Chapter XI -Medical Biology - course content Genetics 2023-2024.pdf

Exercise 11. Topic: Gene and chromosomal mutations. Glossary: Aneuploidy - the state where one or more individual chromosomes of a normal set are absent or present in more than their usual number of copies, e.g. monosomy (missing a chromosome), trisomy (having a single extra chromosome). Autosom - i...

Exercise 11. Topic: Gene and chromosomal mutations. Glossary: Aneuploidy - the state where one or more individual chromosomes of a normal set are absent or present in more than their usual number of copies, e.g. monosomy (missing a chromosome), trisomy (having a single extra chromosome). Autosom - is any of the numbered or nonsex chromosomes of an organism Allosom (heterochromosome) - is a sex chromosome of an organism Chromosomal rearrangements - mutations involving large fragments of the chromosomes; these include the fussion of chromosomes, the duplication or deletion of a chromosomal segment, the inversion of a segment and the translocation of segments between non-homologous chromosomes. Chromosome mutations - changes in the quality and/or number of chromosomes in the cell nucleus, that occur usually during cell division in mitosis or meiosis. Chromosome translocation - a phenomenon that results in unusual rearrangement of chromosomes; includes balanced and unbalanced translocation, with two main types: reciprocal and Robertsonian translocation. Clinical cytogenetics - the field of genetic diagnostics, based on multidirectional analysis of human chromosomes; provides a range of information on genome abnormalities at different levels - from the chromosome to changes in specific genes. Cytogenetics - a science that studies chromosomes, their structure and changes in their structure; it includes cytology and genetics. Euploidy / polyploidy - the state where a cell or organism has one or more than one set of chromosomes beyond the basic set, usually 3 or more, e. g. triploidy (3 sets), tetraploidy (4 sets). Gene mutations - changes in the nucleotide sequence in a fragment of a DNA in one gene including single nucleotide polymorphism (SNP), transition or transversion (substitutions), insertion or deletion. They lead to the creation of a new quality of the gene / allele. Heteroploidy - an abnormal number of chromosomes in the cell, resulting from irregular mitosis, most often in cancer cells. Induced mutations - mutations caused by various mutagens: physical, chemical or biological factors. Lethal mutations - gene and chromosomal mutations causing death of the embryo, foetus, or the offspring soon after birth. Marker chromosomes, extra structurally abnormal chromosomes (ESACs) - additional, small and unlike other chromosomes, structures whose origin cannot be determined on the basis of a classical study; generally cannot be identified without specialized genomic analysis due to the size of the fragment. Meiotic/ mitotic nondisjunction - the failure of homologous chromosomes (during meiosis) or sister chromatids (during mitosis) to properly separate during cell division, resulting in their uneven segregation for daughter cells. Mutation - any change in the genetic material of a given organism, resulting in the appearance of new inherited features. There are two main types of mutations: chromosome (structural) mutations and gene (point) mutations. Numerical chromosome mutations - involve the change in the correct number of chromosomes; its cause may be the failure of homologous chromosomes to separate properly during cell division. Reciprocal translocation - a chromosome abnormality caused by the exchange of parts between non-homologous chromosomes: two fragments of two different chromosomes detach and switch places; if genetic material is not lost – it is so called balanced reciprocal translocation. Robertsonian translocation - the fusion of long arms of non-homologous acrocentric chromosomes (13, 14, 15, 21 and 22) with a simultaneous loss of short arms; it may be balanced or unbalanced. Spontaneous mutations - occur without the participation of external factors; they arise most frequently as a result of errors during the replication or imperfect operation of repair systems that cannot compensate for all polymerase mistakes. Amenorrhea - the absence of a menstrual period in a woman of reproductive age. Aplasia cutis congenita (ACC) - a rare disorder characterized by the congenital absence of skin; the scalp is the most commonly involved area with lesser involvement of trunk and extremities. Brachycephaly - the shape of a skull shorter than typical for its species. Brushfield spots - small, white