As we know, cytogenetics is the study of chromosomal structure and behavior by using different staining techniques. In the year 1962, Lejeune proved Waardenburg’s hypothesis (the cause of Down syndrome could be a chromosomal aberration) by reporting the first case of syndrome due to chromosomal aberrations. It was a major breakthrough in cytogenetics research.[2]

With the discovery of the chromosome and related syndromes, researchers wanted to dive deep into the structural and behavioral details of chromosomes. The introduction of cytogenetics helped researchers to study the chromosomes by using color technologies. Later, research advancement bifurcated cytogenetics into molecular and clinical cytogenetics. Molecular cytogenetics refers to the study of chromosomes at the molecular level whereas clinical cytogenetics deals with the study of chromosomal aberrations and related disorders.

After the first report of Down’s syndrome, it didn’t take long to detect several other syndromes due to chromosomal aberrations. Clinical cytogenetics became a very crucial field to study these diseases and their treatments. Different techniques were developed to study chromosomal aberrations such as Karyotyping, fluorescent in situ hybridization (FISH), Combined genomic hybridization (CGH), and Multiplex-Fluorescent in situ hybridization(M-FISH).[2]

In this article, we will study variant chromosomal syndromes/diseases (for example, Down’s syndrome and turner’s syndrome) due to different chromosomal aberrations (for example aneuploidy and polyploidy), and represent the different techniques that are used to study these diseases.


Clinical Cytogenetics

Clinical cytogenetics is the branch of cytogenetics that deals with the study of diseases due to chromosomal abnormalities to find the medication of different genetic disorders. It is a major area of concern for researchers, as it is difficult to prevent and find a cure for genetic disorders.

Few categories[2] of chromosomal aberrations are given below:

  1. Autosomal aneuploidy
  2. Structural chromosome rearrangements
  3. Sex chromosomal disorders
  4. Infertility
  5. Prenatal cytogenetics
  6. Chromosome instability.
  7. Spontaneous Abortion

Let’s look at the first three categories and their examples one by one, which should give you an overview of how chromosomal aberrations occur and what diseases they cause. The remaining categories are discussed in part-2 of this article.


1. Autosomal aneuploidy

Euploidy is defined as the presence of a complete set of chromosomes in an organism. Any deviation from the normal number of chromosomes in somatic cells (excluding sex chromosomes) leads to a condition called autosomal aneuploidy. Aneuploidy results in an extra (trisomy) or missing chromosome and is a common cause of genetic or birth disorders.

It is estimated that there is 0.2% chance of occurrence of autosomal aneuploidy in newborns.[2] It is also observed that the total estimation of the occurrence of autosomal aneuploidy in different chromosomes ranges between 0.26–0.34%.[2] The most common abnormalities are the result of an extra chromosome in chromosomes 21, 18, and 13. Compared to all the other chromosomes, chromosome 21 was found to have a higher frequency of about 0.29% for the occurrence of aberrations.[2] These studies were done by using cytogenetic techniques like Fluorescent in situ hybridization (FISH) and Primed in situ labeling (PRINS).

Mechanism of Aberrations

The major cause of the occurrence of aberrations in the chromosomes is Nondisjunction. It is defined as the failure of the separation of chromosomes/chromatids during Meiosis I/Meiosis II. Nondisjunction is mostly observed to occur during meiosis I. The nondisjunctions can be studied by using techniques such as FISH and M-FISH in cells undergoing division.


Trisomy, in autosomal aneuploidy, refers to the presence of three copies of a particular chromosome instead of two copies, as usual.

Example of Autosomal trisomies

Trisomy 21

Trisomy of chromosome 21 [47, XX or XY,+21], 95% of the time, causes Down’s syndrome. It was estimated that Down’s syndrome occurs more in males compared to females in a ratio of 1.2:1 (this study was done by using the multicolor FISH technique). It was also estimated that trisomy 21 in newborns is associated with maternal age. The other abnormalities due to trisomy 21 are Robertsonian translocation and mosaicism. By using the karyotype technique, the trisomy of the chromosome can be observed.[2]

The phenotype of down’s syndrome includes craniofacial appearance, flat nasal bridge, small mouth, thick lips, and protruding tongue. Hands and legs are small, having palmar crease; the child also shows short stature and mental retardation.[2]

Trisomy 18

Trisomy of chromosome 18 [47, XX or XY,+18] causes Edward’s syndrome; named after the scientist Edward whose team first described this disease. This disease is found in 1 in 6000-8000 births and is most likely to occur in females rather than males in the ratio of 1:3-4.[2]

The phenotype of Edward’s syndrome includes craniofacial dysmorphism, cardiac anomaly, mental retardation, small-mouth, and clenched hands. It is estimated that the frequency of survival of the child (with trisomy 18) for up to 1 week ranges between 25-35% and 10% or less only survive for at most one year.[2]

Trisomy 13

Trisomy of chromosome 13 [47, XX or XY,+13] causes Patau’s syndrome; named after the scientist Patau whose team first described the disease. This occurs in 1 in 12,000 births and the chances of occurrence are more in females than males.[2] It is found that the chances of occurrence of this syndrome in the fetus increase with maternal age.

