Genetic examination

Genetic examination can be used in case of risk of occurrence of this or that genetic infringement in a family. Such testing is acceptable only if the structure of the genetic inheritance of the disorder is well studied, effective therapy is possible and reliable, reliable, highly sensitive, specific and harmless methods of analysis are used. The predominance in a particular generation must be high enough to justify the effort spent on the tests.

Genetic testing may be aimed at identifying heterozygotes carriers of the recessive disorder gene, but not expressing it (eg, Thea-Sachs disease in Ashkenazi Jews, sickle cell anemia in Negroes, Thalassemia in several ethnic groups). If heterozygous couple is also heterozygote, the spouses are at risk of having a sick child.

Tests may be necessary before symptoms can occur if a majorized inherited disorder has occurred in the history of the family that occurs later in life (eg, Huntington's disease, breast cancer). Testing determines the degree of risk of the development of the violation, which means that a person can later take preventive measures. If the test shows that the person is the carrier of the violation, then he can also make decisions concerning the birth of the offspring.

Prenatal testing may also include amniocentesis, sampling of chorionic villus, umbilical cord analysis, maternal blood analysis, maternal serum analysis, or fetal incarnation. Common reasons for prenatal testing are the age of the mothers (over 35); family history of the disorder, which can be diagnosed using prenatal methods; abnormalities in the results of the analysis of maternal serum, as well as certain symptoms manifested during pregnancy.

The examination of newborns allows the use of prophylaxis (special diet or replacement therapy) of phenylpyruvic oligophrenia, galactose diabetes and hypothyroidism.

Creation of family genealogy. In the genetic consultation is widely used the creation of a family genealogy (a genealogical tree). In this case, conditional symbols are used to denote family members and provide the necessary information about their health status. Some family disorders with identical phenotypes have several patterns of inheritance.

[1], [2], [3], [4]

Mitochondial DNA disorders

The mitochondria contains a unique rounded chromosome, which carries information on 13 proteins, various RNAs and several regulatory enzymes. However, information on more than 90% of mitochondrial proteins is contained in nuclear genes. Each cell has several hundred mitochondria in its cytoplasm.

Mitochondrial disorders may result from mitochondrial anomalies or nuclear DNA anomalies (eg, destruction, duplications, mutations). High energy tissues (for example, muscles, heart, brain) are in the zone of special risk of impaired functions due to mitochondrial anomalies. Different types of tissue function disorders correlate with certain mitochondrial DNA anomalies.

Mitochondrial abnormalities manifest themselves in many common disorders, for example, with some varieties of Parkinson's disease (which can cause extensive mitochondrial deletion mutations in subcortical node cells) and many other types of muscle disorders.

Anomalies of mitochondria of DNA are determined by inheritance from the maternal side. All mitochondria are inherited from the cytoplasm of the egg, so all the offspring of the sick mother are at risk of inheriting the disorder, but there is no risk of inheriting a violation from the sick father. A variety of clinical manifestations is a rule that can be partially explained by the variability of combinations of inherited mutations and normal mitochondrial genomes (heteroplasm) of cells and tissues.

Mitochondrial disorders

Violation	Description
Chronic progressive external ophthalmoplegia	Progressive paralysis of the ectopic muscles, which is usually preceded by a bilateral, symmetrical, progressive omission that begins months or years before paralysis
Kearns-Seyr Syndrome	A multi-system variant of chronic progressive external ophthalmoplegia, which also causes heart blockage, retinal pigmentary degeneration, and degeneration of the central nervous system
Hereditary optical neuropathy Leber	The unstable, but often destructive, bilateral loss of vision that most often occurs during adolescence because of a point mutation in the mitochondria of the DNA
Merrff Syndrome	Myoclonic seizure, rough red fibers, dementia, ataxia and myopathy
Molasses Syndrome	Mitochondrial encephalomyopathy, lactic acidosis and strokes similar to stroke
Pearson's syndrome	Sideroblastic anemia, pancreatic insufficiency and progressive liver disease, which begins in the first months of life and often ends with the death of a child

Defects of one gene

Genetic disorders, which are caused by a violation in only one gene ("Mendelian disorders"), are the simplest for analysis and most thoroughly studied at the moment. Science described many specific violations of this kind. Defects of one gene can be autosomal, or linked to the X-chromosome, dominant or recessive.

[5], [6], [7], [8],

Autosomal dominant trait

Only one autosomal allele of the gene is necessary for the expression of an autosomal dominant trait; this means that the heterozygote and the homozygote of the abnormal gene are affected.

