penetrance is a qualitative characteristic that takes into account only the manifestation or non-manifestation of a feature. Expressivity takes into account the quantitative side of the manifestation of the trait, if it manifested itself.

Expressivity reflects the nature and severity of symptoms, as well as the age of onset of the disease. A clear example of such variability is MEN type I.

Patients from the same family with the same mutation may have hyperplasia or neoplasia of one or all of the endocrine tissues, including the pancreas, parathyroid glands, pituitary gland, and adipose tissue. As a result, the clinical picture of the disease is extremely diverse: in patients from the same family, peptic ulcer disease, hypoglycemia, urolithiasis, or pituitary tumors can be detected.

Sometimes in dominant diseases that are characterized by the formation of tumors, differences in expressivity are due to additional mutations in tumor suppressor genes.

Diseases such as Huntington's disease and polycystic kidney disease manifest themselves at different ages, often only in adults, despite the fact that the mutant gene is present in patients from birth. It is not completely clear whether the variability in the age of onset of the disease should be considered the result of variable expressivity. On the one hand, to prove incomplete penetrance, a complete examination of family members and observation throughout their lives is necessary. On the other hand, the absence of expression can be considered as minimal expression of the gene.

If a person suffering from a dominant disease wants to know how severe the disease will be in his child who has inherited a mutation, then he raises the question of expressivity. With the help of gene diagnostics, it is possible to identify a mutation that does not even manifest itself, but it is impossible to predict the range of expression of a mutation in a given family.

Variable expressivity, up to the complete absence of gene expression, may be due to:

The influence of genes located in the same or in other loci;

The impact of external and random factors.

For example, the severity of hereditary ovalocytosis, caused by a defect in alpha spectrin, depends on the degree of gene expression. In heterozygotes, low expression of the mutant allele facilitates the disease, while the homologous allele (trans allele) aggravates it.

In cystic fibrosis, the severity of the R117H mutation (arginine to histidine substitution at position 117 of the membrane conductance regulator protein) depends on the cis-action of the polymorphism at the splicing site, which determines the concentration of normal mRNA.

Genes located at other loci also affect the manifestation of the mutation. Thus, the severity of sickle cell anemia depends on the genotype of the globin alpha chain locus, and monogenic hyperlipoproteinemias depend on the genotype of several loci.

A gene that is present in the genotype in the amount necessary for manifestation (1 allele for dominant traits and 2 alleles for recessive traits) can manifest itself as a trait to varying degrees in different organisms (expressivity) or not manifest itself at all (penetrance).

Modification variability (exposure to environmental conditions)

Combinative variability (influence of other genes of the genotype).

expressiveness- the degree of phenotypic manifestation of the allele. For example, alleles of blood groups AB0 in humans have constant expressivity (always appear at 100%), and alleles that determine eye color have variable expressivity. A recessive mutation that reduces the number of eye facets in Drosophila reduces the number of facets in different individuals in different ways, up to their complete absence.

Expressivity reflects the nature and severity of symptoms, as well as the age of onset of the disease.

If a person suffering from a dominant disease wants to know how severe the disease will be in his child who has inherited a mutation, then he raises the question of expressivity. With the help of gene diagnostics, it is possible to identify a mutation that does not even manifest itself, but it is impossible to predict the range of expression of a mutation in a given family.

Variable expressivity, up to the complete absence of gene expression, may be due to:

The influence of genes located in the same or in other loci;

The impact of external and random factors.

Penetrance is the probability of a phenotypic manifestation of a trait in the presence of the corresponding gene. For example, the penetrance of congenital hip dislocation in humans is 25%, i.e. only 1/4 of recessive homozygotes suffer from the disease. Medico-genetic significance of penetrance: a healthy person, in which one of the parents suffers from a disease with incomplete penetrance, can have an unexpressed mutant gene and pass it on to children.

It is determined by the percentage of individuals in the population from among those carrying the gene in which it manifested itself. With complete penetrance, the dominant or homozygous-recessive allele appears in each individual, and with incomplete penetrance, in some individuals.

Penetrance may be important in genetic counseling for autosomal dominant disorders. A healthy person, one of whose parents suffers from a similar disease, from the point of view of classical inheritance, cannot be a carrier of a mutant gene. However, if we take into account the possibility of incomplete penetrance, then the picture is completely different: an outwardly healthy person can have an unmanifested mutant gene and pass it on to children.