or greyish/brown spots on the periphery of the iris in the human eye due to the aggregation of connective tissue, a normal constituent of the iris stroma. Calcaneus (heel bone) in humans is a bone of the foot tarsus which constitutes the heel. Clinodactyly - the curvature of a digit (a finger or toe) in the plane of the palm, most commonly the fifth finger towards the adjacent fourth finger. Cubitus valgus - a medical deformity in which the forearm is angled away from the body to a greater degree than normal when fully extended. Cyclopia (cyclocephaly, synophthalmia) - the most extreme form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosencephalon to properly divide the orbits of the eye into two cavities. Epicanthal fold (epicanthus, palpebronasal fold) - the skin fold of the upper eyelid, covering the inner corner (medial canthus) of the eye, formerly known as a Mongolian fold. Gynaecomastia - an endocrine system disorder in which a noncancerous increase in the size of male breast tissue occurs. Hernia - the abnormal exit of tissue or an organ, such as the bowel, through the wall of the cavity in which it normally resides. Holoprosencephaly (HPE) - a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres. Hypertelorism - an abnormally increased distance between two even organs; its professional use in a medical language describing the features of dysmorphia has been limited only to ocular hypertelorism (hypertelorismus ocularis). Hypogonadism - a diminished functional activity of the gonad (the testes or the ovaries) that may result in the diminished production of sex hormones. Hypospadias - a common variation in foetal development of the penis in which the urethra does not open from its usual location in the head of the penis. Hypotonia (commonly known as floppy baby syndrome) - a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Meningomyelocele (spina bifida) - a birth defect in which there is an incomplete closing of the spine and membranes around the spinal cord during early development in pregnancy. Microcephaly - a medical condition in which the brain does not develop properly resulting in a smaller than normal head. Microgenia - an unusually small or deformed chin. Micrognathism (mandibular hypoplasia) - a condition where the jaw is undersized. Microorchidism - a genetic disorder found in males, characterized by abnormally small testes. Microphthalmia (microphthalmos) - a developmental disorder of the eye in which one (unilateral microphthalmia) or both (bilateral microphthalmia) eyes are abnormally small and have anatomic malformations. Omphalocele (exomphalos) - a rare abdominal wall defect in which the intestines, liver and occasionally other organs remain outside of the abdomen in a sac because of the failure of the normal return of intestines and other contents back to the abdominal cavity around the ninth week of intrauterine development. Cryptorchidism (undescended testicles) - the absence of one or both testes from the scrotum. Palpebral fissure - is the elliptic space between the medial and lateral canthi of the two open lids; opening between the eye lids. Proboscis - in teratology, a blind-ended, tube-like structure, commonly located in the middle of the face. Sella turcica (Turkish seat) - a saddle-shaped depression in the body of the sphenoid bone of the human skull and of the skulls of other hominids. Spermatozoon - is a motile sperm cell, or a moving form of the haploid cell that is the male gamete. Strabismus - a condition in which the eyes do not properly align with each other when looking at an object. The milestone in the research on the nature of inheritance was the achievement of Thomas Hunt Morgan, who, thanks to experiments at the fruit fly, Drosophila melanogaster, proved that genes are located on chromosomes and formulated the chromosomal theory of heredity. D. melanogaster is a convenient experimental organism for genetic research: it is characterized by a short development time (lasting for 10-14 days), high fertility (during its lifetime a female can lay up to 3 000 eggs), and the costs of maintaining these insects in laboratory conditions are low and do not require complicated treatments. In the genetic studies, very useful features of fruit flies are as follows: 1) the presence of so-called polytene (giant) chromosomes in the cells of the salivary glands of the insect larval forms, as well as 2) the occurrence of numerous gene mutations, the effects of which relate to many morphological features. Polytene (giant) chromosomes are oversized chromosomes which develop from standard chromosomes and are commonly