Pronatal

Cytogenetics

Anomaly of chromosomes

Chromosomes often succumb to changes and if that takes place in gametes it can be carried to next generations. Anomaly of chromosomes (chromosomal aberrations) can be numeric or structural. Numeric anomaly can effect a whole set of chromosomes (ploidia) or just some chromosomes (aneuploidia). That means if each chromosome is present 3 times, it is triploid, in case of 4 times portion of chromosomal set we are talking about tetraploid. Triploid and tetraploid can not integrate with life and it often occurs during spontaneous miscarriage in I. trimester of gravidity.

Structural aberration influences only part of one or more chromosomes. Outcome of structural changes is either absence of part of chromosome or its excess or its new organizational structure.

Chromosomal aberration is a vital selection factor in human reproduction. It is present in approximately 10% of sperm and 25% of mature eggs. 15 – 20% clinically identified pregnancies end by spontaneous miscarriage. Approximately half of spontaneous miscarriages carry chromosomal anomaly. Based on these facts it is assumed that many more zygotes (fertilized eggs) and early embryos do not evolve and are unable to survive first days and weeks after fertilization, because they carry a serious chromosomal change. Frequency of chromosomal anomaly lowers from fertilization of the egg towards birth and reaches some 0.5 – 1% for newborns. Frequency in case of males and females with reproductive disorders is 5 to 10 times higher, where in case of males with most severe reproductive disorder reaches 15%.

Next part relates to numeric and structural anomaly of chromosomes, which occur most frequently in relation to reproductive disorders.

Numeric anomaly of chromosomes and infertility

Klinefelter’s syndrome – 47,XXY

Males with Klienfelter’s syndrome have an additional X chromosome present in the karyotype (47,XXY instead of 46,XY) – pic. 1. The syndrome is present in frequency 1:1000 newborn males and is most commonly diagnosed chromosomal anomaly of males – with azoospermia (absence of sperm in ejaculation). Anomaly is characterized by number of clinical signs: small testicles, gynecomasty (enlarged breasts) and azoospermia with infertility. Patients with Klienfelter’s syndrome can carry other types of anomaly – for example cryptorchism (unaligned testicles), hypospady (penis fission), most often thromboembolia and osteoporosis are present, malign illnesses and lower intellect has been detected in some patients. Approximately 15% of males with Klienfelter’s syndrome have besides line 47,XXY also cell line present with normal karyotype and their clinical attributes are milder (mosaic form of syndrome). In some cases it is possible to have an own offspring using methods of assisted reproduction.

Presence of more that two gonosomes X, that is karyotype 48,XXXY or 49,XXXXY – males with Klinefelter’s syndrome are rare. Its clinical symptoms are common to anomaly described in patients with karyotype 47,XXY.

(Pic. 1) - Karyotype 47,XXY male with Klinefelter’s syndrome, who has been examined with azoospermia.

Karyotype 47,XYY

Males with an additional Y chromosome (pic. 2) have normal phenotype and sturdy body build. The frequency of presence of the chromosome is 1:1000 of newborn males, males with severe case of spermatogenesis disorder is present in 0.1 – 0.2% of cases. Fertility of patients with syndrome of additional Y chromosome is variable – from unchanged in majority of cases to infertility due to azoospermia. Threat of child being born with chromosomal aberration is minimal, because additional Y chromosome is most probably eliminated in process of spermatogenesis.

(Pic. 2) - Karyotype 47,XYY infertile male

Karyotype 47,XXX

Chromosomal anomaly with additional X chromosome (karyotype 47,XXX) occurs in about 0.1% of females. Females with this chromosomal anomaly usually have normal phenotype, but are slightly mentally retarded. Their reproductive system is not constrained, but there is an increased possibility of child being born with aneuploidia on X chromosome (missing or excessive X chromosome).

Females with more than three chromosomes (karyotype 48,XXXX or 49,XXXXX) have more severe case of intellect affect and state of mental retardation is directly linked to number of additional venereal X chromosomes.

Turner’s syndrome – 45,X

Chromosomal anomaly with missing X chromosome is most commonly present with frequency of 1:5000 – 10 000 of newborn females. Most patients have in newborn age a temporary lymph (swelling) sign on neck and legs. Clinically it can be seen in lower height (to 150 cm) and hypoplasy of inner genital organs, causing primary amenorrhea (absence of menstruation) and underdeveloped breasts. Typical findings include thick shield like chest, short neck with skin cilium and low hair line, often evolution anomaly of aorta and kidneys is present. Additional complication can be presence of tumour illnesses. Clinical picture of patients with Turner’s syndrome is variable depending upon presence of other lines with normal karyotype.

Early substitution treatment of female patients with Turner’s syndrome lowers growths deficit and passes into puberty. New methods of assisted reproduction open new possibilities to women with such disorder in achieving pregnancy with donated eggs.

Structural anomaly of chromosomes and infertility

Deletion

Deletion is name for loss of part of chromosome. Pic. 3 schematically demonstrates original chromosome (left) and next to it chromosome with deletion (right). Breaking point is marked by an arrow.

