Diagnosis of monogenic disorders

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

Autosomal dominant disorders. Dominant diseases are hereditary diseases, manifested in the heterozygous state, that is, in the presence of only one anomalous gene (a mutant allele). For diseases with autosomal dominant type of inheritance, the following features are characteristic.

• Each affected one of the parents (except for the mutations that arose de novo ).
• In an affected person who is married to a healthy spouse, on average half of the children are sick, and the other half is healthy.
• In healthy children affected, own children and grandchildren are healthy.
• Men and women are affected with the same frequency.
• The disease manifests itself in every generation.

Autosomal recessive disorders are clinically manifested only in the homozygous state, that is, if there is a mutation in both alleles of this genetic locus. For diseases with an autosomal recessive type of inheritance, the following characteristics are characteristic.

• The birth of a sick child in phenotypically healthy parents means that the father and mother are heterozygous for the pathological gene [a quarter of their children will be affected (homozygous for the pathological gene), three quarters are healthy (two quarters of the heterozygote, one quarter of the homozygote for the normal gene)].
• When a person enters a marriage with a recessive disease and a person with a normal genotype, all of their children will be phenotypically healthy, but heterozygous for the pathological gene.
• When a patient and heterozygous carrier marry, half of their children will be sick, half healthy, but heterozygous for the pathological gene.
• When two patients with the same recessive disease get married, all their children will be sick.
• Men and women are affected with the same frequency.
• Heterozygous individuals are phenotypically normal, but are carriers of one copy of the mutant gene.

X-linked disorders. Since defective genes are located on chromosome X, the clinical manifestations and severity of the disease are different in men and women. In women, there are two chromosomes X, so they can be hetero- or homozygous for a mutant gene, hence the probability of developing a disease in them depends on its recessivity / dominance. In men, only one chromosome X, so they have inherited the pathological gene disease in all cases, regardless of the recessivity or dominance of the defective gene.

For X-linked dominant inheritance, the following features are characteristic.

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

For X-linked recessive inheritance, the following features are characteristic.

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

To diagnose monogenic hereditary diseases, methods of direct and indirect DNA diagnostics are used. The use of direct diagnostic methods is possible only 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, more precisely the mutation of this gene, the identification of which constitutes the main research task. The use of this approach is especially effective in the presence of accurate information about the nature, frequency and localization of the most common (frequency-dominant) mutations of the corresponding genes. The main advantage of the direct method is a high, up to 100% accuracy of diagnosis.

Nevertheless, there is a huge number of monogenic hereditary diseases for which mutations are not established or major (major, most frequent) mutations in the populations under study have not been found. In addition, in almost all monogenic diseases, in addition to major mutations, there are numerous minor (rare) mutations. Finally, there is always the possibility of the presence of unknown mutations in the patient, 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 polymorphic markers linked to the genome, through which identification of chromosomes carrying the mutant gene in high-risk families is carried out, that is, the parents of the patient and his immediate family.

Most of the most common monogenic defects are manifested by metabolic disorders. Therefore, the following classification of monogenic hereditary metabolic diseases was developed and recommended for use by the WHO scientific group.

• Hereditary disorders of amino acid metabolism.
• Hereditary disorders of carbohydrate metabolism.
• Hereditary disorders of lipid metabolism.
• Hereditary disorders of steroid exchange.
• Hereditary disturbances in the exchange of purines and pyrimidines.
• Hereditary disorders of connective tissue exchange.
• Hereditary disorders of the exchange of heme and porphyrins.
• Hereditary metabolic disorders in erythrocytes.
• Hereditary metabolic disturbances.
• Hereditary disorders of bilirubin metabolism.
• Hereditary disorders of absorption in the digestive tract.

[1], [2], [3], [4], [5], [6], [7], [8],