found in the salivary glands of Diptera larvae e.g. Drosophila melanogaster. They are formed as a result of DNA replication during S phase of the cell cycle without the subsequent mitosis (endoreplication) - all strands of DNA stay attached to each other. Gene amplification occurs – multiple copies of genes permit a high level of gene expression. Genes are located in dark bands and light interband (more active) regions. Upon activation of a specific gene, the heavily coiled chromatid fibre in each chromomere of the corresponding chromosome band is unfolded and forms a loop (puff), along which transcription takes place. Puffs represent active genes. Examples of Drosophila melanogaster mutants:  ebony (dark body colour) - gene mutation in the autosome of pair 3,  nub2 (reduced wings) - gene mutation in the autosome of pair 3,  yellow (yellow body colour) - gene mutation in the X chromosome,  white (white eye colour) - gene mutation in the X chromosome - the first noticed by T.H. Morgan,  Bar mutation (reduced number of ommatidia of the eye) - gene duplication in the X chromosome,  ultra Bar - gene triplication in the X chromosome. MUTATIONS Basic division of mutations Several main types of mutations have been distinguished (Figure 1). Figure 1. Division of mutations (according to Drewa and Ferenc, 2011). Gene mutations Gene mutations concern the change in the nucleotide sequence in the DNA molecule and occur within no more than one gene. They are usually triggered in a spontaneous way. Based on the basic mechanism of their formation, they are divided into (Figure 2): 1. Substitutions - consist in exchanging one pair of nucleotides for another pair. transitions - take place when the purine base is replaced by another purine base [e.g. adenine (A) by guanine (G)] and the pyrimidine base is replaced by another pyrimidine base [e.g. cytosine (C) by thymine (T)]; transversions - take place when the purine base is replaced by a pyrimidine base (e.g. A by T) or the pyrimidine base is replaced by a purine base (e.g. C by G). 2. Deletions = deficiencies - consist in the loss of a single nucleotide or several nucleotides. 3. Insertions - consist in the addition of one or more nucleotide base pairs into a DNA molecule. 4. Inversions - consist in changing the order of nucleotides. Figure 2. Examples of gene mutations with regard to the mechanism of formation. Dynamic mutations - multiplication of the number of copies of the gene or nucleotide fragments (tri- / dinucleotide); they may occur in the non-coding or coding part of the gene and may cause disturbances in the proper course of transcription. As a result of the mutation, the genetic disease is caused by a low protein concentration or a complete lack of a protein, such as the fragile X syndrome (FXS) or Friedreich's ataxia (FRDA, FA). An example of a dynamic mutation is a CGG trinucleotide expansion in the fragile X mental retardation 1 (FMR1) gene sequence (locus Xq27.3), which occurs in the fragile X syndrome. In healthy individuals, the number of trinucleotide copies in FMR1 does not exceed 54, in asymptomatic carriers of FXS this number reaches 200 (permutation: 60-200 CGG repeats), and in patients suffering from FXS it can exceed 1000 repetitions (full mutation: greater than 200 CGG repeats). The second group includes diseases in which the protein product is present, but in an altered form due to the presence of the chain of amino acid - glutamine (effect of CAG codone multiplication in the gene sequence), e.g. spinal and bulbar muscular atrophy (SBMA), popularly known as Kennedy's disease (defect of the AR gene in the X chromosome). The third group contains diseases caused by the multiplication of the trinucleotide motif in non-coding parts of the gene, e.g. type 1 myotonic dystrophy. Based on the effects in the coded protein, the mutations are divided into (Figure 3):  Synonymous mutation (Silent) - a change in a single nucleotide in a gene that does not change the amino acid in the encoded protein.  Non-synonymous mutation - a point mutation that changes the amino acid encoded by the codon.  Missense mutation - a point mutation caused by substitution of a single nucleotide. It changes the sense of the codon encoding one amino acid for a codon encoding another amino acid in the resulting protein.  Nonsense mutation - a mutation in which a single nucleotide is changed and, as a result, STOP codons are created prematurely, leading to premature termination of translation.  