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Chromosome abnormality
Chromosome abnormality
Chromosome abnormality
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A chromosomal abnormality or chromosomal anomaly is a missing, extra, or irregular portion of chromosomal DNA.[1][2] 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.[3] 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.[4] They can be caused by various environmental factors. The implications of chromosomal abnormalities depend on the specific problem, they may have quite different ramifications.[citation needed] Diseases and conditions caused by chromosomal abnormalities are called chromosomal disorders or chromosomal aberrations.[5] 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.[6]

Numerical abnormality

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A karyotype of an individual with trisomy 21, showing three copies of chromosome 21.
Error within meiosis segregation resulting in tetraploid daughter cells with 4 sets of chromosomes instead of two

Maintaining a euploid state, where cells contain the correct number of chromosome sets, is essential for genomic stability.[7] Aneuploidy, characterized by an abnormal number of chromosomes, occurs when an individual is missing a chromosome from a pair (monosomy) or has an additional chromosome (trisomy).[8][9][10] This may be either full, involving a whole chromosome, or partial, where only part of a chromosome is missing or added.[8][9][10] Aneuploidy may arise from meiosis segregation errors such as nondisjunction, premature disjunction, or anaphase lag during meiosis I or II.[11] 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.[11] Additionally, polyploidy occurs when cells contain more than two sets of chromosomes.[12] Polyploidy encompasses various forms, including triploid (three sets of chromosomes) and tetraploid (four sets of chromosomes).[7] 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.[7]

A karyotype of an individual with Turner Syndrome, where there is only a single X chromosome.

Aneuploidy can occur with sex chromosomes or autosomes.[13] Rather than having monosomy, or only one copy, the majority of aneuploid people have trisomy, or three copies of one chromosome.[1] 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".[14] An example of monosomy in humans is Turner syndrome, where the individual is born with only one sex chromosome, an X.[15]

Sperm aneuploidy

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Exposure of males to certain lifestyle, environmental and/or occupational hazards may increase the risk of aneuploid spermatozoa.[16] In particular, risk of aneuploidy is increased by tobacco smoking,[17][18] and occupational exposure to benzene,[19] insecticides,[20][21] and perfluorinated compounds.[22] Increased aneuploidy is often associated with increased DNA damage in spermatozoa.

Structural abnormalities

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The three major single-chromosome mutations: deletion (1), duplication (2) and inversion (3).
The two major two-chromosome mutations: insertion (1) and translocation (2).

Structural abnormalities in chromosomes may result from breakage and improper realignment of chromosome segments.[1] When the structure of a chromosome is altered, it can result in unbalanced rearrangements, balanced rearrangements, ring chromosomes, and isochromosomes.[1][23] To expand, these abnormalities may be defined as follows: [1][23]

  • Unbalanced rearrangements includes missing or additional genetic information in chromosomes.[1] They include:
  • Balanced rearrangements includes the alteration of chromosome segments but the genetic information is not lost or gained.[1] They include:
    • Inversions: A portion of the chromosome has broken off, turned upside down, and reattached, therefore the genetic material is inverted.[1]
    • Translocations: A portion of one chromosome has been transferred to another chromosome.[1] There are two main types of translocations:
Robertsonian translocation. Two chromosomes with the removal of their p (short) arms, and fusion at the centromere with their q (long) arms.
  • Rings: A portion of a chromosome (the ends) has broken off and formed a circle or ring. This happens with or without the loss of genetic material.[1]
Formation of a ring chromosome
  • Isochromosome: Formed by the mirror image copy of a chromosome segment including the centromere.[23] Specifically, they form when one arm of a chromosome is lost, and the remaining arm duplicates.[1]
Isochromosome formation

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.[24]

Inheritance

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Autosomal dominant and autosomal recessive inheritance patterns

Constitutional chromosome abnormalities (present at beginning of development) arise during gametogenesis or embryogenesis, affecting a significant proportion of an organism's cells.[25] These inherited abnormalities most commonly occur as errors in the egg or sperm, meaning the anomaly is present in every cell of the body.[1] Factors such as maternal age and environmental influences contribute to the occurrence of these genetic errors.[1] Offspring inherit two copies of each gene, one from each parent, and mutations (often caused by disease) may be passed down through generations.[26] The diseases that follow a single-gene inheritance pattern are relatively rare but affect millions of individuals.[26] This can be represented through the Mendelian inheritance patterns: [26][27]

X-linked dominant inheritance patterns, differing between maternal and paternal origin, on offspring
X-linked recessive inheritance patterns, differing between maternal and paternal origin, on offspring
  • Autosomal recessive: Both parents are carriers of the mutation (though it may not appear in every generation). The disorder manifests only when both copies of the inherited gene are mutated.[26] Examples include tay-Sachs disease, sickle cell anemia, and cystic fibrosis.[26]
  • 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.[27] 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.[27]
Mitochondrial inheritance pattern and its implication on offspring from a maternal and paternal origin.

