Ley Estatal de Mediación del Estado de Puebla.

In this condition, the structure of one or more chromosomes is changed. The

initial event is chromosome breakage which produces two unstable sticky ends. With an

improper repair process, an abnormal structure of the chromosome results. There are

many possible structural aberrations such as:

Translocation A translocation is the transfer of chromosome material between

two non-homologous chromosomes. This requires breakage of both chromosomes with

the exchange of part of the chromosome between them. Usually there is no loss or gain

of DNA in the genome and this is called a balanced translocation. The affected person is

clinically normal but has a higher risk of producing abnormal gametes, resulting in

reproductive problems. In a reciprocal translocation the chromosome material distal to

the breaks in the two chromosomes is exchanged. This event results in twelve possible

gametes, only one of which is normal, one will carry the balanced translocation and the

rest carry various imbalances which can cause abortion, stillbirth, mental retardation

and multiple congenital anomalies in the offspring. In a Robertsonian translocation,

which involves two acrocentric chromosomes, the breakage takes place at or near the

centromere of each chromosome and the acentric fragments will usually be lost.

However, as this segment often carries only satellites from both original chromosomes,

the individual will suffer no effect. Again, the problem is with gametogenesis of that

individual. There are six possible gametes, one of which is normal, one balanced, and

the other four with varying degrees of unbalanced gametes. A number of trisomie

patients have a parent with a balanced translocation.

P om p im ol R uangvutilert Chapter 1 Introduction

deletions, mental handicap and multiple congenital malformations are usual. Examples

are cri-du-chat syndrome and Wolf-Hirschhom syndrome which are deletions of the

short arm o f chromosomes 5 and 4, respectively.

Deletions of a size that cannot be detected with the light microscope are termed

microdeletions. Some of these involve loss of a few genes at closely adjacent loci,

giving rise to several disorders in the individual. These conditions, such as WAGR

(Wilm’s tumour. Aniridia, Genitourinary malformations, and Retardation of growth and

development), a microdeletion of chromosome llp l3 (Gessler et a l, 1989), are called contiguous gene syndromes and molecular techniques have been developed to aid their

detection (Fantes et a l, 1992).

In some deletions or microdeletions, the parental origin of the deleted region has

a significant effect and results in different syndromes. The difference in expression of

certain genes according to parental contribution is a phenomenon called genomic

imprinting. Examples are Prader-Willi syndrome and Angelman syndrome. They are

clinically different but both involve an abnormality at the same region of the long arm

of chromosome 15 (Knoll et a l, 1989). The abnormality may be a deletion, a uniparental disomy or a mutation. In Prader-Willi syndrome, clinical features arise from

the absence of the paternal contribution of this region whilst the absence of the maternal

contribution causes Angelman syndrome (Cassidy, 1995).

Ring chromosomes A ring chromosome results from breaks in both arms of a

chromosome. The terminal ends are lost and the two proximal sticky ends unite to form

a ring. The most common ring chromosome is X(r); the female carrier manifests a

Duplications These are more common than deletions and have less deleterious

effects. Tiny duplications at the molecular level (repeats) contribute to genomic

diversity. A parental carrier of balanced structural rearrangement accounts for 10-15%

o f cases o f autosome duplication/deletion.

Inversions An inversion requires two breaks in a chromosome and a repair with

the segment between the breaks rotating 180°. A pericentric inversion results when the

rotated segment contains the centromere. A paracentric inversion occurs when the two

breaks are on the same arm of the chromosome. A pericentric inversion has an

incidence of 1 in 100 livebirths. Generally, the affected person has no clinical

abnormalities but problems occur at the pairing of homologous chromosomes during

gametogenesis and may result in unbalanced gametes.

Isochromosomes An isochromosome is an abnormal chromosome which has a

deletion of one arm with a duplication of the other. It may arise from transverse division

of the centromere during cell division or from an isochromatid break and fusion above

the centromere. The commonest isochromosome in livebirths is an isochromosome of

the long arm of the X chromosome. This results in the clinical features of Turner

syndrome due to the effect of short arm deletion.

Marker chromosomes The incidence of a small additional chromosome of

unknown origin (termed a marker chromosome) is 1:3,000 in the general population

(Buckton et a l, 1985). In most o f the cases, the marker is derived from the short arms and pericentromeric regions of acrocentric chromosomes, especially chromosome 15

(Friedrich and Nielsen, 1974; Buckton et a l, 1985). Parental karyotypes should be examined and an attempt made to identify the nature of the additional chromosome

P om p im ol Ruangvutilert Chapter I Introduction