Gene diagnostic methods can determine whether a person has a mutant gene and distinguish a normal gene from a non-manifesting mutant gene.

In practice, the determination of penetrance often depends on the quality of the research methods, for example, with the help of MRI, symptoms of the disease can be detected that were not previously detected.

From the point of view of medicine, the gene is considered manifested even with an asymptomatic disease, if functional deviations from the norm are detected. From the point of view of biology, a gene is considered manifested if it disrupts the functions of the organism.

Polygenic inheritance

Polygenic inheritance- inheritance, in which several genes determine the manifestation of one trait.

complementarity- such an interaction of genes in which 2 or more genes cause the development of a trait. For example, in humans, the genes responsible for the synthesis of interferon are located on chromosomes 2 and 5. In order for the human body to be able to produce interferon, it is necessary that at least one dominant allele be present simultaneously on chromosomes 2 and 5. Let us denote the genes associated with the synthesis of interferon and located on the 2nd chromosome - A (a), and on the 5th chromosome - B (c). Options AABB, AaBB, AAVv, AaBv will correspond to the ability of the body to produce interferon, and options aavb, AAvv, aaBB, Aavv, aaBv - inability.

The type of inheritance of traits due to the action of many genes, each of which has only a weak effect. Phenotypically, the manifestation of a polygenically determined trait depends on environmental conditions. In descendants, there is a continuous series of variations in the quantitative manifestation of such a trait, and not the appearance of classes that clearly differ in phenotype. In a number of cases, when a single gene is blocked, the trait does not appear at all, despite its polygenic conditionality. This indicates a threshold manifestation of the trait.

Since the development of polygenic traits is greatly influenced by environmental factors, it is difficult to identify the role of genes in these cases.

Polymerism Several genes act on the same trait in the same way. At the same time, when forming a trait, it does not matter which pair of dominant alleles belong, their number is important.

For example, the color of a person's skin is affected by a special substance - melanin, the content of which provides a color palette from white to black (except for red). The presence of melanin depends on 4-5 pairs of genes. To simplify the problem, we will conditionally assume that there are two such genes. Then the Negro genotype can be written - AAAA, the white genotype - aaaa. Light-skinned blacks will have the AAAa genotype, mulattoes - AAaa, light mulattoes - Aaaa.

Pleiotropy- the influence of one gene on the appearance of several traits. An example is an autosomal dominant disease from the group of hereditary connective tissue pathologies. In classic cases, individuals with Marfan syndrome are tall (dolichostenomelia), have elongated limbs, extended fingers (arachnodactyly), and underdevelopment of fatty tissue. In addition to the characteristic changes in the organs of the musculoskeletal system (elongated tubular bones of the skeleton, hypermobility of the joints), pathology is observed in the organs of vision and the cardiovascular system, which in the classical versions constitutes the Marfan triad.

Without treatment, people with Marfan syndrome often have a life expectancy of 30–40 years and death occurs due to a dissecting aortic aneurysm or congestive heart failure. In countries with developed health care, patients are successfully treated and live to an advanced age. Among famous historical figures, this syndrome manifested itself in A. Lincoln, N. Paganini, K.I. Chukovsky (Fig. 3.4, 3.5).

epistasis- suppression by one gene of another, non-allelic. An example of epistasis is the "Bombay phenomenon". In India, families are described in which parents had the second (AO) and first (00) blood groups, and their children had the fourth (AB) and first (00). In order for a child in such a family to have an AB blood type, the mother must have a B blood type, but not O. It was found that in the ABO blood group system there are recessive modifier genes that suppress the expression of antigens on the surface of red blood cells, and phenotypically a person manifests blood type O.

Another example of epistasis is the appearance of white albinos in a black family. In this case, the recessive gene suppresses the production of melanin, and if a person is homozygous for this gene, then no matter how many dominant genes responsible for the synthesis of melanin he has, his skin color will be albiotic (Fig. 3.6).

Morris syndrome- androgen insensitivity syndrome (testicular feminization syndrome) is manifested by disorders of sexual development that develop as a result of a weak response to male sex hormones in individuals with a male set of chromosomes (XY). The term "testicular feminization syndrome" was first introduced by the American gynecologist John Morris in 1953.