The phenotype of this disease includes microcephaly, defective scalp, hernia, polydactyly, cardiac anomaly, polycystic kidneys, mental retardation, and bicornuate uterus. The chances of survival of the child (with trisomy 18) are 5% (for up to 6 months). In maximum cases, it is observed that the newborn could not survive more than 3-7 days.[2]

Structural chromosome rearrangement is defined as relocation/reordering of a part of a chromosome from its own location to the other part of the same/other chromosomes, or it can also occur due to gain or loss of a part of the chromosome. The structural rearrangements are of different types which include: deletion, insertion, inversion, translocation, isochromosome, and ring chromosome.

Mechanism of rearrangements

Chromosomal rearrangements occur due to the exchange of regions between non-sister chromatids or non-homologous chromosomes.


Examples of structural chromosome rearrangements

a. Deletions

Deletion is the loss of the genetic material of a chromosome of an organism. But, not all losses of the chromosomal region lead to abnormalities, i.e. the loss of region od short arm of the acrocentric region and the loss of the gene-poor region do not show any major abnormalities or differences in the phenotype of an organism. High resolution molecular cytogenetic techniques are needed to visualize the deleted region of a chromosome.

A few examples[2] of deletions that result in disease conditions are given below:

  1. Wolf-Hirschhorn syndrome: This condition arises due to a deletion in the short arm of chromosome 4 [4p]. The phenotype includes mental retardation, cardiomyopathy, hypotonia, growth delay, flat nose bridge, and seizures.
  2. Cri du chat syndrome: This disease occurs due to the loss of a chromosomal region from the short arm of the 5th chromosome [5p]. The phenotype includes infant crying like a cat, mental retardation, growth delay, and hypertelorism.
  3. Williams syndrome: This disease arises due to the loss of region 3 from the long arm of chromosome 7 [7q11.23]. The phenotype includes short stature, mental retardation, hypercalcemia, hoarse voice, and stellate pattern in the iris.

b. Duplication

Duplication is the gain of a region of a chromosome (an extra copy of the genomic segment) of an organism. Duplications are of two types: direct and inverted. Direct duplications are a copy of a segment of a chromosome in the same order as it exists in the normal chromosome. Inverted duplications are a copy of a chromosomal segment in the opposite/reverse order. Duplications of a segment are generally less severe than the deletion of a segment of a chromosome.

Some of the diseases that are caused due to duplication of a segment of a chromosome are listed below:[2]

  1. Beckwith-Wiedemann syndrome:  This disease occurs due to the duplication of the 15th region of the short arm of chromosome 11 [11p15.5]. The phenotype of the disease includes hypoglycemia, ear creases, macrosomia, susceptible to the tumor, and learning difficulties.
  2. Pallister-Killian syndrome: This disease occurs due to the duplication of a region of the short arm of chromosome 12 (mosaic tetrasomy) [12p]. The phenotype includes hyper or hypopigmentation, mental retardation, prominent forehead, and protruding lower lip.
  3. Potocki-Lupski syndrome: This disease occurs due to the duplication of the 11th region of the short arm of chromosome 7 [17p11.2]. The phenotype of this disease includes hypotonia, cardiac anomalies, mental retardation, abnormal behavior, and dysmorphic features.

c. Inversions

Inversion is a type of structural rearrangement in which a segment of a chromosome breaks at two places and then rejoins in opposite/reverse order. Inversions are of two types: pericentric and paracentric. Pericentric inversions involve the centromere and the inversion in the segment changes the banding pattern of the chromosome and centromeric position (two breaks on the two sides of the centromere). Paracentric inversion does not involve the centromere and the two breaks occur on the same side of the centromere.

The inversions in the chromosomes can be studied by using banding techniques (karyotype or multicolor/karyotyping). Examples of Inversions are inv(3)(p25q21), inv(5)(p13q13), and inv(2)(p12q13).[2]

Some of the disorders caused due to inversions in the chromosomes are given below:

  1. Hemophilia A: This disease occurs due to the homologous recombination between gene A (located within intron 2) and a segment of other copy of gene A (located 500 Kb telomeric position). This recombination creates a defect in factor VIII gene which is present at the long arm of the X chromosome. This causes Hemophilia A.[5]
  2. Hunter Syndrome (or mucopolysaccharidosis type II): This disease occurs due to the homologous intrachromosomal recombination between two locus of the X chromosome, which are IDS and IDS-2 loci. The recombination causes improper functioning of the enzyme iduronate-2-sulfatase that leads to a lysosomal storage disorder.[1]

d. Translocation

Translocations are the exchange of segments between two non-homologous chromosomes. It is of two types: reciprocal and non-reciprocal translocation. Reciprocal translocation is the exchange of a part of a chromosome with the other non-homologous chromosome. This generates two mutations or translocated chromosomes in one event. The non-reciprocal chromosome is a direct (one way) transfer of a part of the chromosome from one chromosome to the other.

