Single-gene abnormalities, chromosomal abnormalities, and multifactorial diseases are the three primary kinds of genetic disorders. A chromosomal anomaly, also known as a chromosomal aberration, is a condition marked by structural or numerical changes in one or more chromosomes, which can impact autosomes, sex chromosomes, or both. The normal human karyotype is made up of 46 chromosomes: 22 pairs of homologous autosomal chromosomes and a set of sex chromosomes that consists of 2 X chromosomes in females or an X and a Y chromosome in males. Chromosomes provide all of the genetic information required for growth and development (around 22 to 25 thousand genes). Chromosome abnormalities are most commonly caused by a mistake in cell division (mitosis or meiosis), which can happen during the prenatal, postnatal, or preimplantation stages. Spontaneous abortions, infant deaths, neonatal death/hospital admission, deformities, intellectual disability, or a recognizable syndrome are all possible outcomes of these abnormalities. For preventative initiatives, genetic counseling, and appropriate intervention, accurate identification of these chromosomal abnormalities is important.
A chromosomal abnormality also referred to as chromosomal anomalies, chromosomal aberrations, or chromosomal disorders, is a lost, additional, or irregular part of chromosomal DNA. These can take the form of numerical abnormalities, in which the number of chromosomes is abnormally increased or decreased, or structural abnormalities, in which one or more individual chromosomes are damaged. An alteration in a chromosomal section encompassing more than one gene was previously referred to as a chromosomal mutation. When a cell divides incorrectly during meiosis or mitosis, chromosome abnormalities arise. Genetic testing can identify or confirm chromosome abnormalities by comparing an individual's karyotype, or the whole set of chromosomes, to a typical karyotype for the species.
Chromosomal Abnormality Causes
Errors in the cellular division are the foremost common explanation of chromosomal abnormalities. Humans divide their cells through mitosis or, through meiosis in sex chromosomes. Mitosis is the process by which cells duplicate their chromosomes and form daughter cells with an equivalent number of chromosomes as the parent cell. In other terms, a cell with 46 chromosomes will divide into two cells, each with 46 chromosomes that are identical. Meanwhile, meiosis comprises two rounds of cell division that allow for genetic material recombination, resulting in four sex cells with only half the number of chromosomes. Meiosis, for example, produces four distinct daughter cells, each with 23 chromosomes, from a cell with 46 chromosomes.
When a meiosis error occurs, aneuploidy can ensue. Nondisjunction is the most prevalent error, which occurs when a set of chromosomes does not properly separate, leaving one or two sex cells with an extra chromosome or one chromosome less. If a sex cell with nondisjunction fertilizes, the baby will have inherited one more or one less chromosome and may have a chromosomal abnormality.
Aneuploidy is caused by structural chromosomal abnormalities, which are less prevalent. When a portion or all of a chromosome is absent, flipped upside down, duplicated, or joined to another chromosome, structural chromosomal abnormalities occur. When this happens in a sex chromosome after meiosis, two copies or no copies of the chromosome may be present and handed down to offspring, resulting in monosomy or trisomy.
Mosaicism, which occurs when a person has two or more distinct cell lines, can cause chromosomal abnormalities. Nondisjunction in a mitotic cell division during early embryonic development can cause mosaicism. As a result, one line of cells will have a chromosomal abnormality, while the other lines will be unaffected.
Chromosomal Abnormality Types
A chromosomal abnormality might be numerical or structural, as seen in the following examples.
The normal human chromosome is made up of 23 pairs of chromosomes, giving each diploid cell a total of 46 chromosomes. Only half of these pairs are present in a typical sperm or egg cell, giving 23 chromosomes. These cells are referred to as haploids.
When the number of chromosomes in each cell is a multiple of n, such as 2n (46, diploid), 3n (69, triploid), 4n (92, tetraploid), and so on, the cell is said to be euploid. Polyploidy refers to the presence of chromosomes in multiples greater than 4n.