This syndrome is the most well-known cause of the development of a man as a girl or the presence of manifestations of feminization in boys who were born with a male set of chromosomes and normal levels of sex hormones. There are two forms of androgen insensitivity: total or partial insensitivity. Children with complete insensitivity have an unambiguously feminine appearance and development, while those with partial form may have a combination of female and male external sex characteristics, depending on the degree of androgen insensitivity. The incidence rate is approximately 1-5 per 100,000 newborns. The syndrome of partial androgen insensitivity is more common. Complete insensitivity to male sex hormones is a very rare disease.

The disease is caused by a mutation in the LA gene on the X chromosome. This gene determines the function of androgen receptors, a protein that responds to signals from male sex hormones and triggers a cellular response. In the absence of androgen receptor activity, the development of male genital organs will not occur. Androgen receptors are necessary for the development of pubic and axillary hair, regulate beard growth and sweat gland activity. With complete androgen insensitivity, there is no androgen receptor activity. If some cells have a normal number of active receptors, then this is partial androgen insensitivity syndrome.

The syndrome is inherited with the X chromosome as a recessive trait. This means that the mutation that causes the syndrome is located on the X chromosome. According to some information, in particular, the study of the reasons for the genius of V.P. Efroimson, Joan of Arc had Morris syndrome.

Pleiotropic action of genes

Pleiotropic action of genes- this is the dependence of several traits on one gene, that is, the multiple action of one gene.

In Drosophila, the gene for white eyes simultaneously affects the color of the body, length, wings, structure of the reproductive apparatus, reduces fertility, and reduces life expectancy. A person has a known hereditary disease - arachnodactyly ("spider fingers" - very thin and long fingers), or Marfan's disease. The gene responsible for this disease causes a violation of the development of connective tissue and simultaneously affects the development of several signs: a violation of the structure of the lens of the eye, anomalies in the cardiovascular system.

Sex-linked inheritance must be distinguished from sex-limited inheritance. All the genes that enter a given organism determine only its genetic potential, i.e. just what it can be. What it actually turns out to be is another matter. Embryonic development depends on the interaction of all genes during their expression, in other words, at the time when they provide or do not provide the formation of certain polypeptides and proteins. Environmental factors also play an important role in development. In the past two decades, we have witnessed several truly terrible cases when, under the influence of drugs taken by pregnant women, the normal development of the fetus was disrupted and ugly babies were born, or when the children of these women fell ill with cancer at an early age (due to the loss of control over cell division in their bodies). ).

The role of sex hormones is mainly to influence the reproductive system and related organs, but these hormones can also affect a number of other signs of the body. Genes whose degree of expression is determined by the level of sex hormones are called sex-dependent genes. (Usually, though not always, such genes are located on autosomes.) A bull, for example, may carry genes for high milk production, but will not produce milk because he has too low levels of female hormones. These genes make him, however, a valuable sire for the dairy herd. Similarly, both males and females have the genetic potential to form organs of the opposite sex, but they develop organs characteristic of their own sex during development because they have higher levels of the corresponding hormones. Females and males also have hormones characteristic of the opposite sex, but their content is much lower.

The gene that determines baldness, typical for men, is localized in the autosome, but its expression depends on male sex hormones. In males, this gene behaves like a dominant gene due to the presence of male sex hormones; in women, it behaves like a recessive gene, so that a woman goes bald if she has two doses of this gene.

Gender affects a person and such a symptom as gout. With gout, uric acid salts are deposited in the tissues, mainly in the joints (most often in the area of ​​the big toe), causing excruciating pain to a person. The gene responsible for this disease is expressed much more strongly in the presence of male sex hormones than in the presence of female ones. In the literature of the Victorian era, gout appears chiefly as one of the causes of frequent temper tantrums in capricious old gentlemen. It was believed that in order to alleviate suffering, the sick should refrain from fatty and spicy foods and not drink red wine. These restrictions, however, only further spoiled the character of gout victims. Fortunately, in our time, gout can be treated.

Sex hormones are far from being the only factors influencing phenotypic gene expression. Many traits that are mainly controlled by only one pair of genes depend to some extent on the influence of the products of other genes, called modifier genes. For a long time it was believed that human eye color is determined by one pair of genes, with brown being dominant over blue. We now know that at least two pairs of modifier genes are also involved in determining eye color, and that blue-eyed parents can have brown-eyed children, although this is extremely rare.