(Pic. 3) - Scheme of chromosome deletion

Missing part can be seen using luminary microscope on striped chromosomes or it can be so small that it can not be seen by eye (microdeletion). Presence of microdeletion is assumed by collection of clinical symptoms, which are typical for given case of microdeletion. Deletion – absence of genetic information is always evident on its carries. Small deletion of X chromosome have been registered in women with early menopause and some males with severe disorder of spermatogenesis deletion of part or whole long limb of Y chromosome. (Pic. 4).

(Pic. 4) - Deletion of long limb of Y chromosome

Duplikation

Duplication is represented by doubling part of chromosome. Individual with such chromosomal change has 3 copies of a gene present in appropriate duplicated section – 1 copy in normal chromosome and 2 copies in duplicated chromosome leading to physical and mental disability.

Picture 5 scheme demonstrates normal chromosome (left) and duplicated chromosome (right). Duplicated part is marked by an arrow.

(Pic. 5) - Scheme demonstrating chromosome duplication

Ring chromosome

Ring chromosome is created when linear chromosome closes into a ring. In such process it is possible that end parts of chromosome break or delete (deletion type of ring chromosome) or end parts come close to each other – associate and connect into a ring structure without loss of chromosome material (associational type of ring chromosome). Deletion type has got physical and mental effect on an individual due to loss of genetic material compared to the association type. Because during cell splitting ring chromosome behaves as unstable structure, some cells can have various numbers of copies of normal – linear chromosome and ring chromosome.

Picture 6 demonstrates scheme of linear (left) and ring chromosome (right).

(Pic. 6) - Scheme of linear and ring chromosome

Fertile females may have one X chromosome in ring form (pic. 7)), males have been found with ring form of Y chromosome.

(Pic. 7) - Ring chromosome X, detected as redundant chromosome X in a female with irregular menstrual cycle. (Missing chromosomes 2 and 18 are artificial.)

Reciprocal translocation

Reciprocal translocation represents an exchange of segments among two chromosomes. Picture 8 schematically represents balanced translocation among two chromosomes – normal chromosomes A and B (left) and chromosomes that were created by reciprocal segment exchange (right). Reciprocal translocation can be balanced – e.g. situation, where chromosomes change segments without loosing (deletion of) genetic material (pic. 9). Unbalanced type of translocation results in deletion of part of chromosome, causing physical and mental affection to its carrier.

(Pic. 8) - Schematic reciprocal translocation of chromosomes

(Pic. 9) -Balanced reciprocal translocation among chromosomes 5 and 6 (shown by arrows), that has been diagnosed in women with repeated spontaneous miscarriages.

Male or female carriers of balanced translocation (carrier) are not physically affected, but produce 4 variable types of the gametes. Fertilization of the egg cell of translocation carrier by a gamete of a partner with normal karyotype creates 4 types of embryos (pic. 10). First two types – embryos with normal karyotype and embryo with balanced translocation same as parent ensure birth of normal, healthy child. Other two types result in embryos with unbalanced karyotype, which can cause implantation failure or a spontaneous miscarriage or child is born affected. Males, carriers of balanced translocation, usually suffer with reproductive disorders – oligospermia to azoospermia (small number to absence of sperms in ejaculate.)

(Pic. 10) - Scheme demonstrating the transfer of reciprocal translocation from parent to offspring

Robertson’s translocation

Robertson’s translocation is a specific type of translocation among two acrocentric chromosomes – at creation both chromosomes break in centromeric area, its long limbs join each other into one entity and long limbs are lost (pic. 11).

(Pic. 11) - Scheme of Robertson’s translocation

Most common type of Robertson’s translocation occurring in human is translocation among chromosomes 13 and 14. Carrier of Robertson’s translocation has got 45 chromosomes and there is no physical or mental defect.

There are various forms of impact of Robert’s translocation on human reproductive abilities – in some cases fertility of the carrier is not limited, for males it can mean lower quality or suspension of spermatogenesis (pic. 12). In reproductive history of women – carriers of such type of translocation suffer from repeated spontaneous miscarriages and birth of dead or affected children.

(Pic. 12) - Male karyotype with oligospermia and Robertson’s translocation among chromosomes 13 and 14

Carrier of Robertson’s translocation creates unbalanced gametes with theoretical risk that offspring can be: 1/3 healthy with normal karyotype, 1/3 healthy carrier of same translocation as parent and 1/3 will suffer unbalanced karyotype, therefore will be affected (spontaneous miscarriages, birth of affected alive or dead child) - pic. 13.

(Pic. 13) - Scheme demonstrating the transfer of Robertson’s translocation from parent to offspring

Inversion

During inversion segment of chromosome turns by 180° in such way that this segment connects back into the mother chromosome (pic. 14). Result is that sequence of genes is altered compared to its previous succession in mother chromosome.

(Pic. 14) - Scheme demonstrating chromosome inversion

Carrier of inversion is usually not affected in its genotype. Splitting of gametes causes mutual change of parts of pair chromosomes, which in case of inversion may result in loss or excess of genetic material. Carrier of inversion has got an increased risk of reproductive losses (spontaneous miscarriages, stillborn children, children born with physical and intellectual affect).

Inversion of chromosomes is very rare, exception is inversion of chromosome 9 in area p11-q13, which is considered physiological variation.