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.[28]

Chromosomal abnormalities can also arise from de novo mutations within an individual.[29] 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.[30] 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.[31] Approximately 7% of de novo mutations are present as high-level mosaic mutations.[31] 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.[11][31] 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.[30] 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.[11] An example of a chromosomal abnormality resulting from genetic mosaicism is Turner syndrome.[11]

Acquired chromosome abnormalities

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Acquired chromosomal abnormalities represent genetic alterations that manifest during an individual's lifetime, as opposed to being inherited from their parents.[25] These modifications predominantly occur within somatic cells and are characterized by their non-heritable nature.[25] Typically, they arise from mutations that transpire during the process of DNA replication or as a consequence of exposure to various environmental factors.[32] In contrast to constitutional chromosomal abnormalities, which are present at birth, acquired abnormalities occur during adulthood and are confined to specific clones of cells, thereby inhibiting their distribution throughout the body.[32]

The development of chromosomal abnormalities and malignancies can be attributed to environmental exposures or may occur spontaneously during DNA replication.[32][33] Spontaneous replication errors typically occur due to DNA polymerase synthesizing new polynucleotides while evading proofreading functions, leading to mismatches in base pairing.[33] Throughout a human's lifetime, individuals may encounter mutagens (which are agents that induce mutations) that lead to chromosomal mutations. These mutations arise when a mutagen interacts with parental DNA, typically affecting one strand, resulting in structural alterations that hinder the successful base pairing with the modified nucleotide.[33] Consequently, daughter molecules inherit these mutations, which may further accumulate additional damage, subsequently being passed down to the next generations of cells.[34] Mutagens can be classified as physical, chemical, or biological:

  • Chemical: Common chemical mutagens include base analogs (molecules that resemble nitrogenous bases), deaminating agents (which remove amino groups), alkylating agents, and intercalating agents.[33]
  • Physical: The most prevalent sources of physical mutagens are exposure to UV radiation, which induces dimerization of adjacent pyrimidine bases, and ionizing radiation, which typically causes point mutations, insertions, or deletions.[33] Heat can also function as a mutagen by promoting the cleavage of the β-N-glycosidic bond, which connects the base to the sugar part of the nucleotide, through water-induced processes.[33]
  • Biological: Biological mutagens are introduced through exposure to viruses, bacteria, and/or transposons and insertion sequences (IS).[35] Transposons and IS can move through DNA by 'jumping,' disrupting the functionality of chromosomal DNA. The insertion of viral DNA can lead to genetic disruption, while bacteria may produce reactive oxygen species (ROS) that cause inflammation and DNA damage, resulting in decreased repair efficiency.[35]

Sporadic cancers are those that develop due to mutations that are not inherited; in these cases, normal cells gradually accumulate mutations and cellular damage.[34] Most cancers, if not all, could cause chromosome abnormalities,[36] with either the formation of hybrid genes and fusion proteins, deregulation of genes and overexpression of proteins, or loss of tumor suppressor genes (see the "Mitelman Database" [37] and the Atlas of Genetics and Cytogenetics in Oncology and Haematology,[38]). Approximately 90% of cancers exhibit chromosomal instability (CIN), characterized by the frequent gain or loss of entire chromosome segments.[39] This phenomenon contributes to tumor aneuploidy and intra-tumor heterogeneity, which are commonly observed in most human cancers.[32][39] For instance, certain consistent chromosomal abnormalities can turn normal cells into a leukemic cell such as the translocation of a gene, resulting in its inappropriate expression.[40]

DNA damage during spermatogenesis

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DNA damage during spermatogenesis plays a crucial role in chromosomal abnormalities and male fertility. In the early stages of sperm development, DNA repair mechanisms such as homologous recombination (HR) and mismatch repair (MMR) efficiently correct replication errors and double-strand breaks (DSBs).[41][42] However, as spermatogenesis progresses, DNA repair capacity declines due to changes in how DNA is packaged inside sperm cells.