At different ages, the body produces different hormones, so age also plays a role in gene expression. Suffice it to recall, for example, the many changes that accompany puberty: in boys, the “breaking” of the voice and the growth of the testicles; in girls - an increase in the mammary glands and the appearance of characteristic fatty deposits, giving the female figure its characteristic roundness; and finally, in both sexes, the growth of hair in the armpits and on the pubis.

Gene expression is also influenced by environmental factors, namely food, light and temperature. Thus, malnourished people are usually shorter than their Iens allow. Now, in many countries, young people have overtaken their fathers in swarming precisely because they ate better from childhood than their parents.

Light is one of the factors affecting gene expression. A person who has been exposed to the sun's rays for some time becomes darker from this (some, however, only blush).

Many genetic diseases clearly defined in the family; those. an abnormal phenotype is easily distinguished from a normal one. From clinical experience, however, it is known that some diseases may not manifest themselves, although the person has the same genotype that causes the disease in other family members. In other cases, the same disease may have extremely variable presentation in terms of clinical severity, range of symptoms, or age of onset.

Phenotypic expression abnormal genotype may be modified by the effects of aging, other genetic loci, or environmental factors. Differences in expression can often lead to difficulties in interpreting the diagnosis and pedigree. There are two different mechanisms that may explain the differences in expression: reduced penetrance and variable expressivity.

Penetrance- the probability that the gene will have any phenotypic manifestations. If the phenotype expression frequency is less than 100%, i.e. there are individuals who have the corresponding genotype without any of its manifestations, they say that the gene has incomplete penetrance. Penetrance is an all-or-nothing concept. This is the percentage of people with a pathological genotype and its manifestations, at least to some extent.

expressiveness- severity of phenotype expression among individuals with one pathological genotype. When the severity of the disease differs between individuals having the same genotype, the phenotype is said to have variable expressivity. Even within the same pedigree, two individuals carrying the same mutant genes may have some of the same signs and symptoms, and other manifestations of the disease may differ depending on the affected tissues and organs.

Some difficulties In understanding the inheritance of the disease phenotype resulting from age-dependent penetrance and variable expressivity, one can consider the example of autosomal dominant neurofibromatosis NF1. Neurofibromatosis type 1 is a common disorder of the nervous system, eyes, and skin, occurring in approximately 1 in 3,500 births. There are no significant differences in the incidence of the disease among ethnic groups.

An example of the inheritance of neurofibromatosis type 1 - NF1

Neurofibromatosis type 1(NF1) is characterized by the growth in the skin of numerous benign volumetric tumors, neurofibromas; the presence of numerous, flat, irregular pigmented patches of skin known as "coffee" spots or "café-au-lait" spots; the growth of small benign tumors (hamartomas) in the iris of the eye (Lish nodules); sometimes mental retardation, CNS tumors, disseminated plexiform neurofibromas, and the development of malignant tumors of the nervous system or muscles. Thus, the disease has a pleiotropic phenotype.

1st type(NF1) was first fully described by the physician von Recklinghausen in 1882, but the disease has probably been known since ancient times. Although adult heterozygotes almost always have some form of disease (i.e. 100% adult penetrance), some may only have coffee spots, axillary freckles, and Lisch nodules, while others may have life-threatening benign tumors. affecting the spinal cord or malignant sarcomas of the extremities.

Thus, there is variable expressivity; even within the same pedigree, some patients are severely affected and others only slightly. Diagnosis is more difficult in children as symptoms develop gradually with age. For example, in the neonatal period, less than half of all those affected have at least the mildest sign of the disease, "coffee" spots. Penetrance is therefore dependent on age.

AT NF1 gene many different mutations have been found that cause a decrease in the function of the gene product, neurofibromin. Approximately half of the cases of NF1 are caused by a new rather than an inherited mutation.

The main genetic problem in counseling families of patients with NF1- the need to choose between two equally probable possibilities: the proband's disease is sporadic, i.e. a new mutation, or the patient has inherited a clinically significant form of the disease from a parent in whom the gene is present but weakly manifested. If the proband has inherited the defect, the risk that any of his or her siblings will also inherit the disease is 50%; but if the proband has the new mutation, there is very little risk to the siblings.

