Nomenclature of chromosomal mutations
It is known that for the description of karyotype there is a system of accepted abbreviations. This provision is also attributed to the description of chromosomal mutations.
Chromosomal diseases
After the introduction of methods for the analysis of human chromosomes in 1956, the chromosome nature of a number of diseases, including Down's syndrome( 47, XX / XY + 21), Klinefelter's syndrome( 47, XXY), Shereshevsky-Turner syndrome( 45, X) and some other syndromes of autosomal trisomy.
At the present level of development of genetics, almost 1000 chromosome syndromes are distinguished. As a percentage, they have quite high rates of spontaneous abortion, neonatal mortality and morbidity. Apparently, at least 50% of all spontaneous abortions are due to chromosomal mutations: the incidence of chromosomal abnormalities among newborns is 0.8%, and among stillborns - 5%.
The pathogenesis of chromosomal diseases is extremely complex, as it depends on the disruption of a large number of genes involved in any type of chromosomal mutation. There is, however, one more feature of chromosomal diseases, which distinguishes them from monogenic diseases. This feature is due to the fact that in chromosomal diseases their symptoms, usually manifested by congenital malformations, are a consequence of the so-called gene dose effect.
These are the most frequent human chromosomal diseases.
Trisomy
The most common of the trisomy and generally one of the most common hereditary diseases is trisomy 21, or Down syndrome. The cytogenetic nature of Down's syndrome was established by J. Lejeune in 1959. The syndrome occurs on average with a frequency of 1 per 700 live births, but the frequency of the syndrome depends on the age of the mothers and increases with its increase. In women older than 45 years, the incidence of patients with Down syndrome is 4%( see Table).
Table
Main clinical manifestations of Down syndrome
| Symptoms of | Prevalence,% |
| Mental retardation | 99 |
| Flat face | 90 |
| Mongoloid cut eye | 80 |
| Epikant | 40 |
| Spots Brushfilda on the iris | 50 |
| Strabismus | 60 |
| Anomalies ears | 50 |
| High or gothic sky | 70 |
| brachycephaly | 75 |
| Flat neck | 78 |
| Small teeth | 65 |
| short wide neck | 45 |
| more languages | 50 |
| Congenital heart disease | 8 |
| Duodenal obstruction | 70 |
| Short limbs | 70 |
| wide shortbrushes, short fingers | 70 |
| Single palmar fold | 20 |
| Sandal-like cleft | 45 |
| Hypotension | 60 |
| Low growth | 80 |
Causes of Down syndromeyayutsya regular trisomy - 95%, the translocation of chromosome 21 to chromosome other - 3%, and mosaicism - 2%.
The recurrence risk for regular trisomy 21 is approximately 1: 100 and depends on the age of the mother. With family translocation, risk indices vary from 1 to 3% if the carrier of the translocation is the father, and 10 to 15% if the carrier of the translocation is the mother. As already noted, in rare cases of 21q21q translocation, the repeated risk is 100%.
Trisomy 18( Edwards syndrome) is significantly less common than trisomy 21. The frequency of the syndrome is approximately 1 per 5000 live births, in girls it is observed about 3 times more often than in boys. The clinical manifestations of Edwards syndrome are much more severe than Down syndrome, usually patients die in the first weeks of life( see Table).
Table
Phenotypic signs of trisomy
| Symptoms | Frequency of occurrence |
| Severe psychomotor and physical development | 100 |
| Difficulty in swallowing, feeding problems | 100 |
| Low birth weight | 100 |
| Hypertonus | 65 |
| Malformation of the brain and spinal cord | 30 |
| Meningomielocele | 15 |
| Protruding nape | 90 |
| Low set, ugly ears | 90 |
| Ptosis, epicanth, microphthalmia | 30 |
| Cleft lip and palate | 15 |
| Micrognathia | 90 |
| Short neck with skin redundancy | 60 |
| Short sternum | 90 |
| Congenital heart diseasekt interventricular septum) | 95 |
| Eventeratsiya aperture | 30 |
| Inguinal hernias and umbilical | 60 |
| Pyloric stenosis | 30 |
The cytogenetic study typically exhibit regular trisomy 18. As with Down's syndrome revealed relationship between the frequency of trisomy 18 and maternal age. In most cases, the additional chromosome is of maternal origin. About 10% of trisomy 18 is due to mosaicism or unbalanced restructuring, more often to Robertson's translocations.