Spermatogenesis occurs in three phases: mitosis (spermatocytogenesis), meiosis, and spermiogenesis. During spermiogenesis, the DNA becomes more tightly packed to fit inside the sperm head.[43] This happens because histone proteins, which normally help organize DNA, are replaced with transition proteins (TNP1, TNP2) and then protamines (PRM1, PRM2). While this packaging protects the DNA, it also makes it harder for repair enzymes to fix any damage.[44] As a result, non-homologous end joining (NHEJ), an error-prone repair process, becomes the main repair mechanism, increasing the risk of mutations.

Oxidative stress is another major factor contributing to DNA damage in sperm cells. Reactive oxygen species (ROS), produced both inside sperm and from external sources such as immune cells in seminal fluid, can break DNA strands. High ROS levels can overwhelm antioxidant defences, leading to further damage and triggering cell death pathways.[45]

Normally, defective sperm cells are removed through apoptosis, a controlled cell death process. However, if this system fails—such as when there is an imbalance between pro-apoptotic (BAX) and anti-apoptotic (BCL-2) factors—damaged sperm may survive.[46] If these sperm fertilize an egg, the oocyte's repair mechanisms may attempt to fix the damage.[47]

The maternal repair machinery is capable of correcting sperm DNA damage post-fertilization, but errors in this process can result in chromosomal structural aberrations in the developing zygote.[48] Notably, exposure to DNA-damaging agents, such as the chemotherapy drug Melphalan, can induce inter-strand DNA crosslinks that escape paternal repair, potentially leading to chromosomal abnormalities due to maternal misrepair. Therefore, both pre- and post-fertilization DNA repair are crucial for maintaining genome integrity and preventing genetic defects in the offspring.[49]

DNA damage in sperm has been linked to infertility, increased miscarriage risk, and conditions such as aneuploidy and structural chromosomal rearrangements. Understanding how DNA damage occurs and is repaired during spermatogenesis is important for studying male reproductive health and genetic inheritance.[50]

Detection

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Chromosomal abnormalities can be detected at either postnatal testing or prenatal screening, which includes prenatal diagnosis.[51] Early detection is crucial for enabling parents to assess their upcoming pregnancy options.[52]

Common techniques used to detect diseases resulting from chromosomal abnormalities:

Karyotyping has been the traditional method used to detect chromosomal abnormalities. It requires entire set of chromosomes to be able to identify fetal aneuploidy and variations in structural arrangements, which could be a result of insertions, inversions, duplications or deletions of chromosomes.[11] The samples used to obtain results from fetal karyotyping can be acquired through various sampling techniques. Amongst the aneuploidy testings, those which use amniotic fluid is preferred due its benefit of having high sensitivity with relatively low risks.[52]

For increased resolution of screening, Chromosomal Microarray Analysis (CMA) can be used which is based on comparative genomic hybridization (CGH) to identify copy number variations (CNVs). This alternative method to karyotyping reduces result uncertainty through its use of invasive fetal cell collection technique.[52]

FISH technique detects chromosomal abnormalities through labeling of the chromosome by fluorescence using specialized probes. It is important that these probes are validated before use as they are carefully regulated by the Food and Drug Administration (FDA).[52]

FISH is a technique used for the treatment of specific cases such as Multiple myeloma (MM) and can be used to analyze bone marrow samples to identify changes in chromosomes at a single-cell level.[53] For the treatment of MM relapse, acquired chromosomal abnormalities such as del (17p), amp (1q) and Tetraploidy can be analyzed to guide future therapy development and updated prognosis.[53]

Spectral Karyotyping (SKY) is a recent technology developed from the FISH technique that colors each human chromosome in a different color for identification in analysis.[54] Through the use of fluorescent dyes such as Cy5, Texas red and spectrum green, 24 distinguishable colors can be generated using imaging spectroscopy.[54]

Depending on the information one wants to obtain, different techniques and samples are needed.[citation needed]

