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Chromosomal Aberrations - a Generic Backlog

Chromosomal Aberrations - a Generic Backlog

Posted By Rupa Jaiswal Posted on Oct 29, 2021

Parents go through different emotions when their child is born with a disability. But the emotion that remains most importantly, in the midst of tests and uncertainties is the beautiful joy of having a baby.

Chromosomal Aberrations - a Generic Backlog

Globally, around 76 lakhs children are born every year with severe genetic or congenital malformations. Ninety percent of them are born in mid to low income countries. It is difficult to give a precise data for a developing country like India, where most of the cases are not reported or remain undiagnosed.

A high prevalence of genetic disorders is observed in particular communities because of their cultural and social factors. The tradition of consanguineous marriage is one such factor which results in higher rate of conditions like mental retardation, stillbirths and congenital malformations.

Also, the age of women being more than 35 years is also associated with higher rates of chromosomal abnormalities in the child." Chromosomal abnormalities are one of the important biological consequences of exposure to ionizing radiations and other genotoxic agents.

Chromosomal abnormalities can be of variable severity, from requiring continuous management throughout the life to being fatal before birth.

Chromosomes and Their Abnormalities Chromosomes are structures found in our cells that hold the genes. Normally humans have 23 pairs of chromosomes, making it 46 chromosomes in total. One set of each of the 23 chromosomes in a human cell is inherited from the biological father and the biological mother.

Chromosomal aberrations are a group of anomalies resulting in the change of structure or number of chromosomes. Most chromosomal aberrations are created randomly during gamete formation i.e., when the egg and sperm are formed, or during the early developmental stages of the fetus. There are various types of chromosomal

Numerical aberrations More or fewer number of chromosomes than normal lead to numerical aberrations in the chromosome. This is also called as aneuploidy, as opposed to euploidy where in the cell contains normal number of chromosomes.

Monosomy When an individual is missing one chromosome from a pair of chromosomes, it is called as monosomy. For example, Turner's syndrome is caused by one missing or incomplete X-chromosome. This happens due to non- dysjunction, when a pair of chromosome fails to separate during sperm or egg formation. A sperm with no chromosome unites with a normal egg, to form an embryo with only one X chromosome, rather than XX. Individuals with Turner's syndrome develop as females; they have traits of a female, but since both X chromosomes are required for growth and sexual development, they have short frame and incomplete sexual characteristics. It does not affect intelligence of the person.

Trisomy When an individual has three copies of a chromosome instead of two, it is called as trisomy. Down syndrome is a result of trisomy of chromosome number 21; a person with Down syndrome has an extra copy of chromosome hence Down syndrome is also called as trisomy 21. Because of the extra chromosome, each of its genes have three copies instead of two. Both, the elevated expression of genes located on chromosome 21 and the imbalance in the proportion of these genes to the genes on other chromosomes are possible mechanisms behind the phenotypic characteristics of Down syndrome. Production of too much or too little proteins has serious consequences. People with this disorder have distinct facial features like flat face, broad nose, a large tongue, and upward slanting eyes. They have moderate to severe intellectual disabilities. People with Klinefelter Syndrome have an extra 'X' chromosome (47, XXY). The distinctive features include intellectual disability, poor coordination, reduced facial and body hair, and severe speech problems. Most of the males with this condition produce little or no sperm and may suffer from infertility.

Structural aberrations chromosome's structure can be altered in different ways such as due to chromosomal breaks and incorrect rejoining that occur during meiosis. Deletions, duplications, insertions, inversions and translocations can affect the integrity of important genes which can result in disease causing abnormal phenotypes.

Deletions A portion of the chromosome segment is deleted or missing. The consequences of this deletion depend on the size of the chromosomal segment missing and the genes on it. For example, a deletion in the short arm chromosome 5 is responsible for "Cri-du-Chat" syndrome, referring to the distinct cat-like cry of a child with this disorder. The child may have abnormal larynx development and suffer from respiratory problems skeletal problems, poor muscle tone heart defects hearing and vision problems. example .

Duplication When a segment of chromosome is copied or doubled, it is called as duplication or sometimes, partial trisomy. It may lead to congenitial deformations or developmental problems. For example, Charcot-Marie-Tooth disease type 1A, is caused by gene duplication of chromosome 17. This is a neurological disorder that affects the peripheral nerves.

Inversion When there are two breaks in a chromosome, and the fragment gets inverted and reattached onto the chromosome, it is called inversion. If the chromosome with an essential function breaks off, the breakpoint may lead to a lethal gene mutation. Inversions that include centromere with a breakpoint at each arm of the chromosome are called pericentric inversions. Whereas those which do not include centromere and the break occurs at one of the arm are called paracentric inversions.

Insertion When genomic arrangements occurs in a way where a A chromosome segment is inserted into a non homologous chromosome, it is called insertion. The chromosome segment may also be inserted into a nonadjacent locus on the same chromosome or the other homologous chromosome. Such aberrations can be balanced and can remain in the somatic cells, and get transmitted to several cell generations.

