Nomenclature of chromosomal mutations

August 12, 2017 17:51 | Genetic Diseases

known that the karyotype to describe a system of abbreviations.This provision also applies to the description of chromosomal mutations.

Chromosomal disease

Once in 1956, were introduced methods for the analysis of human chromosomes, chromosome nature of a number of diseases has been established in a short time, including Down's syndrome (47, XX / XY + 21), Klinefelter's syndrome(47, XXY), Turner's syndrome (45, X) and several other syndromes of autosomal trisomies.

At the present level of development of genetics of nearly 1,000 distinguished chromosomal syndromes.In percentage terms, they have a fairly high rates of spontaneous abortion, neonatal mortality and morbidity.Apparently, at least 50% of all spontaneous abortions due to chromosomal mutations: the frequency of chromosome abnormalities in newborns is 0.8%, and among stillborn - 5%.

pathogenesis of chromosomal disease is extremely complex, since it depends on the existence of a large number of violations of the genes involved in any type of

chromosomal mutations.There is, however, another feature of chromosomal diseases, which distinguishes them from monogenic diseases.This feature is due to the fact that the chromosomal diseases their symptoms, usually manifested congenital malformations are the consequence of the so-called effect of gene dosage.

Here are the most frequent chromosomal disease in humans.

Trisomy

most frequent of trisomies and generally one of the most common hereditary disease is trisomy 21, or Down syndrome.Cytogenetic nature of Down syndrome was established by J. Lejeune in 1959. The syndrome is found in the middle with a frequency of 1 in 700 live births, but the frequency of the syndrome depends on the age of mothers and increases with its increase.In women older than 45 years, the frequency of birth of patients with Down syndrome reaches 4% (see. Table.).

Table

main clinical manifestations of Down syndrome

Symptoms

Prevalence,%

Mental retardation

99

flat face

90

Mongoloid eye shape

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 short hand, short fingers

70

only palmar crease

20

Sandalevidnaya slot

45

Hypotension

60

Low growth

80

Causes Down syndrome are regular trisomy - 95%, the translocation of chromosome 21 to other chromosomes - 3%, and mosaicism - 2%.

repeated at regular risk of trisomy 21 is about 1: 100, depending on the age of the mother.In familial risk of translocation rates range from 1 to 3% when the carrier is father translocation, and from 10 to 15% if the mother is a carrier translocation.As already noted, in rare cases the translocation 21q21q second risk is 100%.

Trisomy 18 (Edwards syndrome) occurs much less frequently than trisomy 21. The frequency of the syndrome is about 1 in 5000 live births in girls it is observed approximately 3 times more often than boys.The clinical manifestations of the syndrome Edwards - much more severe than Down syndrome, usually patients die in the first weeks of life (see Table..).

Table

phenotypic features of trisomy

Symptoms

Incidence,%

Heavy delayed psychomotor and physical development

100

difficulty swallowing, problemsfeeding

100

Low birthweight

100

gipertonus

65

malformations of the brain and spinal cord

30

meningomyelocoele

15

Speaker neck

90

Low set, malformed ears

90

ptosis, epikant, microphthalmia

30

Cleft lip and palate

15

micrognathia

90

short neck with redundant skin

60

short sternum

90

Congenital heart disease (ventricular septal defect)

95

Eventeratsiya diaphragm

30

inguinal and umbilical hernia

60

Pyloric stenosis

30

In cytogenetic studies generally find regular trisomy 18. As with Down syndrome, revealed a link between the frequency of trisomy 18and the age of the mother.In most cases, the extra chromosome is maternal in origin.About 10% of trisomy 18 mosaicism, or due to unbalanced rearrangements, Robertsonian translocations often.

Trisomy 13 (Patau syndrome) occurs with a frequency of 1 per 10 000 live births.The clinical manifestations of the syndrome Patau, as well as Edwards syndrome, is usually very severe and include multiple congenital malformations (see. Table.).Mortality among infants with trisomy 13 syndrome in the first weeks of life is very high.

Table

main clinical manifestations of the syndrome Patau

Symptoms

Incidence,%

Deep delayed mental and physical development

100

microcephaly

70

Presumably deafness

70

Hypotension

45

Cramps

45

Defects scalp

30

hypertelorism

90

Microphthalmia

65

Epikant

65

lack of eyebrows

30

Coloboma of the iris

30

Low set, malformed ears

90

lip cleft and (or) palate

65

short neck

65

Congenital heart disease (DMZHP.DMPP.coarctation of the aorta)

65

only umbilical artery

30

inguinal and umbilical hernia

30

omphalocele

15

capillary hemangioma

65

Polydactyly

65

Cleft brushes

20

Clubfoot

20

Anomalies renal

90

cytogenetic usually detected regular trisomy 18, is a danger to which low.

Even rarer than trisomy 13 and 18, found full or partial trisomy other autosomes.Almost all of them are manifested by multiple congenital malformations.

Trisomy or, more generally, polysomy on the sex chromosomes are found almost as often as trisomy of chromosome 21 (see. Table.).