Nomenclature

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  • Three chromosomal abnormalities with ISCN nomenclature, with increasing complexity: (A) A tumour karyotype in a male with loss of the Y chromosome, (B) Prader–Willi Syndrome i.e. deletion in the 15q11-q12 region and (C) an arbitrary karyotype that involves a variety of autosomal and allosomal abnormalities.[55]
    Three chromosomal abnormalities with ISCN nomenclature, with increasing complexity: (A) A tumour karyotype in a male with loss of the Y chromosome, (B) Prader–Willi Syndrome i.e. deletion in the 15q11-q12 region and (C) an arbitrary karyotype that involves a variety of autosomal and allosomal abnormalities.[55]
  • Human karyotype with annotated bands and sub-bands as used for the nomenclature of chromosome abnormalities. It shows dark and white regions as seen on G banding. Each row is vertically aligned at centromere level. It shows 22 homologous autosomal chromosome pairs, both the female (XX) and male (XY) versions of the two sex chromosomes, as well as the mitochondrial genome (at bottom left).
    Human karyotype with annotated bands and sub-bands as used for the nomenclature of chromosome abnormalities. It shows dark and white regions as seen on G banding. Each row is vertically aligned at centromere level. It shows 22 homologous autosomal chromosome pairs, both the female (XX) and male (XY) versions of the two sex chromosomes, as well as the mitochondrial genome (at bottom left).
Further information: Karyotype

The International System for Human Cytogenomic Nomenclature (ISCN) is an international standard for human chromosome nomenclature, which includes band names, symbols and abbreviated terms used in the description of human chromosome and chromosome abnormalities. Abbreviations include a minus sign (-) for chromosome deletions, and del for deletions of parts of a chromosome.[56]

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Chromosome abnormality

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from Grokipedia
A chromosome abnormality, also referred to as a chromosomal aberration, is a genetic disorder characterized by a morphological or numerical alteration in one or more chromosomes, which are structures in the cell nucleus that carry genetic information in the form of DNA. These abnormalities disrupt the normal complement of 46 chromosomes (23 pairs) in human cells and can affect autosomes or sex chromosomes, often leading to developmental issues, congenital anomalies, or increased risk of miscarriage. They are a major cause of human genetic disorders, occurring in approximately 0.6% of live births and contributing to 50-60% of first-trimester miscarriages. Chromosome abnormalities are broadly classified into two main types: numerical and structural. Numerical abnormalities involve an abnormal number of chromosomes, with aneuploidy—the presence of extra or missing chromosomes—being the most common form, affecting 5-10% of all pregnancies. Examples include trisomy 21 (Down syndrome), where there is an extra chromosome 21, occurring in about 1 in 700 live births and associated with intellectual disability, characteristic facial features, and heart defects; trisomy 18 (Edwards syndrome); and trisomy 13 (Patau syndrome), both of which often result in severe developmental delays and high infant mortality. Sex chromosome aneuploidies, such as Turner syndrome (45,X, monosomy X) in females, occurring in about 1 in 2,000 to 2,500 live female births and leading to short stature and infertility, or Klinefelter syndrome (47,XXY) in males, occurring in about 1 in 500 to 1,000 live male births and causing hypogonadism. Structural abnormalities, on the other hand, arise from rearrangements like deletions, duplications, inversions, translocations, or ring chromosomes, resulting in a net gain or loss of genetic material. Notable examples include Cri du chat syndrome from a deletion on the short arm of chromosome 5, characterized by a high-pitched cry and microcephaly, and DiGeorge syndrome from a 22q11.2 deletion, involving heart defects and immune deficiencies. The primary causes of chromosome abnormalities are errors during cell division, particularly nondisjunction in meiosis, where chromosomes fail to separate properly, leading to gametes with extra or missing chromosomes. This risk increases with advanced maternal age, as seen in trisomy 21, where incidence rises from 1 in 1,500 at age 20 to 1 in 100 at age 40. Structural changes often stem from chromosome breakage and faulty rejoining, influenced by environmental factors like radiation or chemicals, though most occur sporadically without a clear trigger. Mosaicism, where only some cells are affected due to post-zygotic mitotic errors, can result in milder phenotypes. Diagnosis typically involves karyotyping to visualize chromosomes, supplemented by advanced techniques like fluorescence in situ hybridization (FISH) or chromosomal microarray for detecting submicroscopic changes. These conditions underscore the importance of genetic counseling and prenatal screening to manage risks and support affected individuals.