Importantly, in both cases, the risk that the patient will pass on the gene offspring, is 50%. Given this uncertainty, families of patients with NF1 need to be aware that the disease can be detected presymptomatically and even prenatally using molecular genetic analysis. Unfortunately, molecular diagnostics can usually only answer the question of whether a disease will develop, but cannot determine its severity. With the exception of the association of complete gene deletion with dysmorphias, mental retardation, and a high number of neurofibromas at an early age, no correlation was found between the severity of the phenotype and specific mutations in the NF1 gene.

Another example of an autosomal dominant malformation with incomplete penetrance is ectrodactyly hand division disorder. The malformation occurs in the sixth or seventh week of development, when the hands and feet are formed. The disease shows locus heterogeneity. At least five loci have been identified, although the responsible gene has actually been confirmed in only a few of them. Incomplete penetrance in pedigrees with hand malformations can lead to skipped generations, and this complicates genetic counseling because a person with normal hands may still pass on the disease gene and thus have affected children.

Although in general the rules of inheritance monogenic diseases can be easily classified as autosomal or X-linked and dominant or recessive, inheritance in an individual pedigree can be obscured by many other factors that make it difficult to interpret the mode of inheritance.

Diagnostic difficulties may be due to incomplete penetrance or variable expressiveness of the disease; gene expression can be influenced by other genes and environmental factors; some genotypes do not survive to birth; there may be no accurate information about the presence of the disease in relatives or family relationships; dominant and X-linked diseases can cause new mutations; and finally, with a small family size, typical today in most developed countries, the patient may accidentally be the only patient in the family, when it is very difficult to decide on the type of inheritance.

genetic disease can appear at any time throughout a person's life, from early fetal development to old age. Some may be lethal in utero, others may interfere with normal fetal development and be detected prenatally (eg, by ultrasonography), but are compatible with live birth; still others can only be identified after birth. (Genetic and congenital diseases are often confused.

These concepts were first introduced in 1926 by N.V. Timofeev Ressovsky and O. Vogt to describe the varying manifestation of traits and the genes that control them. expressiveness there is a degree of expression (variation) of the same trait in different individuals who have a gene that controls this trait. There is low and high expressivity. Consider, for example, the different severity of rhinitis (runny nose) in three different patients (A, B, and C) with the same diagnosis of ORI. In patient A, rhinitis is mild (“sniffing”), which allows one handkerchief to be dispensed with during the day; in patient B, rhinitis is moderately expressed (daily 2-3 handkerchiefs); Patient C has a high degree of rhinitis (5-6 handkerchiefs). When talking about the expressiveness not of a single symptom, but of the disease as a whole, doctors often assess the patient's condition as satisfactory or of moderate severity, or as severe,

those. in this case, the concept of expressivity is similar to the concept of "severity of the course of the disease."

Penetrance- is the probability of manifestation of the same trait in different individuals who have a gene that controls this trait. Penetrance is measured as the percentage of individuals with a particular trait out of the total number of individuals who are carriers of the gene that controls that trait. 0 is incomplete or complete.

An example of a disease with incomplete penetrance is the same rhinitis with 0RVI. So, we can assume that patient A does not have rhinitis (but there are other signs of the disease), while patients B and C have rhinitis. Therefore, in this case, the penetrance of rhinitis is 66.6%.

An example of a disease with complete penetrance is autosomal dominant chorea of ​​Huntington(4r16). 0na manifests mainly in persons aged 31-55 years (77% of cases), in other patients - at a different age: both in the first years of life, and at 65, 75 years and more. It is important to emphasize that if the gene for this disease is passed on to a descendant from one of the parents, then the disease will definitely manifest itself, which is complete penetrance. True, the patient does not always survive to the manifestation of Huntington's chorea, dying from another cause.

Genecopying and its causes
Genocopies (lat. genocopia) are similar phenotypes formed under the influence of different non-allelic genes.
A number of signs similar in external manifestation, including hereditary diseases, can be caused by various non-allelic genes. This phenomenon is called genocopy. The biological nature of genocopies lies in the fact that the synthesis of the same substances in the cell in some cases is achieved in different ways.

Phenocopies - modification changes - also play an important role in human hereditary pathology. They are due to the fact that in the process of development, under the influence of external factors, a trait that depends on a particular genotype may change; at the same time, traits characteristic of another genotype are copied.

That is, these are the same changes in the phenotype, caused by alleles of different genes, as well as occurring as a result of various gene interactions or violations of various stages of one biochemical process with the cessation of synthesis. It manifests itself as the effect of certain mutations that copy the action of genes or their interaction.