Aneuploidy is the most prevalent type of chromosomal aberration, characterized by the presence of an extra chromosome or a missing chromosome. Down's syndrome, also known as Trisomy 21, is characterized by an extra copy of chromosome 21 and hence 47 chromosomes. Turner's syndrome, on the other hand, is caused by the lack of an X chromosome, resulting in just 45 chromosomes.
Mosaicism is the occurrence of aneuploid and normal diploid cells coexisting at the same time. Two or more distinct cell populations are formed from a single fertilized egg in this situation. Mosaicism mostly affects sex chromosomes, although it can also affect autosomal chromosomes.
Different cell lines produced from more than one fertilized egg are engaged in chimerism, which is different from mosaicism.
When the chromosomal structure is disrupted due to an atypical placement of the centromere and hence abnormal lengths of the chromosome's short and long arms, structural problems arise.
The chromosome is considered metacentric if the centromere lies in the middle and the arms are roughly the same length. The chromosome is called submetacentric if the centromere is towards one end and the arms are uneven in length. The chromosome is considered to be acrocentric when the centromere is so close to one end that the short arm is very short. Another irregularity is the presence of two centromeres, which is known as dicentric, and the absence of a centromere, which is known as acentric.
Chromosomes are dyed to produce banding patterns that can be utilized to detect any changes in structural arrangements within or between chromosomes in chromosomal analysis. Chromosome break and rearrangement inside the chromosome or between two or more other chromosomes may be involved. If chromosomal material is added (insertion mutation) or lost (deletion mutation) throughout the process, an unbalanced karyotype can arise.
Translocation occurs when a chromosome splits and joins with one or more additional chromosomes. The chromosomal translocation 9:22, for example, indicates that a section of chromosome 9 was removed and later reinserted into chromosome 22. The presence of this chromosome, known as the Philadelphia chromosome, raises the risk of chronic leukemia.
Chromosomal Abnormality Diagnosis
Many novel chromosome testing techniques have been created throughout the last century in cytogenetics. Karyotyping and fluorescence in-situ hybridization are the two most common procedures for detecting chromosomal abnormalities (FISH).
Because it detects fetal aneuploidies, structural rearrangements, and duplications and/or deletions of greater than 5 Mb, karyotyping has long been regarded as the gold standard for finding chromosomal abnormalities. The total collection of chromosomes in an organism is referred to as the karyotype. Cells must be inoculated and cultivated for 10 to 12 days at 37 °C, after which they must be treated with colchicine solution, a mitotic blocker, to stop them from entering metaphase. To cause cell lysis, the medium is substituted with a hypo-osmotic solution after incubation and centrifugation. Finally, the sample is placed on a glass slide, and the chromosomes are labeled with a specific dye (such as Giemsa stain) for light-microscopy analysis. Chorionic villus sampling and amniocentesis both have diagnostic rates of 98% and 99.5%, respectively.
Unfortunately, this method necessitates the use of cells at the metaphase stage. Only about a quarter of embryos develop metaphase cells of sufficient quality for precise chromosomal quantification, and only about a quarter of these cases are sufficient for comprehensive cell analysis. Furthermore, because cells must be cultured, the complete procedure normally takes 7 to 14 days. Despite this, karyotyping is regarded as the gold standard for detecting fetal aneuploidies in amniotic fluid samples.
Fluorescent in-situ Hybridization (FISH)
By hybridization, this approach assesses the presence, position, and copy number of the complementary DNA sequence of relevance in an individual's genome using fluorescent-labeled DNA probes. Depending on the existence of fluorescent nucleotides or nucleotides that act as haptens for fluorescently labeled antibodies, the probes must be labeled either directly or indirectly. The sample is first cultured to determine if it is in the metaphase stage. The sample is examined under a fluorescence microscope after incubation, hybridization, and washout to eliminate unbounded probes. This approach is particularly useful for structural chromosomal abnormalities involving short pieces of DNA (microdeletions, translocations, and so on) and for diagnosing trisomies due to a more distinct fluorescence reading. FISH eventually produced dozens of new more powerful techniques, including spectral karyotyping (SKY), multicolor FISH (M-FISH), and comparative genomic hybridization (CGH), all of which overcome some of FISH's early disadvantages (single probe, color, and region of analysis).