Types of Chromosome Abnormalities

Numerical Abnormalities

Numerical abnormalities refer to deviations in the total number of chromosomes from the normal diploid complement of 46 in humans, encompassing conditions where cells have an abnormal count of whole chromosomes. These abnormalities are broadly classified into , which involves gains or losses of specific chromosomes, and , which features extra complete sets of chromosomes. Such changes typically arise during and can lead to significant genetic imbalances in affected individuals. Aneuploidy represents the most common form of numerical abnormality, characterized by the presence of an abnormal number of chromosomes in otherwise diploid cells, such as 45 or 47 chromosomes instead of 46. Subtypes include monosomy, where one chromosome is missing (resulting in 45 chromosomes, denoted as 2N-1), and trisomy, where one chromosome is present in three copies (resulting in 47 chromosomes, denoted as 2N+1). Rarer variants encompass tetrasomy (four copies of a chromosome, 2N+2) and nullisomy (complete loss of a chromosome pair, 2N-2), though these are exceptionally uncommon due to their severe genetic disruptions. The primary mechanism underlying numerical abnormalities is , an error in chromosome segregation during . In , which occurs in formation, homologous chromosomes or fail to separate properly, producing gametes with extra or missing chromosomes that, upon fertilization, form zygotes. can also occur during in early embryonic development, leading to where only some cells are affected. These errors are more frequent in meiosis I of and increase with maternal age due to aging oocytes. A well-known example of is , where three copies of result in 47 chromosomes, illustrating how a single extra chromosome can alter . , in contrast, involves entire extra sets, such as triploidy (3N, 69 chromosomes) or tetraploidy (4N, 92 chromosomes), often arising from fertilization of an egg by two sperm or failure of . These conditions are rare in viable human pregnancies, as polyploid embryos typically fail to develop beyond early stages and are incompatible with life. Numerical abnormalities affect approximately 5-10% of all recognized pregnancies, with the vast majority being non-viable and resulting in spontaneous ; only a small fraction, around 0.4-0.9% of live births, involve surviving cases like certain aneuploidies.

Structural Abnormalities

Structural abnormalities of are alterations in the physical structure or morphology of one or more , resulting from breaks, rearrangements, or losses and gains of genetic segments, without a change in the overall chromosome number. These changes disrupt the normal arrangement of genetic material and can lead to various health effects depending on the extent of imbalance. The main types of structural abnormalities include deletions, duplications, inversions, translocations, insertions, isochromosomes, and ring chromosomes. Deletions involve the loss of a chromosome segment, potentially causing conditions like cri-du-chat syndrome when occurring on the short arm of 5. Duplications result in an extra copy of a segment, leading to imbalances. Inversions occur when a segment breaks, rotates 180 degrees, and rejoins, classified as paracentric (not involving the ) or pericentric (involving the ). Translocations involve the exchange of segments between non-homologous chromosomes and can be balanced (no net loss or gain of material) or unbalanced (resulting in partial or ). Insertions occur when a segment from one chromosome is inserted into another, often non-homologous, chromosome. Isochromosomes form when one chromosome arm is duplicated and the other lost, creating mirror-image arms. Ring chromosomes arise when both ends of a chromosome break and fuse into a circle, typically with loss of terminal material. These abnormalities typically form through chromosome breakage followed by faulty repair mechanisms. Breakage can be induced by external factors such as or chemical mutagens, or by internal errors during or . The repair process, involving enzymes like DNA ligases, may misjoin broken ends, leading to rearrangements; during can also contribute. Balanced structural abnormalities do not alter the total genetic content and often have no phenotypic effects in carriers, though they may cause issues in offspring if gametes receive unbalanced segments. In contrast, unbalanced abnormalities result in net gain or loss of genetic material, frequently causing developmental disorders or due to effects. Structural chromosome abnormalities are observed in approximately 0.5-1% of live births, though exact rates vary by population and detection method; they are more prevalent in miscarriages, accounting for a significant portion of pregnancy losses where chromosomal issues are involved. Cryptic rearrangements, which are subtle structural changes not visible under standard microscopy, can only be detected using advanced molecular techniques like fluorescence in situ hybridization (FISH) or array comparative genomic hybridization (aCGH).

