Chromosome abnormality

A chromosomal abnormality or chromosomal anomaly is a missing, extra, or irregular portion of chromosomal DNA. These can occur in the form of numerical abnormalities, where there is an atypical number of chromosomes, or as structural abnormalities, where one or more individual chromosomes are altered. Chromosome mutation was formerly used in a strict sense to mean a change in a chromosomal segment, involving more than one gene. Chromosome anomalies usually occur when there is an error in cell division following meiosis or mitosis. Chromosome abnormalities may be detected or confirmed by comparing an individual's karyotype, or full set of chromosomes, to a typical karyotype for the species via genetic testing.
Sometimes chromosomal abnormalities arise in the early stages of an embryo, sperm, or infant. They can be caused by various environmental factors. The implications of chromosomal abnormalities depend on the specific problem, they may have quite different ramifications. Diseases and conditions caused by chromosomal abnormalities are called chromosomal disorders or chromosomal aberrations. Some examples are Down syndrome and Turner syndrome. However, chromosomal abnormalities do not always lead to diseases. Among abnormalities, structural rearrangements of genes between chromosomes can be harmless if they are balanced, which means that a set of the chromosomes remains complete and there are no gene breaks across the chromosomes.

Numerical abnormality

Maintaining a euploid state, where cells contain the correct number of chromosome sets, is essential for genomic stability. Aneuploidy, characterized by an abnormal number of chromosomes, occurs when an individual is missing a chromosome from a pair or has an additional chromosome. This may be either full, involving a whole chromosome, or partial, where only part of a chromosome is missing or added. Aneuploidy may arise from meiosis segregation errors such as nondisjunction, premature disjunction, or anaphase lag during meiosis I or II. For aneuploidy, nondisjunction, the most frequent error, particularly in oocyte formation, occurs when replicated chromosomes fail to separate properly, leading to germ cells with an extra or missing chromosome. Additionally, polyploidy occurs when cells contain more than two sets of chromosomes. Polyploidy encompasses various forms, including triploid and tetraploid. Tetraploidy often arises from developmental errors during mitosis, such as cytokinesis failure, endoreplication, mitotic slippage, and cell fusion. These errors can subsequently lead to aneuploidy.
File:45,X.jpg|thumb|A karyotype of an individual with Turner Syndrome, where there is only a single X chromosome.
Aneuploidy can occur with sex chromosomes or autosomes. Rather than having monosomy, or only one copy, the majority of aneuploid people have trisomy, or three copies of one chromosome. An example of trisomy in humans is Down syndrome, which is a developmental disorder caused by an extra copy of chromosome 21; the disorder is therefore also called "trisomy 21". An example of monosomy in humans is Turner syndrome, where the individual is born with only one sex chromosome, an X.

Sperm aneuploidy

Exposure of males to certain lifestyle, environmental and/or occupational hazards may increase the risk of aneuploid spermatozoa. In particular, risk of aneuploidy is increased by tobacco smoking, and occupational exposure to benzene, insecticides, and perfluorinated compounds. Increased aneuploidy is often associated with increased DNA damage in spermatozoa.

Structural abnormalities

Structural abnormalities in chromosomes may result from breakage and improper realignment of chromosome segments. When the structure of a chromosome is altered, it can result in unbalanced rearrangements, balanced rearrangements, ring chromosomes, and isochromosomes. To expand, these abnormalities may be defined as follows:

Unbalanced rearrangements includes missing or additional genetic information in chromosomes. They include:
* Deletions: A portion of the chromosome is missing or has been deleted.Known disorders in humans include Wolf–Hirschhorn syndrome, which is caused by partial deletion of the short arm of chromosome 4; and Jacobsen syndrome, also called the terminal 11q deletion disorder.
* Duplications: A portion of the chromosome has been duplicated, resulting in extra genetic material. Known human disorders include Charcot–Marie–Tooth disease type 1A, which may be caused by duplication of the gene encoding peripheral myelin protein 22 on chromosome 17.
* Insertions: A portion of one chromosome has been deleted from its normal place and inserted into another chromosome.
Balanced rearrangements includes the alteration of chromosome segments but the genetic information is not lost or gained. They include:
* Inversions: A portion of the chromosome has broken off, turned upside down, and reattached, therefore the genetic material is inverted.
* Translocations: A portion of one chromosome has been transferred to another chromosome. There are two main types of translocations:
** Reciprocal translocation: Segments from two different chromosomes have been exchanged.
** Robertsonian translocation: A pair of chromosomes break at their centromeres, lose their short p arms, and fuse at their q arms, forming a single chromosome with one centromere. This type of translocation typically occurs between chromosomes 13, 14, 15, 21, and 22 in humans.
Rings: A portion of a chromosome has broken off and formed a circle or ring. This happens with or without the loss of genetic material.
Extrachromosomal DNA : 100 kb to 5 Mb-sized circular DNA molecules found in the nucleus that undergo non-Mendelian inheritance and do not have detectable centromeric activity. A primary mechanism for ecDNA formation is chromothripsis. Since ecDNA can reach high copy numbers and possesses highly-accessible chromatin, it can drive massive oncogene expression in cancer and is associated with poor clinical outcomes
Isochromosome: Formed by the mirror image copy of a chromosome segment including the centromere. Specifically, they form when one arm of a chromosome is lost, and the remaining arm duplicates.

Chromosome instability syndromes are a group of disorders characterized by chromosomal instability and breakage. They often lead to an increased tendency to develop certain types of malignancies.

Inheritance

Constitutional chromosome abnormalities arise during gametogenesis or embryogenesis, affecting a significant proportion of an organism's cells. These inherited abnormalities most commonly occur as errors in the egg or sperm, meaning the anomaly is present in every cell of the body. Factors such as maternal age and environmental influences contribute to the occurrence of these genetic errors. Offspring inherit two copies of each gene, one from each parent, and mutations may be passed down through generations. The diseases that follow a single-gene inheritance pattern are relatively rare but affect millions of individuals. This can be represented through the Mendelian inheritance patterns:

Autosomal dominant: Where at least one affected parent passes the mutation, and the condition appears in every generation. Examples include Huntington's disease, achondroplasia, and neurofibromatosis.
Autosomal recessive: Both parents are carriers of the mutation. The disorder manifests only when both copies of the inherited gene are mutated. Examples include tay-Sachs disease, sickle cell anemia, and cystic fibrosis.
X-linked inheritance: Mutated X chromosomes may be inherited in a dominant or recessive manner. Within X-linked recessive inheritance, males are more frequently affected than females. Since males have only one X chromosome, they will express the disease if that single X carries the mutation. Examples include hemophilia and fabry disease. In contrast, females, with two X chromosomes, must inherit the mutated gene from both parents for the disorder to manifest. X-linked dominant diseases can affect both males and females. A father with an X-linked dominant trait may only pass it to his daughters, while a mother can pass the trait to both sons and daughters. An example of this is incontinentia pigmenti.
Mitochondrial inheritance: This pattern affects both males and females but is inherited and passed only through the mother. Examples include Leber's hereditary optic neuropathy and Kearns-Sayre syndrome.

Given these patterns of inheritance, chromosome studies are often conducted on parents when a child is found to have a chromosomal anomaly. If the parents do not exhibit the abnormality, it was not inherited but may be passed down in subsequent generations.
Chromosomal abnormalities can also arise from de novo mutations within an individual. De novo mutations are spontaneous, somatic mutations that occur without prior inheritance, and they can emerge at various stages of life, including during the parental germline, embryonic or fetal development, or later in life due to aging. These mutations may occur during gametogenesis or postzygotically, resulting in new mutations that appear in a single generation without prior evidence of mutation in the parental chromosomes. Approximately 7% of de novo mutations are present as high-level mosaic mutations. Genetic mosaicism, which refers to a post-zygotic mutation, occurs when an individual possesses two or more genetically distinct cell populations derived from a single fertilized egg. This can lead to chromosomal abnormalities, and these mutations may be present in somatic cells, germ cells, or both, in the case of gonosomal mosaicism, where mutations exist in both somatic and germline cells. Somatic mosaicism involves multiple cell lineages in somatic cells, while germline mosaicism occurs in multiple lineages within germline cells, allowing the mutation to be passed to offspring. An example of a chromosomal abnormality resulting from genetic mosaicism is Turner syndrome.