Translocation It occurs when a portion of a chromosome is excised and reattached to some other chromosome or occasionally to its homologue or somewhere else in the same chromosome. The phenotypic effects of these insertions are generally inconspicuous during mitosis, as the chromosome segment is not lost and can be transmitted for many cell generations. But the consequences can be devastating during meiosis. Translocations can be of 2 types:

a) Reciprocal Translocation Occurs when two segments of non-homologous chromosomes are interchanged. It is a relatively frequent anomaly with an incidence of 1:500. These types of translocations are usually balanced as the amount of entire genetic material remains the same. But it can create problems during gamete formation, because chromosomes in the region of translocation cannot readily pair, as the pair of chromosomes would not be completely homologous to each other.

b) Robertsonian Translocation When the whole long arm of (acrocentric) chromo some attaches itself to the long arm of another at its centromere, to form a single large chromosome with two long arms and one centromere. It is another frequent anomaly with the occurrence of 1:1000.' It is also called as centric fusion of two acrocentric chromosomes. In this specialised translocation, the very short, satellite-bearing arm of the acrocentric chromosome is lost and a centric fusion occurs between the remaining long arms. In humans, Robertsonian translocations occur in the five acrocentric chromosome pairs, namely 13, 14, 15, 21 and 22.

Today, it is a well known fact that unbalanced translocations lead to pathological disorders related to proto-oncogenes. These genes when not mutated, are responsible for normal growth and proliferation of cells, but can be transformed to oncogenes through these balanced translocation events. These oncogenes are responsible for formation of many types of tumours and cancers. For example, a reciprocal translocation between the long arms of chromosome 9 and 22 leads to conversion of a protooncogene to an oncogene which is responsible for chronic myeloid leukemia.

Isochromosomes These are formed when an arm of a chromosome is lost and is replaced by an exact mirror image of the remaining arm. This usually happens in the X-chromosome when it is divided not along its length but transversely. This results in isochromosomes with either two short arms or two long arms. Isochromosomes are usually seen in Turner's Syndrome.

Rings The ends of the chromosomes sometimes break off and are lost, and the rest of the chromosomes form an individual circular structure as the arms fuse together. This may happen with or without loss or gain of genetic material.

Causes of Chromosomal Aberrations' The causative factors of different chromosomal aberrations can be failed cytokinesis leading to aneuploidy, nondysjunction or premature separation of chromosomes leading to aneuploidy, and chromosome breakage leading to structural rearrangements. A variety of internal and external factors come into play to produce chromosomal aberrations like temperature shock and chemical agents to interfere with cytokinesis or spindle fiber formation. Chromosomal abnormalities in humans are also attributed to X-ray exposure of the mother, parental metabolic impairment, delayed fertilization and dietary deficiencies.

Clinical Indications Prenatal Diagnostic testing for chromosomal aberrations should be done considering following factors:
Elderly primigravida
Bad obstetric history
Repeated miscarriages
Recurrent pregnancy loss
Couple infertility
Structural aberrations in previous Pregnancy
Positive serum screening
Viral infections
Delayed developmental milestones
Positive NIPT result
Family history

Diagnosis Visible changes in the chromosomal structure and morphology are crucial indicators of genetic damage in both clinical and cancer studies. There are various invasive and non-invasive techniques of prenatal diagnosis available to determine the health and condition of a newborn. Chorionic villi sampling and amniocentesis (invasive test) are few sampling techniques for prenatal diagnosis of chromosomopathies. Maternal blood sampling (non-invasive test) is done to analyse the fetal blood cells that enter the maternal circulation through the placental villi.

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Fluorescent In Situ Hybridisation (FISH) is one of the techniques that can be used to diagnose aneuploid conditions such as trisomies and monosomies. Interphase FISH and quantitative fluorescence polymerase chain reaction (QF PCR) are some of the efficient tools for rapid prenatal diagnosis of selected aneuploidies. The results of these techniques are generally followed up with a Karyotype analysis.

A more recent method for rapid analysis of chromosomal abnormalities is high resolution array Comparative Genomic Hybridization (aCGH). This technique uses chip technology to identify genetic causes of dysmorphic features, mental retardation, developmental delays, multiple congenital abnormalities.

Techniques like FISH and Single Nucleotide Polymorphism (SNP) based arrays, PCR based screenings and copy number measurements can provide the genomic data for prediction of neoplastic disorders that are inheritable.

For all chromosomal aberrations, parental chromosome status should be examined. People who are carriers of balanced translocations can be found very frequently in certain sects of the population. Mostly, such carriers are phenotypically inconspicuous and healthy, but it is imperative that they check their genomic status and examine the possibility of their offspring to have chromosomal aberrations. A pre-conceptional and then prenatal diagnosis is advised, followed by genetic counselling in such cases.

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