Causes and Mechanisms

Inherited Abnormalities

Inherited chromosome abnormalities are constitutional changes that originate in the cells of parents and are transmitted to offspring via gametes, resulting in their presence in the and most cells of the developing . These differ from de novo abnormalities, which arise spontaneously during or early embryogenesis in the affected individual without parental origin. Such inherited variants can involve numerical alterations, like , or structural changes, such as balanced translocations, and are often identified through parental karyotyping when a presents with related phenotypes. Transmission of inherited chromosome abnormalities follows mendelian patterns adapted to chromosomal scale. Structural abnormalities, such as balanced translocations, are typically passed in an autosomal dominant fashion, where phenotypically normal carrier parents have a 50% chance of transmitting the rearranged to each , though only unbalanced forms may cause clinical issues. Sex-linked abnormalities on the X or Y exhibit X-linked , with males more severely affected due to hemizygosity, as seen in conditions involving X-chromosomal structural variants. Mosaicism, where only a subset of cells carry the abnormality, introduces variable inheritance risks, potentially leading to gonadal mosaicism in parents and unpredictable transmission to multiple . Key mechanisms include meiotic segregation errors in carrier parents. For instance, parents with balanced reciprocal translocations face risks of producing unbalanced gametes through adjacent-1 or 3:1 segregation, resulting in partial trisomies or monosomies in offspring; viable unbalanced outcomes occur in approximately 10-15% of pregnancies for many translocations, though theoretical risks can reach 50% depending on involvement. inheritance is rarer due to meiotic selection against unbalanced gametes, which often fail to fertilize or implant, coupled with high rates of embryonic lethality for most autosomal aneuploidies, limiting multi-generational transmission primarily to viable cases like trisomy 21. Risk factors for inherited chromosome abnormalities center on parental characteristics. over 35 years elevates the likelihood of during , increasing the chance of transmitting aneuploid gametes, while paternal age has minimal impact. A family history of chromosomal carriers, such as balanced translocation holders, substantially raises recurrence risks in subsequent generations, often prompting preconception screening. Early recognition of inherited chromosome abnormalities occurred in the 1950s and 1960s through pedigree analysis, following the 1959 identification of trisomy 21 as a chromosomal cause of , which revealed familial clustering in some cases and established inheritance patterns for structural variants like translocations. Inherited chromosomal abnormalities contribute to a small fraction (less than 5%) of congenital anomalies, with total chromosomal issues accounting for about 15%, though most overall chromosomal issues in newborns are de novo.

Acquired Abnormalities

Acquired abnormalities, also known as somatic abnormalities, refer to non-inherited genetic alterations that arise in body cells after fertilization, typically during an individual's lifetime, and are confined to specific tissues rather than being present in all cells. These changes occur in somatic cells and do not affect gametes, distinguishing them from mutations that can be passed to . Unlike constitutional abnormalities present from birth, acquired ones often result from errors in or external insults, leading to genomic instability that can drive clonal expansion in affected cell populations. The mechanisms underlying acquired chromosome abnormalities include environmental exposures, viral infections, and intrinsic cellular processes such as aging-related replication errors. can induce DNA double-strand breaks, leading to chromosomal breaks, translocations, or in exposed cells, as observed in radiation-induced leukemias. Chemical agents like , a known , cause chromosome aberrations including and structural rearrangements in cells, contributing to the development of . Viral infections, such as high-risk human papillomavirus (HPV) in , promote chromosomal instability through integration into the host genome, disrupting pathways and causing or amplifications. Additionally, aging contributes via cumulative replication errors during , exacerbated by telomere shortening and , which generate that damage telomeric DNA and trigger chromosome end fusions or breakage-fusion-bridge cycles. Recent studies up to 2025 highlight how -induced telomere instability accelerates the acquisition of these abnormalities, fostering a pro-tumorigenic environment in aging tissues. As of 2025, editing studies have elucidated how specific gene disruptions in pathways accelerate acquired chromosomal instability in aging tissues. These abnormalities play a central role in disease pathogenesis, particularly cancer, where they facilitate clonal evolution—the sequential accumulation of genetic changes that confer growth advantages to malignant cells. In chronic myeloid leukemia (CML), the arises as an acquired t(9;22) translocation in hematopoietic stem cells, creating the BCR-ABL1 fusion gene that drives leukemogenesis and subsequent clonal progression with additional aberrations. Prevalent types include numerical abnormalities like , such as commonly seen in and myelodysplastic syndromes, which promotes tumor heterogeneity and progression. Structural changes, including gene amplifications like HER2 on chromosome 17q12 in , enhance expression and are associated with aggressive tumor behavior. Somatic mutations, encompassing these chromosomal alterations, accumulate with age, and chromosomal instability is a feature in approximately 90% of cancers, underscoring its contribution to oncogenesis across tumor types.

