Diagnosis of monogenic disorders

Monogenic defects (determined by one gene) are observed more often than chromosomal ones. Diagnosis of diseases usually begins with the analysis of clinical and biochemical data, the pedigree of the proband (the person in whom the defect was first detected), and the type of inheritance. Monogenic diseases can have autosomal dominant, autosomal recessive and X-linked types of inheritance. Currently, more than 4,000 monogenic disorders have been identified.

Autosomal dominant disorders. Dominant disorders are hereditary diseases that manifest themselves in a heterozygous state, i.e. in the presence of only one abnormal gene (mutant allele). The following features are characteristic of diseases with an autosomal dominant type of inheritance.

• Every affected person has one affected parent (except for mutations that arose de novo ).
• An affected person married to a healthy spouse has, on average, half of the children sick and the other half healthy.
• The healthy children of the affected person have healthy children and grandchildren.
• Men and women are affected with equal frequency.
• The disease manifests itself in every generation.

Autosomal recessive disorders are clinically manifested only in the homozygous state, that is, in the presence of a mutation in both alleles of a given genetic locus. The following features are characteristic of diseases with an autosomal recessive type of inheritance.

• The birth of a sick child to phenotypically healthy parents means that the father and mother are heterozygous for the pathological gene [a quarter of their children will be affected (homozygotes for the pathological gene), three quarters will be healthy (two quarters heterozygotes, a quarter homozygotes for the normal gene)].
• If a person with a recessive disease marries a person with a normal genotype, all their children will be phenotypically healthy, but heterozygous for the pathological gene.
• If a sick person and a heterozygous carrier marry, half of their children will be sick and half will be healthy, but heterozygous for the pathological gene.
• If two people with the same recessive disease marry, all their children will be sick.
• Men and women are affected with equal frequency.
• Heterozygous individuals are phenotypically normal but carry one copy of the mutant gene.

X-linked disorders. Since the defective genes are located on the X chromosome, the clinical manifestations and severity of the disease differ in men and women. Women have two X chromosomes, so they can be heterozygous or homozygous for the mutant gene, therefore, the probability of developing the disease in them depends on its recessiveness/dominance. Men have only one X chromosome, so if they inherit a pathological gene, they develop the disease in all cases, regardless of the recessiveness or dominance of the defective gene.

The following features are characteristic of X-linked dominant inheritance.

• Affected men pass the disease on to all their daughters, but not to their sons.
• Heterozygous women pass the disease on to half of their children, regardless of their sex.
• Homozygous women pass the disease on to all their children.

The following features are characteristic of X-linked recessive inheritance.

• Almost exclusively men are affected.
• The mutation is always transmitted through a heterozygous mother who is phenotypically healthy.
• A sick man never passes the disease on to his sons.
• All daughters of an affected man will be heterozygous carriers.
• A female carrier passes the disease to half of her sons, none of her daughters will be sick, but half of them will be carriers.

Direct and indirect DNA diagnostics are used to diagnose monogenic hereditary diseases. Direct diagnostic methods are only possible for cloned genes with a known nucleotide sequence of full-length code DNA. When using direct methods (DNA probes, PCR), the object of molecular analysis is the gene itself, or more precisely, the mutation of this gene, the identification of which is the main objective of the study. The use of this approach is especially effective in the presence of accurate information on the nature, frequency and localization of the most common (dominant in frequency) mutations of the corresponding genes. The main advantage of the direct method is its high, up to 100%, diagnostic accuracy.

However, there are a great number of monogenic hereditary diseases for which mutations have not been established or major (main, most frequent) mutations have not been found in the populations under study. In addition, in almost all monogenic diseases, in addition to major mutations, there are numerous minor (rare) mutations. Finally, there is always a possibility that the patient may have unknown mutations, which does not allow the use of direct methods. In such cases, indirect (indirect) methods of molecular diagnostics are used. The indirect approach is based on the detection of gene-linked polymorphic markers, which are used to identify chromosomes carrying the mutant gene in high-risk families, i.e., the patient's parents and immediate relatives.

The majority of the most common monogenic defects manifest themselves as metabolic disorders. Therefore, the WHO scientific group has developed and recommended for practical use the following classification of monogenic hereditary metabolic diseases.

• Hereditary disorders of amino acid metabolism.
• Hereditary disorders of carbohydrate metabolism.
• Hereditary disorders of lipid metabolism.
• Hereditary disorders of steroid metabolism.
• Hereditary disorders of purine and pyrimidine metabolism.
• Hereditary disorders of connective tissue metabolism.
• Hereditary disorders of heme and porphyrin metabolism.
• Hereditary disorders of red blood cell metabolism.
• Hereditary disorders of metal metabolism.
• Hereditary disorders of bilirubin metabolism.
• Hereditary disorders of absorption in the gastrointestinal tract.

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