Finally, keep in mind that cytogenetic diagnostics can uncover some chromosome abnormalities that aren't linked to clinical problems.
Invasive tests, such as amniocentesis, chorionic villus sampling, and cordocentesis, were used to collect samples from amniotic fluid, chorionic villi, and fetal blood for cytogenetic examination of fetal cells. Miscarriage and other significant problems are possible with these procedures. Noninvasive genetic prenatal tests, on the other hand, have been developed to allow for even higher aneuploidy identification rates in high-risk pregnancies. Because almost 5% to 15% of cfDNA in maternal blood is of fetal origin, these noninvasive diagnostics look at cell-free DNA (cfDNA) in the maternal blood. Since its launch in 2011, cfDNA has seen massive growth in adoption. Despite the fact that these approaches are only for screening common trisomies and have limitations such as the risk of test failure, they offer considerable benefits over other tests and are likely to become more extensively utilized for prenatal screening in the future. It is essential to diagnose chromosomal abnormalities early in pregnancy. Doctors can go over and discuss a variety of medical choices with parents so that they can make the best decision possible.
Roughly 0.5 to 1 percent of neonates have chromosomal abnormalities, and about half of them have a phenotype that is atypical. The following sections list the most clinically important aneuploidies as well as important points about each.
Down Syndrome (Trisomy 21)
Down syndrome affects approximately 1:700 to 1/800 live births (most common autosomal trisomy).
The disease's clinical manifestations include Flat facies, prominent epicanthic folds, flat occiput, Brushfield spot in irises, sluggish muscle tone at birth, single transverse palmar crease (simian crease), clinodactyly, congenital gastrointestinal and cardiac defects, intellectual disability, increased risk for leukemia, Alzheimer's disease, and vision and hearing problems.
In comparison to other trisomies, its prognosis is favorable. Approximately 78% of all conceptions die during the embryonic or fetal stages. Nonetheless, if a child is born, the prognosis is often favorable (median survival is 47 years). It's the most prevalent aneuploidy that can survive for a long time.
Patau Syndrome (Trisomy 13)
This chromosomal anomaly affects about 1 in 5000 to 1 in 16000 babies born (the third most common autosomal trisomy).
Microcephaly, holoprosencephaly, microphthalmia, underdeveloped eyes, cleft lip and palate, polydactyly, rocker-bottom feet, congenital heart disease, cryptorchidism, brain or spinal cord abnormalities, weak muscle tone at birth, severe intellectual disability are some of the clinical features.
Miscarriage, stillbirth, or early death are the most common outcomes (median survival around one year of age).
Edward Syndrome (Trisomy 18)
This disease affects from 1/3000 to 1:5000 live newborns (second most common autosomal trisomy).
Low birth weight, microcephaly, micrognathia, low-set, deformed ears, clenched fists with overlapping fingers, congenital cardiac and renal problems, rocker-bottom feet, significant intellectual disability, and a one-year survival rate are among the clinical symptoms.
Miscarriage, stillbirth, or early death are all possible outcomes of this condition (median survival around one year of age).
Klinefelter syndrome affects 1 in 500 to 1 in 1000 male live births.
The karyotype is usually 47 XXY (greater than 90 percent). Other karyotypes, however, have been identified including 46, XY/47, XXY, 48, XXXY, and 49, XXXXY (mosaicism)
Increased height, long limbs, low upper/lower segment ratio, gynecomastia, reduced facial and body hair (female hair distribution), delayed and incomplete puberty, small testes (testicular atrophy), infertility, learning disabilities, delayed speech and language development, raising the risk for breast cancer are some of the clinical manifestations of the disorder.
The prognosis varies. It varies according to the degree of clinical signs and treatment, but it is often satisfactory. The life expectancy is reduced slightly.
Approximately 1 in every 1000 male births is afflicted.
