CHROMOSOMAL AND

GENE ABERRATION(Duplication, Deletion, Inversion, Translocation)

ENDAYA, DANICA FAYE M.MANGOSING VIDA FAYE S.

Introduction

Congenital abnormalities can be caused by an anomaly in the number or structure of the chromosomes. Disorders in the gametogenesis, that is, in the first and second meiotic divisions in the formation of oocytes and sperm cells, lead to such defects.

Staining method

Chromosomal mutations can be made visible with staining methods (banding techniques). Following the staining the chromosomes are analyzed using a 1000x enlargement. With this one can recognize the chromosomes as striped cords and display them in a karyogram, after they have been ordered according to their size and the positions of the centromeres. Various groups of similar chromosomes are created in this way.

Today, small aberrations are examined using a molecular cytogenetic (FISH) approach. Among other things, the FISH (fluorescence-in-situ-hybridizing) method makes possible the targeted identification of partial aneuploidies such as deletions, duplications and unbalanced translocations (see below) that cannot be resolved with a light microscope. A comprehensive array of DNA probes and techniques are today available from which one can choose for utilization, depending on the diagnostic problem being worked on. With the FISH method chromosomal alterations can be analyzed down to a size of ca. 5 million nucleotides

Origin of the deviating chromosome structure

Structural aberrations are the result of chromosomal breaks that occur during meiosis. deletion, duplication isochromosome formation lead to an abnormal

phenotype.

while; insertion inversion translocation can be balanced.

This means that the carrier of this structural chromosome aberration can escape notice phenotypically, because the entire genetic material is present.

Deletion

A deletion can happen in every chromosome and exhibit every size. The consequences of a deletion depends on the size of the missing segment and which genes are found on it.

Cri du Chat syndrome

A partial deletion on the short arm (p) of chromosome 5 is responsible for the “cri du chat" syndrome

The "cri du chat" syndrome manifests itself through cat-like crying of the newborn. This disorder is accompanied by microcephaly, severe psychosomatic and mental retardation and cardiac defects.

Duplication

A chromosome duplication is the doubling of a chromosome piece.

A duplication is sometimes termed a "partial trisomy".

If, therefore, a duplication is present, the person is equipped with 3 copies of the genes in the associated chromosome segment. This means that extra directions (genes) are present, leading to congenital abnormalities or developmental problems.

Fragile X syndrome

The fragile X syndrome results from multiple duplications of a CGG segment (trinucleotide) in the 5' untranslated region of the FMR1 gene on the X chromosome (Xq27).

Since it is an X linked mutation men are more affected than women. The fragile X syndrome leads to one of the most frequent forms of inherited mental retardation. In addition, the syndrome causes a prognathism, the face is long and small and the patient has large ears.

Inversion

If chromosome pieces that have been broken out become inserted again, but reversed, an inversion has occurred.

The phenotype of this disorder is usually unobtrusive, since the entire chromosomal information is still present.

When the interchanged region includes the centromere, one refers to it as a pericentric inversion,

otherwise to a paracentric inversion

Insertion

If chromosome pieces are reinserted somewhere else, this is referred to as an insertion. Carriers of such insertions can be phenotypically inconspicuous because no information has been lost.

Isochromosomiebildung

Isochromosome formation is a relatively frequent chromosomal aberration, mainly in X chromosomes. Here the chromosomes are not divided along their length (see the normal division of the chromosomes figure) but transversely.

The resulting isochromosomes (karyogram) either have two short or two long arms. Persons with this X chromosome anomaly have the same phenotype as patients suffering from Turner's syndrome (45, X0). This is explained by the fact that a X chromosome arm is missing.

Normal division of the chromosome

Isochromosome formation

Reciprocal translocation

In a reciprocal translocation two broken off chromosome pieces of non-homologous chromosomes are exchanged. This is a relatively frequent anomaly. One finds it with an incidence of 1:500 newborns.

Reciprocal translocations are frequently balanced because the entire genetic material is present. Problems occur, though, in gamete formation.

Cancer and Tumors

Today it is known that balanced translocations can also lead to pathogenic disorders in that proto-oncogenes, which as normal genes in their customary environment are frequently responsible for the controlling cell proliferation, can be transformed into oncogenes through translocation events. They are the cause for the origin of many tumors and types of cancer because in other environments they achieve totally different effects.

Robertsonian translocation Another frequently observed

anomaly (1:1'000 newborns) is the robertsonian translocation, which occurs between two acrocentric chromosomes of groups G and D. It is also referred to as the centric fusion of two acrocentric chromosomes.

Carriers of such robertsonian translocations are phenotypically inconspicuous. Also here, though, problems arise when it comes to gamete formation because, normally, the diploid chromosome set is halved thereby.

END