There are two types of segregation involved in the meiosis event of heterozygote (which include translocated chromosome and normal chromosome) and they are adjacent segregation and alternate segregation. The adjacent segregation (segregation of chromosomes by the side/adjacent to the other chromosome) generates inviable products because of the presence of duplicated or deleted regions in the chromosome. The alternate segregation (segregation of chromosomes alternates to each other) generate viable products.

Robertsonian translocation

This is a type of reciprocal translocation that involves two acrocentric chromosomes. In this translocation, breaks occur near the centromere that affects the short arm of both the chromosomes. The transfer of a segment takes place between both the chromosome that generate one very large chromosome and one very short chromosome. This pattern of translocation has been seen between chromosomes 13 and 14, 14 and 21, and 14 and 15.

The abnormalities related to the translocations of chromosomes are given below:

  1. Burkitt’s lymphoma: This disease occurs due to the translocation of a region of chromosome 8 that contains the Myc gene to chromosome 14. The translocation disturbs the normal functioning of the Myc gene to control cell growth and proliferation. The overexpression of the Myc gene occurs that leads to cancer.
  2. Chronic myeloid leukemia: This is a type of cancer that occurs due to the transfer of a segment from chromosome 9 that contains the BCR gene to chromosomes 22. This translocation causes an abnormal fusion between BCR and ABL (located at chromosome 22) and causes cancer.

e. Isochromosome and ring chromosome

Isochromosome is a type of structural rearrangement of chromosomes in which the centromere is divided transversely rather than longitudinally. This way, the two copies of the chromosome arms look like mirror images of each other.

A ring chromosome is formed when two breaks occur in a chromosome, giving rise to two sticky ends that reunite to form a ring.


3. Sex chromosomal disorders

The sex chromosome (X and Y) contains hereditary information and decides the gender of an organism. The abnormalities of the sex chromosomes are less severe than the autosomal aneuploidies but are most common among living beings. It is estimated that the numerical abnormality of the sex chromosome occurs at the frequency of 1 in 500 births.

A few examples[2] of the numerical abnormality of the sex chromosome are explained below, in brief:

  1. Turner syndrome: This disease appears due to one missing X-chromosome [45, X]. The frequency of occurrence of this disease is 1 in 2500 births. The phenotype of this disease includes congenital heart anomaly, neck webbing, edema in hands and legs, and renal anomaly. An adult having this disease will have short stature,  dysmorphic features, and ovarian failure.
  2. Klinefelter syndrome: This was the first identified sex chromosome disorder. This disease results due to the appearance of an extra X chromosome. The frequency of its occurrence is estimated to be 1 in  575-1000 newborn males. The phenotype of this disease includes small testicles and penile, infertility, pear-shaped hips, gynecomastia, and decreased facial and body hair.

There are more numerical disorders of sex chromosome such as XXX, XXXY, and XXYY. All these disorders are studied by the Karyotyping technique, which helps the researcher to have a clear view of the genome of an organism and detect the numerical abnormalities.



Cytogenetic techniques are crucial in helping researchers to have a deep insight into the structure and function of the chromosome. Clinical cytogenetics provides information regarding chromosomal disorders, and the cause of the disease, and helps the doctors in genetics counseling. It is also helpful in finding the cure for the disease and to diagnose and monitoring the effects of treatments (such as in the case of cancer). There is a huge scope of evolution of this technique and the combination of high throughput technologies can provide precise and high-resolution results in the future.

So far, we looked into the structural and numerical chromosomal disorders and the diseases they cause. In Clinical Cytogenetics – Pt. 2, we discuss prenatal cytogenetics, the cause of spontaneous abortions, and how it helps in detecting diseases in the fetus, as well as in the process of genetic counseling.


  1. Bondeson, M.-L., Dahl, N., Malmgren, H., Kleijer, W. J., Tönnesen, T., Carlberg, B.-M., & Pettersson, U. (1995). Inversion of the IDS gene resulting from recombination with IDS-related sequences in a common cause of the Hunter syndrome. Human Molecular Genetics, 4(4), 615–621. DOI:10.1093/hmg/4.4.615
  2. Gersen Steven L. and Keagle Martha B. (2013). The Principles of Clinical Cytogenetics (3rd ed.), Springer, New York.
  3. Miller, M. A., & Zachary, J. F. (2017). Mechanisms and Morphology of Cellular Injury, Adaptation, and Death1. Pathologic Basis of Veterinary Disease, 2–43.e19. DOI:10.1016/b978-0-323-35775-3.00001-1
  4. Mostapha Ahmad, Silvera-Redondo C., Muna Hamdan Rodríguez (2010). Nondisjunction and chromosomal anomalies. Salud Uninorte, 26 (1): 117-133.
  5. Rosslter, J. P., Young, M., Kimberland, M. L., Hutter, P., Ketterling, R. P., Gitschier, J., and Antonarakis, S. E. (1994). Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells. Human Molecular Genetics, 3(7), 1035–1039. DOI:10.1093/hmg/3.7.1035