In general, the following rules apply here:

• A sick person has a sick parent.
• A heterozygous sick parent and a healthy parent have, on average, the same number of sick and healthy children; this means that the risk of developing the disease is 50% for each child.
• Healthy children of a sick parent do not pass the line to their descendants.
• Men and women are at the same risk of developing the disease.

[9], [10], [11], [12]

Autosomal recessive trait

For the expression of an autosomal recessive trait, two copies of an abnormal allele are needed. In some generations, the percentage of heterozygotes (carriers) is high due to the initiator effect (ie, the group was initiated by several people, one of which was a carrier) or because the carriers have a selective advantage (for example, heterozygosity in sickle cell disease disease protects against malaria).

In general, the following inheritance rules apply:

• If a sick child is born to healthy parents, both parents are heterozygous and, on average, one in four of their children will be sick, one of the two is heterozygous, and one in four is healthy. 
• All children of a sick parent and a genotypically normal person are phenotypically normal heterozygotes.
• On average, half the children of a sick person and one heterozygous carrier are infected, in 1/3 they are heterozygous.
• All the children of two sick parents fall ill.
• Men and women are equally vulnerable to infection.
• Carriers of heterozygotes are phenotypically normal, but they are conductors of the line. If the trait is caused by a defect of a specific protein (for example, enzymes), a heterozygous person usually has a limited amount of this protein. If the disorder is known, with the help of molecular genetic techniques it is possible to identify heterozygous, phenotypically normal people.

Relatives most likely inherit the same mutant allele, for this reason, marriages between close relatives (single-fingered) increase the likelihood of sick children. In a parent-child pair or a sister-brother, the risk of having a sick child increases due to the presence of 50% of the same genes.

[13], [14],

The dominant linked to the X chromosome

The dominant features linked to the X chromosome are contained in the X chromosome. Most of them are very rare. Usually, men become more infected, but women who carry only one abnormal allele are also infected, only less seriously.

In general, the following inheritance rules apply:

• A sick man passes the line to all his daughters, but not to his sons; However, if a sick man marries a sick woman, they may have a sick son.
• Patients heterozygous women pass a line to half of their children, without gender.
• Sick homozygous women pass the line to all their children.
• In 2 times more sick women than men, have a line, unless it caused death in men.

The inheritance of a dominant linked to an X chromosome may be difficult to distinguish from an autosomal dominant inheritance, unless molecular tests are used. This requires large pedigrees with the condition of increased attention to the children of sick parents, since the transfer of the line from male to male excludes cohesion with the X-chromosome (men transmit only Y-chromosomes to their sons). Some disorders of the X-linked dominant cause mortality in men.

The recessive gene linked to the X chromosome

Recessive traits linked to the X chromosome are contained in the X chromosome.

In general, the following inheritance rules apply:

• Almost all patients are representatives of the male sex. 
• Heterozygous women are usually phenotypically normal, but how carriers can transmit an anomaly to their children (but the trait may represent a new mutation in the male body).
• A sick man never passes this trait to his sons.
• All the daughters of a sick man are bearers of a dash.
• A female carrier passes the line to half of her sons.
• The dash is not passed to the daughters of the mother carrier (unless they inherit the line - for example, color blindness - from their father), but half of them are carriers.

A sick woman usually should be the owner of an abnormal gene in both X chromosomes (homozygote) in order for the line to be expressed, ie, it has a sick father and mother with a mutation in a heterozygote or homozygote.

Sometimes the gene gets some expression in women heterozygous for mutations associated with the X chromosome, but such women are very rarely affected as seriously as it does in men who have only one pair of genes (semi-zygotons). Heterozygous women can get sick if structural chromosomal rearrangement occurs (for example, translocation of the X-autosome, absence or destruction of the X chromosome) or distorted X-inactivation. The latter takes place at an early stage of development; it usually involves a random but balanced inactivation of the X chromosome inherited from the father or from the mother. Sometimes, however, the greatest proportion of inactivation occurs in the X chromosome inherited from one parent; this phenomenon and was called the distorted X-inactivation.

Co-dominance

In the case of codominant inheritance, the heterozygote phenotype is different from the phenotype of both homozygotes. Each allele in a genetic locus usually has a pronounced effect. For example, codominance is recognized in blood group antigens (eg, AB, MN), leukocyte antigens (eg, DR4, DR3), whey proteins with different mobility of electrophoresis (eg, albumin, tactile globulin), and in enzymatic processes (eg, paraoxonase ).