Trisomy 13( Patau syndrome) occurs at a frequency of 1 per 10,000 newborns. The clinical manifestations of the Patau syndrome, as well as the Edwards syndrome, are usually very severe and include multiple congenital malformations( see Table).Mortality among newborns with trisomy 13 syndrome in the first weeks of life is very high.
Table
Main clinical manifestations of the Patau syndrome
| Symptoms | Incidence,% |
| profound mental retardation and physical development | 100 |
| Microcephaly | 70 |
| Presumably deafness | 70 |
| Hypotension | 45 |
| Convulsions | 45 |
| Defects scalp | 30 |
| hypertelorism | 90 |
| Microphthalmia | 65 |
| Epikant | 65 |
| absence of eyebrows | 30 |
| Coloboma iris | 30 |
| Low set, malformed ears | 90 |
| Cleft lip and( or) of the sky | 65 |
| Short neck | 65 |
| Congenital heart disease( DMF.DMD) Coarctation of the aorta | 65 |
| Single umbilical artery | 30 |
| Inguinal and umbilical hernia | 30 |
| Omphalocele | 15 |
| Capillary hemangioma | 65 |
| Polydactyly | 65 |
| Cleft of the hands | 20 |
| Clubfoot | 20 |
| Kidney anomalies | 90 |
Cytogenetically, regular trisomy 18 is detected, the repeated risk for which is low.
More rare than trisomy 13 and 18, complete or partial trisomy is found in other autosomes. Virtually all of them are manifested by multiple congenital malformations.
Trisomy or, more generally, polysomy on sex chromosomes occur almost as often as trisomy on chromosome 21( see Table).
Table
Main clinical manifestations of Klinefelter's syndrome with karyotype 47, XXY
| Symptoms | Frequency of occurrence,% |
| High growth, asthenic physique | 80 |
| Mental retardation | 5 |
| Small external genitals | 50 |
| Histological evidence of spermatogenesis disorders | 100 |
| Gynecomastia | 55 |
| Reduced testosterone level | 80 |
| Elevated level of gonadotropin | 75 |
| Poor growth of facial hair | 80 |
Clinical manifestations of Klinefelter's syndrome increase with increasethe number of chromosomes X in the karyotype. Of the mosaic karyotypes, the most frequent is 46, XY / 47, XXY.
In women with additional chromosomes X, the number of which can reach up to 4, the clinical manifestations of the polysomy syndrome on chromosome X may either be absent altogether, or may show little mental retardation. Such women are usually fertile, and the karyotype of their offspring is usually normal.
Men with a karyotype of XYY are relatively common. Clinical manifestations of this karyotype do not have, however, it is noted that men XYY higher than average in the population, and more aggressive.
Monosomy
Monosomy in humans is known only for chromosome X. The general name for different types of monosomy on the chromosome X is the Shereshevsky-Turner syndrome( frequency in the population of 1 per 1000 women).
Shereshevsky-Turner syndrome occurs not only with complete, but also partial monosomy on chromosome X( see Table).
Table
Manifestations of Turner's syndrome
| Symptoms | Incidence,% |
| Low growth | 97 |
| primary amenorrhea | 96 |
| Sterility | 70 |
| lymph edema of the hands and feet at birth | 40 |
| Pterygoid folds at neck | 53 |
|
| 20 |
| Heart Malformations Malformations | 40 |
| kidney Mental retardation | 18 |
| High sky | 45 |
| Broad chest, often with deformation | 40 |
| Hearing loss | 53 |
Deletions
Deletion of short chromosome 4 captive( 4p syndrome, or Wolff-Hirschhorn syndrome).This deletion was first described in 1965.
Deletion of short chromosome 5 captivity( 5p- syndrome, or cat-scream syndrome).The chromosomal nature of the 5p syndrome was established by J. Lejeune and coworkers in 1963 in a newborn with developmental delay, microcephaly and a kind of crying similar to that of a cat.
Clinical manifestations of the syndrome 5p- have much in common with the 4p- syndrome.
