Pediatric Medical Genetics - S.I. Smiian 2003

General Principles of Medical Genetics
Methods of Medical Genetics

Various Methods are used to study the inheritance of normal and pathological human traits.

The genealogical method is based on the compilation and analysis of pedigree charts. This method helps determine the type of inheritance of a trait or disease within a given family. Constructing a pedigree requires information on at least 3 to 4 generations of the proband (the patient under examination). Specific symbols are used when drawing up a pedigree.

Brothers and sisters (siblings), along with their spouses of the same generation, are placed in a horizontal row from left to right in birth order and are designated by Arabic numerals (1, 2, 3, etc.). Generations are denoted by Roman numerals (I, II, III), with the oldest generation considered the first.

The population-statistical method studies the genetic Structure of populations, their Gene pool, and the factors and patterns responsible for its preservation and changes across generations. In medical genetics, the population method is used to investigate the incidence of Hereditary diseases in the population, their spread patterns, and the frequency of pathological genotypes in specific localities, cities, or countries. For example, in Sweden, the heterozygous carrier rate for the mutant amaurotic idiocy gene is 1:200, while among Ashkenazi Jews this figure is even higher at 1:50. On average, among the global population, it does not exceed 1:500,000. Among the white population of South Africa, There is a high concentration of the mutant porphyria gene (1:100). It is hypothesized that it was brought there by a Dutch individual with porphyria and, due to the high fertility rate of the colonists who emigrated to Africa, rapidly spread within this isolate.

In other cases, the accumulation of a mutant gene is associated with natural Selection. For instance, in the southern Sahara, The high frequency of Sickle-Cell Anemia is due to the fact that heterozygous carriers of the gene are resistant to tropical malaria.

The twin method makes it possible to study the roles of HEREDITY AND ENVIRONMENT in The Development of normal and pathological traits. It was developed by F. Galton more than 100 years ago. In 1876, his paper "The history of Twins, as a Criterion of the Relative Powers of Nature and Nurture" was published. Based on certain traits, F. Galton divided twins into monozygotic (identical) and dizygotic (fraternal). Identification is carried out by assessing the concordance (similarity) of genetically determined traits (Skin, eye, and Hair color; shape of the Nose, Lips, and Mouth; shape and size of the HEAD, ears, fingers, and hands; tooth structure and enamel color; distribution of skin spots and palm/finger dermatoglyphic patterns). Blood types in monozygotic twins are identical. Investigating The Role of heredity and environment in the onset of diseases and syndromes relies on studying their frequency in monozygotic and dizygotic twins. For example, there is a very high degree of concordance for oligophrenia in monozygotic twins (94.5%) and a relatively moderate one in dizygotic twins (42.6%), indicating a high degree of genetic predisposition to this condition. Nervous system disorders, cleft lip and palate, Clubfoot, congenital hip dislocation, Diabetes Mellitus, and even tuberculosis exhibit a high degree of heritability.

Dermatoglyphics is The Study of the epidermal ridge patterns on the fingertips, palms, and soles. Chromosomal Disorders present deviations in dermatoglyphic parameters from the norm. For example, in Down syndrome, a single transverse palmar crease is observed in 40–60% of cases (normally, its frequency in the population does not exceed 1%). Other features also change.

The application of dermatoglyphics, alongside other methods, allows for the targeted selection of individuals who require more complex genetic testing.

The cytogenetic method involves determining X and Y sex Chromatin and analyzing Chromosomes to establish the karyotype.

Chromosome analysis is performed during Cell Division at the metaphase stage, when chromosomes have a more distinct structure. Bone Marrow and embryonic Cells serve as material for the direct method, while skin cells and Blood Leukocytes are used for the indirect method. Karyotyping allows for the precise identification of chromosomal anomalies, distinguishing, for instance, pseudo-Down syndrome from true Down syndrome.

The study of sex chromatin was initiated in 1949 by Barr and Bertram, who discovered a dark body in the nuclei of somatic cells, which was named sex chromatin or the Barr body. It turned out to be an obligatory component of somatic cells in individuals with at least two X chromosomes. When multiple X chromosomes are present, the number of Barr bodies is always one less than the number of chromosomes. Knowing this rule makes it possible to identify an individual's biological sex and detect an abnormal number of X chromosomes.

Specifically, males with sexual development defects may have cells with "female sex chromatin," whereas the cells of certain females with characteristic infantile development (Turner syndrome) lack sex chromatin because their karyotype is XO instead of XX.

The study of sex chromatin has provided a deeper understanding of intersex states. These include testicular feminization syndrome, in which a phenotypically normal female exhibits an absence of sex chromatin in oral mucosa cells and a normal male XY chromosomal Complement. These women lack a Uterus, have a shallow or absent Vagina, present with an inguinal hernia, do not menstruate, have normally developed breasts, and are infertile. Upon laparotomy, Testes are found in place of Ovaries. These women are characterized by excessive industriousness and neurovegetative instability. Their psychological profile is entirely feminine.

Sex chromatin analysis is of great importance for determining fetal sex in cases of X-linked diseases. Furthermore, it helps determine sex in newborns with genital malformations. This is necessary both for the timely correction of these defects and for the proper upbringing of these children. There are also reports on The Use of sex chromatin analysis for postmortem Sex Determination of Tissues in forensic medical examinations.

Of particular interest is the study of sex chromatin in various benign and malignant tumors. This issue has not yet been fully explored, but some experience has been accumulated, allowing for certain Conclusions. Specifically, all tumors of the FEMALE REPRODUCTIVE Organs can be divided into 3 groups based on their sex chromatin content.

Group I: tumors of male (nuclear) sex—low count of Barr bodies (1–19%). These are the most malignant tumors. Patients deteriorate rapidly, especially when treated with Male Sex Hormones. They exhibit rapid metastasis.

Group II: intermediate nuclear sex—sex chromatin is present in 20–39% of cells. The prognosis is also poor, and hormones are contraindicated.

Group III: Cells of the female nuclear type. Sex chromatin is detected in 40–70% of cells. Patients in the third group have the highest survival rate, respond well to hormone therapy, and remain free of metastasis for a long time. Oophorectomy is not recommended for them unless the pathological process has spread to the ovaries.

The Significance of studying sex chromatin is as follows:

1. The number of Barr bodies indicates the number of sex chromosomes.

2. It AIDS in the investigation of tumors.

3. It allows for fetal sex determination using Amniotic Fluid cells.

4. It helps determine sex in cases of Hermaphroditism.

5. It assists in deciding on the use of hormone therapy.

Amniotic fluid analysis is an essential method of prenatal Diagnosis that makes it possible to determine fetal sex, detect certain hereditary diseases in the future child, and, based on Medical and Genetic indications, make a decision regarding Pregnancy termination. Determining fetal sex at 16–17 weeks of gestation helps prevent the birth of children with X-linked disorders (hemophilia A and B, Duchenne muscular dystrophy, agammaglobulinemia, etc.). Biochemical analysis of amniotic fluid can identify the majority of hereditary Metabolic Disorders in the fetus. A direct indication for amniocentesis followed by amniotic fluid analysis is having a child with a hereditary disease in the family history.

In addition to the aforementioned methods, immunological, biochemical, ontogenetic, and modeling methods are also used.