Table

main clinical manifestations of the syndrome Klinefelter with the karyotype 47, XXY

Symptoms

Incidence,%

Tall, adynamic figure

80

Mental retardation

5

Small vulva

50

Histological evidence of violations spermatogenesis

100

Gynecomastia

55

Reduced testosterone levels

80

Elevated levels of gonadotropin

75

Bad hair growth on the face

80

Clinicalmanifestations of Klinefelter's syndrome increase with the increase in the number of X chromosomes in the karyotype.From mosaic karyotypes of the most common is 46, XY / 47, XXY.

In women with extra X chromosome, the number of which can reach up to 4, the clinical manifestations of chromosome X syndrome polysomy can either absent altogether or be shown a small mental retardation.Such women tend to be fertile and their offspring karyotype is usually normal.

Men with XYY karyotype occur relatively frequently.Clinical manifestations of this karyotype has not, however, noted that XYY males taller than the average in the population, and are more aggressive.

monosomy

monosomy in humans is known only to the chromosome X. The common name for various types of monosomy for chromosome X - Turner's syndrome (frequency in the population of 1 per 1,000 women).

Turner syndrome occurs not only in full but partial monosomy for chromosome X (see. Table.).

Table

manifestations of Turner's syndrome

Symptoms

Incidence,%

Low growth

97

Primary amenorrhea

96

Sterility

70

Lymphatic swelling of hands and feet at birth

40

pterygoid folds on the neck

53

heart disease

20

Vices kidney development

40

Mental retardation

18

High sky

45

broad chest, often with deformation

40

hearing loss

53

Deletions

Deletion of short captivity chromosome 4 (4p syndrome, or syndromeWolf-Hirschhorn).For the first time this deletion was described in 1965

deletion of chromosome 5 short captivity (5r- syndrome, or syndrome of "cat cry").Chromosomal nature 5r- syndrome was established by J. Lejeune and co-workers in 1963 in infants with developmental delay, microcephaly, and a kind of cry, like the cry of a cat.

clinical manifestations of the syndrome 5r- have much in common with the syndrome 4r-.

With age, the phenotype of patients varies considerably.Patients usually low growth, they have a long face, often asymmetrical, poor development of the muscular system, scoliosis, premature graying and malocclusion.

Approximately 85% of all cases of the syndrome are spontaneous, 15% is derived from phenotypically normal parent carrier of a balanced chromosomal rearrangement (translocation or inversion).

Deletions of the short arm of acrocentric chromosomes hardly have any serious clinical manifestations.

As individual nosological forms (syndromes) described 18P deletion, 18q, 22q, and 21 q.

main clinical manifestations of the syndrome deletion 5p ( "cat cry" syndrome) are presented below.

1. Low birth weight - 80%.

2. Mental retardation - 100%.

3. Difficulties in swallowing - 30%.

4. Crying, like the cry of a cat - 100%.

5. Respiratory stridor - 60%.

6. Laringomalyatsiya - 20%.

7. Microcephaly - 90%.

8. hypertelorism - 70%.

9. Squint - 50%.

10. palpebral - 50%.

11. The low-set, malformed ears - 60%.

12. «Monkey» fold - 70%.

At the core of every human somatic cells of the body normally contains 46 chromosomes.Set each individual chromosomes, both normal and pathological, is called karyotype.Of the 46 chromosomes that make up the human chromosome set, 44 or 22 pairs of autosomal chromosomes are, the last pair - sex chromosomes.In women, sex chromosome constitution normally represented by two chromosomes X, men - X and Y. The chromosomes of a pair are called homologues or homologous chromosomes.The germ cells (sperm and egg) contains haploid set of chromosomes, 23 chromosomes.

Each chromosome is detected constriction, which is called the centromere.The position of the centromere of chromosome classified as metacentric, acrocentric and submetacentric.

material from which constructed chromosomes called chromatin.It is composed of DNA and histones surrounding and other proteins.That part of the chromatin, which is slightly stained with special dyes to chromosomes, called euchromatin, and one that is colored intensely - heterochromatin.It is believed that euchromatin chromosome regions comprise highly expressed genes, heterochromatic regions, in contrast, contain inactive genes and non-expressing DNA repetitive sequence.

Somatic cell can exist in two states - interphase and dividing.The change of these states together are called the cell cycle.During interphase cell doubles its contents, including the chromosomes.Interphase can be divided into three stages.

process of dividing somatic cells, in which also is the division of the nucleus, called mitosis.Prior to entry into mitosis cells each chromosome represented by two identical yarns, which are the result of DNA replication during the cell cycle phase synthesis.These threads are called chromatids.During the division of the cell nucleus chromatids of each chromosome differ in two newly emerging cells.Thus, somatic cells throughout life retained the same number of chromosomes and therefore all somatic cells are genetically identical to each other.

Mitosis can be divided into separate stages (or phases): prophase, prometaphase, metaphase, anaphase and telophase.

Meiosis is the process of dividing germ cell nuclei in their transformation in the gametes.Meiosis involves two cell division, called meiosis I and, respectively, meiosis II.Each of these divisions formally consists of the same stages as mitosis: prophase, metaphase, anaphase and telophase.Meiosis I and meiosis called as a result of dividing the number of chromosomes in the newly formed cells is reduced by 2 times.Meiosis II mechanism is similar to the conventional mitosis, but mitotically divided doubled haploid set of chromosomes.