What is a chromosomal aberration? | Chromosomes

What is a chromosomal aberration?

The structural chromosomal aberration basically corresponds to the definition of chromosomal mutation (see above). If the amount of genetic material remains the same and is only distributed differently, this is called a balanced aberration. This is often done by translocation, i.e. the transfer of a chromosome segment to another chromosome.

If this is an exchange between two chromosomes, it is called reciprocal translocation. Since only about 2% of the genome is needed to produce proteins, the probability that such a gene is located at the breakpoint and thus loses its function or is impaired in it is very low. Therefore, such a balanced aberration often goes unnoticed and is passed on over several generations.

However, this can lead to a maldistribution of chromosomes during the development of the germ cells, which can result in infertility, spontaneous miscarriage or even offspring with an unbalanced aberration. An unbalanced aberration can also occur spontaneously, i.e. without a family history. The probability that a child with unbalanced aberration will be born alive depends strongly on the chromosomes affected and varies between 0 and 60%.

This results in the loss (= deletion) or doubling (= duplication) of a chromosome segment. In this context one also speaks of partial mono- and trisomies. In some cases these occur together at two different regions, whereby the partial monosomy is usually more decisive for the occurrence of clinical symptoms.

Prominent examples of a deletion are the cat cry syndrome and the wolf deer horn syndrome. One speaks of a microdeletion if the change can no longer be detected with the light microscope, i.e. if it is the loss of one or a few genes. This phenomenon is considered to be the cause of the Prader-Willi syndrome and the Angelman syndrome and is strongly related to the development of the retionoblastoma.

A special case is the Robertson translocation: Here two acrocentric chromosomes (13, 14, 15, 21, 22) unite at their centromere and form a single chromosome after the loss of the short arms (see structure). Although this results in a reduced number of chromosomes, it is called a balanced aberration, because the loss of the short arms can be compensated for well with these chromosomes. Here, too, the effects are often only noticeable in the following generations, as there is a very high probability of miscarriages or living children with a trisomy.

If there are two breaks within one chromosome, it is possible that the intermediate segment is inserted into the chromosome rotated by 180°. This process, known as inversion, is only unbalanced if the break is within an active gene (2% of the total genetic material). Depending on whether the centromere lies inside or outside the inverted segment, it is a peri- or paracentric inversion.

These changes can also contribute to the uneven distribution of the genetic material to the germ cells. Paracentric inversion, where the centromere is not in the inverted segment, can also result in germ cells with two or no centromere. As a result, the corresponding chromosome is lost during the very first cell divisions, which almost certainly leads to miscarriage.

Insertion refers to the insertion of a chromosome fragment at another location. Here, too, the offspring are primarily affected in a similar way. A ring chromosome can occur in particular after a deletion of the end pieces.

The type and size of the sequences are decisive for the severity of the symptoms. In addition, this can lead to maldistribution and thus to mosaic types within the body cells. If the metaphase chromosome separates incorrectly during cell division, isochromosomes may result.

These are two exactly identical chromosomes that consist only of long or only of short arms. In the case of the X chromosome, this can manifest itself as an Ulrich Turner syndrome (monosomy X). Trisomy 21, better known as Down syndrome, is probably the most common numerical chromosomal aberration among live births, with the male sex being affected slightly more frequently (1.3:1).

The likelihood of the occurrence of trisomy 21 depends on various demographic factors, such as the average age of mothers at birth, and varies slightly from region to region. Trisomy 21 occurs in 95% of cases as a result of a division error in meiosis (germ cell division), namely nondisjunction, i.e. the failure to separate the sister chromatids. These are known as free trisomies and are produced in 90% of cases in the maternal, 5% in the paternal and a further 5% in the embryonic genome.

A further 3 % are caused by unbalanced translocations either on chromosome 14 or as a 21; 21 translocation, resulting in a normal and a double chromosome 21. The remaining 2% are mosaic types in which the trisomy was not formed in germ cells and therefore does not affect all body cells. Mosaic types are often so mild that they can remain completely undetected for a long time.

In any case, a chromosomal examination should be performed to distinguish the symptomatically identical free trisomy from the possibly inherited translocation trisomy. A family anamnesis of the previous generations can then be performed. Trisomy 13 or syndrome has a frequency of 1:5000 and is much rarer than Down syndrome.

However, the causes (free trisomies, translocations and mosaic types) and their percentage distribution are largely identical. Theoretically almost all cases could be diagnosed prenatally by ultrasound or PAPP-A-test. However, since the PAPP-A test is not necessarily a routine examination, about 80% of cases in Central Europe are diagnosed before birth.

Already in the ultrasound, a growth retardation, a bilateral cleft lip and palate and unusually small eyes (microphthalmia) can be detected. In addition, malformations of the forebrain and face of varying severity are usually present (holoprosencephaly). While in the lobar form the separation of the cerebral hemispheres is almost complete and lateral ventricles are created, in the semilobar form often only the posterior part of the brain is separated and the lateral ventricles are missing.

In the most severe form, the alobaric form, there is no separation of the cerebral hemispheres at all. Infants with the semi- or alobaric form usually die immediately after birth. After one month the mortality rate is about 50% of live births.

By the age of 5, the mortality rate increases to 90% for trisomy 13. Due to the malformations in the brain, in most cases patients remain bedridden and unable to speak for the rest of their lives, which is why they are dependent on complete care. In addition, extensive physical manifestations of Trismoie 13 can also occur.