[15], [16]

Multifactorial inheritance

Many features (for example, growth) are distributed along a parabolic bend (normal distribution); this distribution is consistent with the polygenic definition of the line. Each feature adds something or takes something from the devil, regardless of other genes. With such a distribution, a very small number of people discover extremes, and most are in the middle, since people do not inherit many factors acting in one direction. Various environmental factors that accelerate or slow down the end result contribute to a normal distribution.

Many relatively common congenital disorders and family illnesses are the result of multifactorial inheritance. In a sick person, the disorder is the sum of the factors of genetics and the environment. The risk of developing such a trait is much higher among relatives of the first degree (50% of the genes of a sick person) than in more distant relatives, who, most likely, will inherit only a few abnormal genes.

Common disorders caused by a variety of factors include hypertension, arteriosclerosis, diabetes, cancer, spinal cord diseases and arthritis. Many specific genes are susceptible to diagnosis. Genetically determined predisposing factors, including family history, biochemical and molecular parameters, can help identify people at risk of developing the disease for taking preventive measures.

Unconventional inheritance

Mosaic. Mosaic is the presence of 2 or more cell lines, differing in genotype or phenotype, but going back to the same zygote. The probability of a mutation is high during cell division in any large multicellular organism. Every time there is a cell division, in the genome, according to calculations, there are 4 or 5 changes. Thus, any large multicellular organism has subclones of cells with slightly different genetic composition. These somatic mutations - mutations that occurred during the mitotic division of a cell - may not lead to a pronounced trait or disease, but can be classified as disruptions, resulting in fragmentary changes. For example, McCune-Albright syndrome causes fragmentary dysplastic changes in the bones, endocrine gland disorders, fragmentary pigmentary changes and, in very rare cases, disruption of the heart or liver. If such a mutation occurred in all cells, it would cause an early death, but the mosaic (chimera) survive because normal tissues support the work of abnormal tissues. Sometimes a parent with a single gene disorder seems to possess a weak form of the disease, but in fact is a mosaic. The offspring can be affected in a more severe form if they inherit an embryonic cell with a mutation in the alleles and, therefore, receive an anomaly in each cell. Chromosome mosaic is evident in some embryos and can be detected in the placenta by taking samples of chorionic villi. Most embryos and fetuses that have chromosomal abnormalities are prone to spontaneous miscarriage. However, the presence of normal cells in the early stages of development can support some chromosomal abnormalities, allowing the baby to be born alive.

Genomic imprinting. Genomic imprinting is a differentiated expression of genetic material, depending on whether it is inherited from the mother or father. The difference in expression arises from the different activation of the gene. Genomic imprinting depends on the tissue and stage of development. A bivalle, or inherited from both parents expression of an allele, can occur in some tissues, with the expression of an allele inherited from one parent occurring in other tissues. Depending on whether the genetic manifestation is inherited from the mother or from the father, a new syndrome may occur if the gene has been genetically imprinted. Particular attention should be paid to genomic imprinting in the event that violations or illnesses were transmitted through a generation.

Dysomia of one of the parents. The disomy of one of the parents occurs when the two chromosomes of the pair are inherited from only one parent. This happens extremely rarely and, as is commonly believed, is associated with trisomic release. This means that the zygote initially had three chromosomes, but one of them was lost, which led to the considered disomy in one third of cases. In this case, the effects of imprinting may appear, since there is no information about the second parent. Also, if there are copies of the same chromosome (isodisome) that contain an abnormal allele of an autosomal recessive disorder, sick people are at risk of infection by the latter even though only one parent carries it.

Triplet (trinucleotide) recurring disorders. A nucleotide triplet occurs frequently and sometimes has many repetitions. It happens that the number of triplets in the gene grows from generation to generation (the normal gene has relatively few triplet repetitions). When a gene is transmitted from one generation to another, or sometimes it happens as a result of cell division in the body, triplet repetition can expand and increase, preventing the normal functioning of the gene. This increase can be detected in molecular studies, this type of genetic change is not common, but occurs with certain disorders (eg, dystrophic myotonia, fragile X-oligophrenia), especially those associated with the CNS (eg, Huntington's disease).

Anticipation (anticipation). Anticipation occurs when the disease has an early phase of onset and is more pronounced in each subsequent generation. Anticipation can occur when the parent is a mosaic (chimera), and the child has a complete mutation in all cells. It is also capable of manifesting itself in a triplet repeating expansion if the number of repetitions, and consequently the severity of the phenotype damage, increases with each subsequent offspring.