Increased height and the likelihood of learning problems, impaired speech, language, and motor skills development, poor muscle tone, hand tremors, convulsions, asthma, scoliosis, and behavioral and emotional disorders are all clinical characteristics. Some patients may appear to be phenotypically normal (i.e., they did not show clinical manifestations).
The prognosis is uncertain. It varies according to the degree of clinical signs and treatment, but it is often satisfactory.
The most prevalent sex chromosomal defect in females, as well as the most common hereditary etiology primary amenorrhea. Turner syndrome affects about 1 in 2000 to 1 in 2500 live female newborns.
Short stature, webbed neck, low posterior hairline, shield chest, amenorrhea, lack of puberty, early loss of ovarian function (ovarian dysgenesis), infertility, skeletal abnormalities (i.e., cubitus valgus), lymphedema, congenital renal and/or cardiac disease are some of the clinical manifestations.
The prognosis varies. It varies according to the degree of clinical signs and treatment, but it is often satisfactory.
Structural Chromosomal Abnormality
When a section of a chromosome is deleted or duplicated, it can cause chromosomal abnormalities. Birth malformations in one or more organ systems can result from these anomalies. The following are some examples:
- Cri-du-chat syndrome. Cri-du-chat syndrome refers to a disorder in which a baby's crying sounds like a cat. They may also have congenital cardiac abnormalities and intellectual disabilities. There is no treatment for this condition. Special education and counseling are used to address intellectual impairment. Cardiac defects are dealt with as needed.
- Angelman syndrome. Angelman syndrome affects infants who have intellectual disabilities, are unable to talk, and have motor development issues. Angelman syndrome does not have a conventional treatment plan. Interventions such as educational programs, physical and occupational therapy, and speech therapy are all beneficial.
- Prader-Willi syndrome. Obesity, intellectual incapacity, lower-than-normal testosterone levels in boys, testes that do not descend correctly into the scrotum, and muscles that are overly relaxed in tone are all symptoms of Prader-Willi syndrome. This syndrome does not have a cure; however, the physical symptoms can be treated. Obesity can be managed with a healthy diet and regular exercise. Muscle tone can also be improved by exercise. Speech therapy and special education may also be beneficial.
- Fragile X syndrome. After Down syndrome, Fragile X syndrome is the second most prevalent genetic cause of significant intellectual disability. Other distinguishing characteristics include an extended face, broad mouth, huge ears, and enlargement of the testicles. There could also be issues with behavior and cognition. Fragile X syndrome has no known cure. Education programs, strategies to alleviate anxiety, and drugs to manage underlying psychiatric problems may all be part of supportive therapy.
Chromosomal Abnormality Prevention
Parents can lower their child's chance of chromosomal abnormalities by taking care of their own nutritional needs, minimizing their exposure to harmful chemicals, and consulting a specialist before becoming pregnant. Eating well, not smoking or consuming alcohol, and getting prenatal vitamins before pregnancy are all general risk reduction techniques. When the pregnant woman is over the age of 35, chromosomal abnormalities are more probable to arise. A healthcare physician may propose counseling to review different choices, including assisted reproductive procedures if a chromosomal issue has been detected within the family.
In our community, chromosomal abnormalities are the most common cause of mental retardation and developmental impairments. The phenotypes are frequently complex and the consequence of many, dosage-sensitive genes being gained or lost in the changed regions. The discovery of genes underlying specific characteristics of the syndrome has been made possible because of the characterization of these complicated symptoms with overlapping deletions. The adoption of high-resolution technology such as microarrays has enabled the identification of new syndromes using a genotype-first approach at a frequency never seen before with a light microscope. Cytogenetics is no longer in its infancy, and a new genome science has evolved that has established the causes of mental retardation, developmental impairments, and birth defects in our population using new technology.
Down syndrome, Turner syndrome, trisomy 18, and trisomy 13 are only a few of the chromosomal mutations produced by missing or extra chromosomes. Chromosome abnormalities can cause a range of birth malformations, dysmorphic facial features, and growth and developmental delays, depending on their size and location. In many circumstances, chromosomal disorders have no cure or treatment. Genetic counseling, occupational therapy, physiotherapy, and medications may all be suggested.