Basically, trisomy 16 is the most common trisomy (about 32% of all trisomies), but living children with trisomy 16 are very rare. In general, live births occur only with partial trisomies or mosaic types. For this reason, among trisomies, it is most frequently responsible for stillbirths: 32 of 100 miscarriages due to chromosomal aberrations are due to this trisomy form.

Therefore, mainly prenatally, i.e. prenatal, detectable features have been documented. Worth mentioning here are various heart defects, slowed growth, a single umbilical cord artery (otherwise double) and increased nuchal transparency, which is explained by fluid accumulation due to the not yet fully developed lymphatic system and the increased elasticity of the skin in this area. In addition, the physiological umbilical hernia, i.e. the temporary displacement of a large part of the intestine through the navel to the outside, often does not regress properly, which is called omphalocele or umbilical cord hernia.

A flexion contracture with crossed fingers can also often be detected by ultrasound. In the few live births a generalized muscle hypotonia, i.e. a general muscle weakness, is conspicuous. This leads to a weakness in drinking and can mean that the infant has to be artificially fed.

The four-finger furrow, which is so characteristic of trisomies, also occurs frequently. Here too, the frequency of trisomy occurrence is directly related to the mother’s age. Edwards syndrome, trisomy 18, occurs with a frequency of 1:3000.

Prenatal diagnosis is similar to that of syndrome: Here, too, the same examinations would make it possible to find all the affected individuals before birth. The causes and their distribution can be compared with other trisomies (see trisomy 21). In addition, partial trisomies also occur in trisomy 18, which, like the mosaic types, lead to considerably milder clinical courses.

The associated dysmorphia are also extremely characteristic in Edwards syndrome: Patients already have a strongly reduced body weight at birth with 2 kg (normal: 2.8-4.2 kg), a receding broad forehead, a generally underdeveloped lower half of the face with a small mouth opening, narrow eyelid crevices and backward rotated ears of changed shape (faunal ear). In addition, the back of the head, which is unusually strongly developed for a newborn, is conspicuous. The ribs are unusually narrow and fragile.

Newborns also have a permanent tension (tonus) of the entire musculature, which, however, recedes in the survivors after the first weeks. Also characteristic is the crossing of the 2nd and 5th fingers over the 3rd and 4th when the fingers are all impacted, while the feet are unusually long (elapsed), have a particularly pronounced heel, atrophied toenails and a set-back big toe. Severe organ malformations are common and usually occur in combination: Heart and kidney defects, malfolding (malrotation) of the intestine, adhesions of the peritoneum (mesenterium commune), a closure of the oesophagus (oesophageal atresia) and many others.

Due to these malformations, the mortality rate is about 50 % within the first 4 days, only about 5-10 % will live beyond one year. Survival into adulthood is the absolute exception. In any case, an intelligence reduction is very pronounced and cannot speak, are bedridden and incontinent, i.e. completely dependent on outside help.

  • Trisomy 18 (Edwards Syndrome)
  • Trisomy 18 in the unborn

Trisomy X is the most inconspicuous form of numerical chromosomal aberration, the appearance of the affected persons, who are logically all female, does not differ greatly from other women. Some of them are conspicuous because they are particularly tall and have somewhat “plump” facial features. Mental development can also be largely normal, ranging from borderline normal to mild mental retardation.

However, this intelligence deficit is somewhat more severe than in the other trisomies of the sex chromosomes (XXY and XYY). With a frequency of 1:1000, it is actually not that rare. However, since trisomy is usually not accompanied by clinically significant symptoms, a large proportion of women with the disease will probably never be diagnosed in their lifetime.

Carriers are usually discovered by chance during a family clarification or prenatal diagnosis. Fertility may be slightly reduced and the rate of sex chromosomal aberrations in the subsequent generation may be slightly increased, so that genetic counselling is recommended if you wish to have children. As with the other trisomies, trisomy X is most frequently caused as a free trisomy, i.e. by a lack of division (nondisjunction) of the sister chromatids.

Here, too, it usually occurs during the maturation of the maternal egg cells, whereby the probability increases with age. Fragile X syndrome or Martin Bell syndrome is more common in men, as they have only one X chromosome and are therefore more affected by the change. Among the male live births of a year it occurs with a frequency of 1:1250 and is therefore the most frequent form of unspecific mental retardation, i.e. of all mental disabilities that cannot be described by a specific syndrome with typical signs.

Fragile X syndrome can also occur in girls, usually in a somewhat weaker form, which is due to the accidental inactivation of one of the X chromosomes. The higher the proportion of the switched-off healthy X chromosome, the more severe the symptoms. Mostly, however, women are carriers of the premutation, which does not yet cause clinical symptoms, but massively increases the probability of full mutation in their sons.

In very rare cases, men can also be carriers of the premutation, which they can then pass on exclusively to daughters, who are usually also clinically healthy (Sherman paradox). The syndrome is triggered by an extremely increased number of CGG triplets (a certain base sequence) in the FMR gene (fragile-site-mental-retardation). Instead of the 10-50 copies, the premutation contains 50-200 copies, and 200-2000 copies when fully developed.

Under the light microscope, this seems like a fracture in the long arm, which gave the syndrome its name. This leads to the switching off of the affected gene, which in turn causes the symptomatology. Affected persons show a slowed development of speech and movement and can show behavioural abnormalities that can go in the direction of hyperactivity, but also autism.

Purely external abnormalities (dysmorphic signs) are a long face with prominent chin and protruding ears. With puberty, strongly enlarged testicles (macroorchidia) and a coarsening of the facial features often occur. Among female carriers of the premutation there is a slight accumulation of psychological abnormalities and a particularly early menopause.