Abnormalities Arising During Gametogenesis

Chromosome abnormalities arising during gametogenesis refer to de novo errors in chromosome segregation that occur specifically during meiosis I or II in the formation of sperm or eggs, resulting in aneuploid gametes with an abnormal number of chromosomes. These errors primarily involve nondisjunction, where homologous chromosomes or sister chromatids fail to separate properly, leading to gametes that carry extra or missing chromosomes. Such abnormalities are a leading cause of infertility and birth defects, as aneuploid gametes often produce nonviable embryos upon fertilization. In , chromosome abnormalities stem from vulnerabilities in processes, including DNA damage induced by and failures in the spindle assembly checkpoint that monitors chromosome alignment. arises from elevated levels in aging testes, which overwhelm defenses and cause DNA strand breaks in germ cells. Paternal age significantly exacerbates these risks; sperm rates in normal men typically range from 0.9% to 1.7%, with only slight or no significant increase in men over 40 years, remaining around 1-2% per chromosome analyzed. In infertile men, these rates can be three times higher than in fertile individuals, often linked to structural issues like thickened basal membranes in seminiferous tubules that disrupt . Oogenesis exhibits parallel mechanisms but with a pronounced maternal age effect, where nondisjunction risk escalates due to the prolonged arrest of oocytes in prophase I from fetal development until ovulation. After age 35, the incidence of aneuploid oocytes rises sharply, from about 19% in women aged 23–40 to 65–78% in those over 40, primarily from errors in meiosis I. This is attributed to progressive loss of cohesin proteins, such as SMC1, which stabilize chiasmata and prevent premature separation of chromosome arms during prolonged dictyate arrest. For instance, the risk of any trisomic pregnancy (referring to any autosomal trisomy in clinically recognized pregnancies) increases from approximately 2% at age 25 to 35% at age 42, underscoring cohesin degradation as a key driver of age-related segregation failures. Environmental factors, including toxins like pesticides and chemotherapy agents, further contribute to these abnormalities by inducing oxidative damage and disrupting meiotic progression in germ cells. Pesticides such as DDT and deltamethrin generate free radicals that promote apoptosis and DNA fragmentation in spermatogonia and oocytes, elevating aneuploidy rates. Chemotherapy drugs, including thalidomide derivatives, similarly trigger redox imbalances that impair spindle function and chromosome alignment during gametogenesis. Exposure to perfluorinated compounds has been associated with increased chromosomal aneuploidies in spermatozoa, highlighting their interference with meiotic segregation. The outcomes of aneuploid gametes are predominantly adverse, with most resulting in early embryonic arrest and ; chromosomal abnormalities account for 61% of first-trimester spontaneous abortions, including 37% autosomal trisomies and 9% polyploidies. Viable pregnancies are rare but can lead to conditions like (47,XXY), often arising from in maternal I, where an XX egg fertilizes with a Y . Such cases represent about 3.4% of chromosomally abnormal miscarriages but are 40 times more prevalent in abortuses than live births. Recent research since 2020 has highlighted epigenetic modifications during as modulators of abnormality rates, with environmental exposures inducing heritable changes like and retention that persist across generations. For example, ancestral exposure to pesticides like vinclozolin alters regions in prospermatogonia and spermatocytes, increasing transgenerational risks of meiotic errors and . Studies on lysine-4 methylation have shown its role in regulating oocyte , where disruptions contribute to higher in aged or exposed germ cells. These findings suggest that epigenetic during I and II can either mitigate or amplify segregation defects, influencing overall quality.