Frameshift mutation (framing error, reading frame shift) – a mutation caused by indels (insertions or deletions) of a number of nucleotides in the DNA sequence that is not divisible by three (that is not a multiple of the codon). This involves a change in the sequence of the protein.  Loss-of-function mutation (inactivating mutation) – a mutation causing the formation of a protein devoid of normal function - having less or no function (being partially or wholly inactivated).  Gain-of-function mutation (activating mutation) - the type of mutation leading to the formation of a protein whose effect gets stronger (enhanced activation) or even is superseded by a different and abnormal function.  Splice-site mutation – a change in the DNA sequence occurring at the border of the exon and intron (splicing site). This change may disrupt RNA splicing causing loss of exons or inclusion of introns and as a result changes the sequence encoding the protein (Figure 4). A B C D E Figure 3. Examples of gene mutations based on the effect: A. correct translation; B. missense mutation; C. frameshift mutation - insertion; D. frameshift mutation - deletion; E. nonsense mutation. Figure 4. Mutation at the splicing site. Each mutation involves a change in genetic material. It is often disadvantageous to the organism, but it happens to be indifferent or even beneficial. The last two possibilities are of great importance in the evolution and are the reason for the variability of organisms. Mutations can also be divided into mutations occurring in:  somatic cells (body cells) - the changes affect only the selected part of the organism and are not inherited by offspring (e.g. different colour of the left and right eyes);  reproductive cells (gametes) - all cells of the organism have a changed genetic information and this change is passed on to next generations - hereditary mutation. Based on the cause/reason of mutations factor causing mutations, they are divided into:  Induced mutations - mutations caused by various mutagens: physical, chemical or biological factors.  Spontaneous mutations - occur without the participation of external factors; they arise most frequently as a result of errors during the replication or imperfect operation of repair systems that cannot compensate for all polymerase mistakes. Induced or spontaneous mutations may be related to the effect on the organism/cells of the mutagenic agent/factors (mutagens) A mutagen is defined as an agent that causes irreversible and heritable changes (mutations) in the cellular genetic material, deoxyribonucleic acid (DNA). Physical, chemical and biological factors can be distinguished among mutagenic factors inducing mutation (Table 1). Table 1. Induced mutations - mutagenic agents (physical, chemical, biological). The type of mutagenic agent Ionizing radiation Physical UV radiation High temperature Nitric acid HNO2 Hydroxylamine NH2OH Alkylating agents, Effect - Mutation Fragmentation of chromosomes → chromosome aberrations Substitution of thymine and cytosine dimers → point mutations Chromosomal breaks; DNA replication disorders Removal of the amino group from nitrogen bases in DNA → point mutations Reactions with cytosine → point mutations; interference with the activity of selected enzymes Alkylation of nitrogen → point mutations of nitrogen bases e.g. diepoxybutane Chemical Nitrogen base analogues, Incorporated in DNA → point mutations e.g. 5-bromouracil Acridine dyes Incorporation into the DNA chain → mutations: deletions and insertions during replication Colchicine Disorganization of the mitotic spindle → polyploidy Streptomycin Mutations of mitochondrial DNA Retroviruses (HIV virus, Rous Insertion mutation → insertion of viral genetic material into the cell's genome Biological sarcoma virus) → slow, long-term cell transformation Hepatitis B virus Containing oncogenes in the genetic material → strong expression → rapid Epstein-Barr virus cell transformation The effects of mutations are presented in Table 2 and Table 3. Table 2. Phenotypic effects of point mutations in the cell. Type of mutation Description of change Phenotypic effect at the DNA level Missense mutation Amino acid substitution It can lead to a change in protein function Nonsense mutation, null mutation Induces the formation of a translation Stop of protein synthesis termination signal Silent mutation change in a single nucleotide in a gene In the case of mutations in the coding region, it that does not change the amino acid in has no effect on protein functions, in non-coding the encoded protein regions - no functional meaning, useful in individual identification and evolutionary studies Synonymous mutation change in a single nucleotide in a gene It can affect the rate of the translation