With age, the phenotype of patients varies significantly. Patients usually of low stature, they have an elongated face, often asymmetric, poor development of the muscular system, scoliosis, premature graying and an incorrect bite.
Approximately 85% of all cases of the syndrome are spontaneous, 15% is inherited from phenotypically normal parents, carriers of balanced chromosomal rearrangement( translocation or inversion).
Deletions of the short arm of all acrocentric chromosomes practically do not have any serious clinical manifestations.
As separate nosological forms( syndromes), deletions of 18p, 18q, 21q and 22q are described.
The main clinical manifestations of the syndrome of 5p deletion( cat-scream syndrome) are presented below.
1. Low birth weight - 80%.
2. Mental retardation - 100%.
3. Difficulty in swallowing - 30%.
4. Crying, similar to the cry of a cat - 100%.
5. Respiratory stridor - 60%.
6. Laryngomalacia - 20%.
7. Microcephaly - 90%.
8. Hypertelorism - 70%.
9. Strabismus - 50%.
10. Anti-Mongoloid eye incision - 50%.
11. Low set, ugly ears - 60%.
12. "Monkey" fold is 70%.
The nucleus of each somatic cell of the human body contains 46 chromosomes. The set of chromosomes of each individual, both normal and pathological, is called a karyotype. Of the 46 chromosomes that make up the human chromosome set, 44 or 22 pairs are autosomal chromosomes, the last pair is the sex chromosomes. In women, the constitution of sex chromosomes is normally represented by two chromosomes X, in men X and Y. Chromosomes of one pair are called homologues, or homologous chromosomes. In the sex cells( spermatozoa and ovules) contains a haploid set of chromosomes, 23 chromosomes.
Each chromosome reveals a constriction, which is called a centromere. By position, the chromosome centromeres are classified into metacentric, acrocentric and submetacentric.
The material from which chromosomes are constructed is called chromatin. It consists of DNA and the surrounding histones and other proteins. That part of the chromatin, which is poorly colored by special dyes for chromosomes, is called euchromatin, and the one that is stained intensely is heterochromatin. It is believed that euchromatic regions of chromosomes contain actively expressed genes, heterochromatin regions, on the contrary, contain inactive genes and non-expressing repeating DNA sequences.
A somatic cell can be in two states - interphase and division. The change of these states by each other is called the cell cycle. During interphase, the cell doubles its contents, including chromosomes. Interphase is divided into three stages.
The process of dividing the somatic cells, during which the fission of the nucleus also occurs, is called mitosis. Before the cell enters mitosis, each chromosome is represented by two identical strands that are the result of DNA replication during the cell cycle synthesis phase. These strands are called chromatids. During the division of the nucleus, the chromatin cells of each chromosome divide into two newly formed cells. Thus, somatic cells retain the same number of chromosomes throughout the life of a person and, consequently, all somatic cells are genetically identical to each other.
Mitosis is divided into separate stages( or phases): prophase, prometaphase, metaphase, anaphase and telophase.
Meiosis is the process of dividing the nuclei of germ cells when they are converted into gametes. Meiosis includes two cell divisions, which are called respectively meiosis I and meiosis II.Each of these divisions formally consists of the same stages as mitosis: prophase, metaphase, anaphase and telophase. Meiosis I is also called reduction division, because as a result of this division the number of chromosomes in newly formed cells decreases by a factor of 2.Meiosis II is similar in mechanism to the usual mitosis, but the doubled haploid set of chromosomes is mitotically divided. As a result of the second meiotic division, two spermatids are formed in male gametogenesis, and in female gametogenesis an egg is formed, since the so-called directing body is formed from the second daughter cell. Meiosis explains many genetic phenomena, including the Mendelian rules of inheritance.
There are two main types of chromosomal mutations - numerical and structural. Numerical mutations are divided into aneuploidy, when mutations are expressed in the loss or appearance of an additional one or more chromosomes, and polyploidy, when the number of haploid sets of chromosomes increases. The loss of one of the chromosomes is called monosomy, and the emergence of an additional homologue in a pair of chromosomes - trisomy. Trisomy usually occurs as a result of a discrepancy between the homologous chromosome divergence in the anaphase of meiosis I. As a result, both homologous chromosomes fall into one daughter cell, and none of the chromosomes enter the second daughter cell.