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.
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.