process, that does not change the amino acid in because tRNA for different codons occurs with the encoded protein different frequency (change from the preferred to the rare codon, it can affect the rate of protein synthesis) Frameshift mutation Deletion or insertion of a single Creation of a dysfunctional protein nucleotide affects the amino acid sequence Mutations of repetitive sequences Most often without significance, except The cause of many neurodegenerative and for the so-called dynamic mutations neuromuscular genetic diseases functioning in the medical nomenclature under the common name of Triplet Repeat Expansion Diseases Chromosome mutations - chromosomal aberrations The term chromosome aberration refers to any abnormalities in the structure and / or number of chromosomes. According to the classical definition, it is a mutation so extensive that it is possible to observe in a light microscope. Like point mutations, they may be created de novo or be inherited from parents, they can be formed in somatic cells or in gametes. Aberrations: a. structural: inversion, translocation, duplication, deletion, insertion; ring chromosome, dicentric chromosome, isochromosome; b. numerical: aneuploidy, euploidy / polyploidy. Aberrations of the chromosome structure in humans (Table 3): Translocation - breaking of chromosomes and rearrangement of fragments between two chromosomes. There are two main types of translocation: reciprocal, and Robertsonian translocation. They may be balanced or unbalanced. Reciprocal translocation - happens when the break occurs in two different non-homologous chromosomes and mutual exchange of sections takes place, e. g. Burkitt’s lymphoma (BL, Burkitt's tumour, malignant lymphoma, Burkitt's type) caused by the translocation between the chromosomes of pairs 8 and 14. Robertsonian translocations (centric fusion) - occur as a result of the breaks of two acrocentric chromosomes of group D (13, 14, 15) and group G (21 -22) at the centromere site or close to it, followed by the cross connection of products. In this type of translocation, the short arms of the chromosomes are lost, and the long arms connect in the centromere, forming a single chromosome.  Balanced Robertsonian translocation - the amount of genetic material does not change, but there is a change in its location in the genome. The total number of chromosomes in the human genome is then 45; such person is considered a balanced translocation carrier with no clinical symptoms.  Unbalanced Robertsonian translocation - the amount of genetic material is increased by an additional copy of a translocated chromosome or its fragment. The total number of chromosomes in the human genome is then 46 phenotypic disorders, e.g. Down syndrome occurs due to a translocation between the chromosomes of group D and the chromosome 21. Duplication - involves doubling a specific segment of the chromosome; presence of an additional copy of a chromosome fragment. Deletion = deficiency - loss of the chromosome segment; if the detached fragment does not contain a centromere, it is eliminated during cell division.  Terminal deletion - a deletion that occurs towards the end of a chromosome (lost part is at the end of a chromosome);  Intercalary deletion - a deletion that occurs from the interior of a chromosome;  Micro-deletion - a relatively small amount of deletion. Micro-deletion is usually found in children with physical abnormalities. A large amount of deletion would result in immediate abortion (miscarriage). Inversion - occurs as a result of breaks in two places of a chromosome, when the separated parts of a chromosome are reversed by 180o and re-incorporated into a chromosome. When the inversion includes a centromere, it is called the pericentric inversion, and when it does not include a centromere - the paracentric inversion. Insertion - insertion of a fragment of a chromosome into a different place of the same chromosome or other chromosome. Ring chromosome - is formed as a result of two breaks in the distal sections of both arms of a chromosome, followed by the connection of the ends of a chromosome. Dicentric chromosome - is usually formed as a result of translocation and contains two centromeres. Isochromosome - structural rearrangement within a chromosome due to the division of a chromosome along an axis perpendicular to the normally occurring axis of division; this leads to the formation of chromosomes with either two long or two short arms. Philadelphia chromosome, Philadelphia translocation (Ph) - is the result of a reciprocal translocation between the long arms of chromosomes 9 and 22. It occurs