One and the same trait (group of traits) may be due to different genetic causes (or heterogeneity). Such an effect, at the suggestion of the German geneticist H. Nachtheim, was obtained in the mid-40s of the XX century. title gencopying. Three groups of causes of genocopy are known.

Causes of the first group combines heterogeneity due to polylocus, or the action of different genes located at different loci on different chromosomes. For example, 19 types (subtypes) of mucopolysaccharidoses have been identified among hereditary diseases of the metabolism of complex sugars - glucoseaminoglycans. All types of character

teriziruyutsya defects of different enzymes, but are manifested by the same (or similar) symptoms gargoylic dysmorphism or the phenotype of the ringer Quasimodo - the main character of the novel "Notre Dame Cathedral" by the classic of French literature Victor Hugo. A similar phenotype is often observed in mucolipidoses (lipid metabolism disorders).

Another example of polylocus is phenylketonuria. Now, not only its classical type, due to a deficiency of phenylalanine-4-hydroxylase (12q24.2), but also three atypical forms have been identified: one is caused by a deficiency of dihydropteridine reductase (4p15.1), and two more are caused by a deficiency of pyruvoiltetrahydropterin synthetase and tetrahydrobiopterin enzymes (corresponding to genes have not yet been identified).

Additional examples of polylocus: glycogenoses (10 genocopies), Ellers-Danlos syndrome (8), Recklinghausen neurofibramatosis (6), congenital hypothyroidism (5), hemolytic anemia (5), Alzheimer's disease (5), Bardet-Biedl syndrome (3), breast cancer (2).

Causes of the second group unites intralocus heterogeneity. It is due either to multiple allelism (see Chapter 2) or to the presence genetic compounds, or double heterozygotes having two identical pathological alleles in identical loci of homologous chromosomes. An example of the latter is heterozygous beta-thalassemia (11p15.5), resulting from deletions of two genes encoding beta-chains of globins, which lead to an increased content of hemoglobin HbA 2 and an increased (or normal) level of hemoglobin HbF.

Causes of the third group combines heterogeneity due to mutations at different points in the same gene. An example is cystic fibrosis (7q31-q32), which develops due to the presence of almost 1000 point mutations in the gene responsible for the disease. With a total length of the cystic fibrosis gene (250 thousand bp), it is expected to detect up to 5000 such mutations in it. This gene encodes a protein responsible for the transmembrane transport of chloride ions, which leads to an increase in the viscosity of the secretion of exocrine glands (sweat, salivary, sublingual, etc.) and blockage of their ducts.

Another example is classical phenylketonuria, caused by the presence of 50 point mutations in the gene encoding phenylalanine-4-hydroxylase (12q24.2); in total, more than 500 point mutations of the gene are expected to be detected in this disease. Most of them arise from restriction fragment length polymorphism (RFLP) or tandem repeat number polymorphism (VNTP). Found: the main mutation of the phenylketonuria gene in Slavic populations is R408 W/

Pleiotropy effect

The aforementioned ambiguity in the nature of the relationships between genes and traits is also expressed in pleiotropy effect or pleiotropic action, when one gene causes the formation of a number of traits.

For example, the gene for autosomal recessive ataxia-telangiectasia, or Louis Bar syndrome(11q23.2) is responsible for the simultaneous damage to at least six body systems (nervous and immune systems, skin, mucous membranes of the respiratory and gastrointestinal tract, as well as the conjunctiva of the eyes).

Other examples: gene Bardet-Biedl syndrome(16q21) causes dementia, polydactyly, obesity, retinitis pigmentosa; the anemia gene Fanconi (20q13.2-13.3), which controls the activity of topoisomerase I, causes anemia, thrombocytopenia, leukopenia, microcephaly, aplasia of the radius, hypoplasia of the metacarpal bone of the first finger, malformations of the heart and kidneys, hypospadias, pigment spots of the skin, increased fragility of chromosomes .

Distinguish between primary and secondary pleiotropy. Primary pleiotropy due to biochemical mechanisms of action of the mutant enzyme protein (for example, lack of phenylalanine-4-hydroxylase in phenylketonuria).

Secondary pleiotropy due to complications of the pathological process that developed as a result of primary pleiotropy. For example, due to increased hematopoiesis and hemosiderosis of parenchymal organs, a patient with thalassemia develops thickening of the skull bones and hepatolienal syndrome.