in over 95% of chronic myeloid leukemia cases; Philadelphia chromosome is also found in acute lymphoblastic leukemia. Table 3. Examples of structural aberrations. Deletion Duplication Inversion Translocation Ring chromosome Isochromosome Example of structural aberration of chromosomes Cri du chat syndrome is caused by the deletion of part of the short arm of chromosome 5. The condition affects 1 in 37,000 to 50,000 live births. It is more common in females by a 4:3 ratio. Possible karyotypes of a person with cri du chat syndrome are: 46,XX,5p- or 46,XY,5p-, as well as 46,XX,del(5p) or 46,XY,del(5p). Symptoms of cri du chat syndrome include:  low birth weight and delayed growth  hypotonia  short fingers  microcephaly (small head)  unusual facial features which may change over time - round, asymmetrical face and micrognathism (undersized jaw) in newborns; in older children, the jaw grows and the facial part is prolonged  prominent frontal eminence (tuber frontale)  small, low-set, dysplastic auricles (visible part of the ear)  flat nasal bridge  short philtrum  ocular hypertelorism, epicanthal folds  small, receding chin  down-turned mouth  hypoplasia of the larynx and the entire vocal apparatus (the larynx is small and flaccid)  crying reminiscent of a cat meowing  excessive drooling  feeding problems because of difficulty in swallowing and sucking  severe cognitive, speech, and motor delays  intellectual disability to varying degrees  behavioural problems, such as hyperactivity, aggression, tantrums, and repetitive movements  impairment of the functioning of many internal organs: there may be problems with the heart, kidneys and genitourinary system Numerical aberrations of chromosomes are the result of nondisjunction, which can be defined as a lack of separation or uneven separation of homologous chromosomes (during meiosis) or sister chromatids (during mitosis), resulting in their uneven segregation into daughter cells. The meiotic nondisjunction usually occurs in the maternal gamete, during oogenesis (90% of cases), and the nondisjunction rarely occurs during spermatogenesis. The nondisjunction is associated with the mother's age (age effect) - in women between 20 and 29 years of age the risk is constant, while after the age of 30, the risk of nondisjunction successively increases with the mother's age. The age-related risk is the same for women who have previously given birth to a child, as well as for women for whom it is the first pregnancy. The nondisjunction may occur as a result of: - depolarization of the meiotic spindle, - premature segregation of sister chromatids, - spontaneous nondisjunction, - stimulation with radiation, - disturbance of repair systems during cell divisions, - lack of kinetochore tension. The course of the nondisjunction during the first and second meiotic division is shown in Figure 5. A B C Figure 6. Diagram of the meiotic nondisjunction process: A. correct meiosis; B. nondisjunction in the first meiotic division; C. nondisjunction in the second meiotic division. A specific form of chromosomal aberrations is mosaicism. It occurs after fertilization, during the first divisions of the zygote as a result of the nondisjunction during the mitotic division. In 1/2500 pregnancies, small additional chromosomes of unclear origin are also found, which are referred to as marker chromosomes. In 90% of cases they are fragments of the short arms of acrocentric chromosomes (mainly chromosome 15). They are identified by molecular cytogenetic methods, e.g. FISH. Numerical aberrations include:  aneuploidy: - nullisomy – lack of chromosomes from a given pair (2n-2), - monosomy – lack of one chromosome from a given pair (2n-1), - trisomy – an additional chromosome from a given pair (2n+1), - tetrasomy – two additional chromosomes from a given pair (2n+2);  euploidy / polyploidy - the presence of more than two complete haploid sets of chromosomes (triploidy-3n, tetraploidy4n, octaploidy-8n). Full monosomy of autosomal chromosomes in a human is always lethal. Whereas, the full trisomy of autosomal chromosomes occurs postnatally only within small acrocentric chromosomes. It was found that the frequency of autosomal trisomy at birth is inversely proportional to the activity of natural selection in utero (in the uterus). If polyploidy (most often triploidy) occurs, there is usually a miscarriage. Individual cases of live birth of a child with karyotype 69,XXX or 69,XXY have been described; newborns had multiple developmental defects and dysmorphic features. A child with triploidy usually dies within 1 day, but it is possible to survive up to one year - single cases have been documented in the medical literature. Cells with heteroploidy / polyploidy, which arises from asymmetric mitotic divisions, are often used in scientific experiments. Such cells are for example HeLa tumour cells being a line of human epithelial cells originating from the cervix, which underwent neoplastic transformation as a result of human papillomavirus infection HPV 18. This cell line derived from cervical cancer cells taken in 1951 from Henrietta Lacks without her consent. HeLa cells are considered immortal because they are capable of infinite number of mitotic divisions. They are cultured in many laboratories continuously since their collection. The line karyotype is diverse. HeLa cells have, among others mutated gene for glucose6-phosphate dehydrogenase (G6PD, G6PDH). The line is characterized by a remarkably fast growth, surpassing other cancer cell lines. Currently, the total mass of HeLa cells significantly exceeds the body weight of the patient from whom the sample was taken. It is the oldest human artificially maintained in vitro tissue culture and it is a convenient object of research on tumours, protein synthesis, and mutations. The second known cell line is NK-Ly cells (Nemeth-Kellner Lymphoma) derived from lymphoma in mice. It was developed in 1961 by an intraperitoneal inoculation of leukemia cells from the spleen of an old inbred mice with spontaneous leucosis to a newborn mouse and a subsequent transplantation of developed tumour as ascites, thereafter as a solid tumour. In the past, the usefulness of this tumour model in testing anti-tumour activity of different chemical substances was confirmed by numerous investigations. However, nowadays it is rarely used in experimental oncology. Based on epidemiological studies, the incidence of chromosomal aberrations in newborns was determined. It has been found that different types of aberrations occur at different rates. Autosomal aberrations and unbalanced rearrangements occur at a frequency of 1: 230; most often these are trisomies of chromosomes: 21 - 1:700; 18 - 1:6000 and 13 - 1:10000; unbalanced rearrangements occur less frequently - 1:17000. Balanced rearrangements are found with a frequency of 1:500; including the Robertsonian translocations occurring in 1:1000 cases, and the reciprocal translocations - 1:11000 births. Aberrations of heterosomes are found in individuals with the karyotype: 47,XXY in 1:1000 male newborns; 47,XYY in 1:1000 male newborns; 45,X - 1:5000 female newborns and 47,XXX - 1:1000 female newborns (according to Jorde et. al. 2016). Examples of disease entities associated with chromosomal aberrations are described in Table 4. Table 4. Examples of chromosomal aberrations in human. Name of a disease entity Typical karyotype/ karyotypes Basic clinical symptoms/ dysmorphic features Numerical aberrations of heterosomes Turner syndrome 45,X Short stature, rudimentary ovaries, poorly developed nipples, underdevelopment of secondary sexual characteristics, primary amenorrhea (lack of menstruation) Klinefelter syndrome 47,XXY Female type silhouette, gynaecomastia, testicular dysgenesis, atrophy of seminiferous tubules (no spermatogenesis) XXX syndrome 47,XXX normal phenotype XYY syndrome 47,XYY normal phenotype Numerical aberrations of autosomes Down syndrome 47,XX,+21 Epicanthal fold, large fissured tongue, Brushfield 47,XY,+21 spots on the iris, hypotonia, mental retardation translocations of chromosome 21 with other chromosomes Edwards syndrome Patau syndrome 47,XX,+18 Numerous congenital malformations, mental 47,XY,+18 retardation 47,XX,+13 Numerous congenital malformations (especially of 47,XY,+13 CNS and vision organs), mental retardation Structural aberrations of autosomes Cri du chat syndrome Prader–Willi syndrome Philadelphia syndrome 46,XX,del5p hypoplasia of the larynx, facial abnormalities, mental 46,XY,del5p retardation 46,XX,del15q hypotonia, 46,XY,del15q retardation t(9:22)(q34:q11) chronic myeloid leukemia or acute lymphoblastic leukemia hypogonadism, obesity, mental Examples of numerical aberrations of heterosomes (Sex chromosomes, allosomes) 1. Turner syndrome Turner syndrome (Ullrich–Turner syndrome, Bonnevie–Ullrich–Turner syndrome, Gonadal dysgenesis) is a monosomy of X chromosome and occurs in 1:2000 – 1:3000 female newborns. Possible karyotypes of a person with Turner syndrome are:  45,X - classic monosomy (50-60% of cases)  45,X/46,XX - mosaicism or 'Turner mosaicism' (20-30% of cases)  46,X,i(Xq) - isochromosome (5-13% cases)  45,X/46,XX/47,XXX and 45,X/47,XXX - other mosaic karyotypes (7% of cases)  46,X,del(Xp) or 46,X,del(Xq) (