Detection and Diagnosis

Traditional Cytogenetic Methods

is the branch of that involves the direct microscopic analysis of chromosomes to study their number, size, shape, and structure, enabling the identification of abnormalities such as or large-scale rearrangements. This field relies on visual examination of stained chromosomes prepared from cell samples, providing a foundational approach for detecting chromosomal variations that may underlie genetic disorders. The development of traditional cytogenetic methods accelerated in the mid-20th century, with significant advancements in the late 1960s and 1970s through the introduction of banding techniques. Prior to banding, chromosomes were visualized using basic staining methods like those developed by in the late , but these offered limited resolution for distinguishing individual chromosomes. Q-banding (quinacrine ), developed by Lore Zech and Torbjörn Caspersson in 1970, was the first differential banding technique. The breakthrough for routine use came with , independently discovered in 1971, notably by Marina Seabright, who used Giemsa staining after treatment to produce characteristic light and dark bands along chromosome arms, allowing for precise identification of each of the 46 human chromosomes and detection of structural anomalies. Other banding methods, such as R-banding (reverse Giemsa), were introduced concurrently in 1971, further refining the ability to map chromosomal landmarks. The standard procedure for karyotyping, the primary traditional cytogenetic technique, begins with obtaining a cell sample, typically from peripheral blood lymphocytes for postnatal analysis or amniotic fluid via amniocentesis for prenatal diagnosis. Cells are cultured in a nutrient medium to stimulate division, reaching the metaphase stage where chromosomes are most condensed and visible. To arrest cells in metaphase, colchicine or colcemid is added, which disrupts microtubule formation and halts spindle assembly, preventing chromosome segregation. Following this, a hypotonic solution (usually potassium chloride) is applied to swell the cells, improving chromosome spreading, after which they are fixed with a methanol-acetic acid mixture and dropped onto glass slides. The slides are then stained using G-banding protocols: chromosomes are briefly exposed to trypsin to partially digest proteins, followed by Giemsa dye, which binds preferentially to AT-rich regions, creating alternating G-positive (dark) and G-negative (light) bands. Under a light microscope at 400-550x magnification, a karyogram is constructed by arranging the banded chromosomes into pairs by size, centromere position, and banding pattern, with abnormalities scored against standard ideograms like those from the International System for Human Cytogenomic Nomenclature (ISCN). This process achieves a resolution of approximately 5-10 megabases (Mb), sufficient for identifying large deletions, duplications, translocations, or numerical changes like trisomy 21 in Down syndrome. Traditional cytogenetic methods are widely applied in clinical settings for both prenatal and postnatal . In prenatal testing, samples from (CVS) at 10-13 weeks or at 15-20 weeks allow detection of fetal chromosomal issues, such as sex chromosome aneuploidies, with results guiding decisions on pregnancy management. Postnatally, blood samples from individuals with developmental delays or congenital anomalies are karyotyped to identify causes like (45,X). These techniques excel at detecting whole-chromosome gains or losses and gross structural alterations that affect large genomic segments, providing a holistic view of the . Key advantages of traditional cytogenetics include the direct visualization of all chromosomes in a single analysis, offering an unbiased survey of the entire without requiring prior knowledge of specific loci, and its relative cost-effectiveness compared to advanced genomic sequencing. It remains a first-line tool in many laboratories due to its established protocols and interpretability by trained cytogeneticists. However, limitations are notable: the method's resolution restricts detection to abnormalities larger than 5-10 Mb, missing submicroscopic changes like small deletions in microdeletion syndromes; the process is labor-intensive, requiring 7-14 days for culture and analysis; and it demands viable, dividing cells, which can be challenging in certain tissues. Despite these constraints, traditional methods continue to play a crucial role in initial screening before escalating to higher-resolution techniques.

Modern Molecular Techniques

Modern molecular cytogenetics has revolutionized the detection of chromosome abnormalities by providing sub-microscopic resolution, enabling the identification of genetic alterations too small to be visualized through traditional karyotyping. These techniques focus on DNA-level analysis, bridging the gap between conventional and to uncover copy number variations, structural rearrangements, and sequence-level changes with high precision. A cornerstone technique is (FISH), which uses fluorescently labeled DNA probes to target specific chromosomal loci, such as telomeres or centromeres, allowing visualization of numerical and structural abnormalities in or cells. FISH is particularly valuable for rapid detection of or microdeletions in conditions like , offering targeted analysis without requiring . Chromosomal microarray analysis (CMA) represents a genome-wide approach to detect copy number variants (CNVs) and , achieving resolutions as fine as 50 kb, far surpassing traditional methods for identifying submicroscopic imbalances associated with developmental disorders. As a first-tier diagnostic tool, CMA scans the entire for deletions and duplications, providing comprehensive profiling in prenatal and postnatal settings. Next-generation sequencing (NGS) enables whole-genome or targeted sequencing to detect , mosaicism, and complex rearrangements at the base-pair level, including through non-invasive prenatal testing (NIPT) that analyzes (cfDNA) in maternal blood. NIPT via NGS achieves over 99% for trisomies 13, 18, and 21, facilitating early screening with minimal risk. In applications, these techniques support rapid prenatal screening, where NIPT has transformed for common aneuploidies, and , where NGS profiles tumor-specific chromosomal alterations to guide personalized . For instance, NGS identifies somatic CNVs in leukemias, informing and treatment. Recent advancements as of 2025 include the integration of , which reveals low-level mosaicism in embryonic tissues by analyzing individual cells for , enhancing detection in preimplantation . AI-assisted variant calling in NGS pipelines improves accuracy by automating the identification of chromosomal variants, reducing false positives in large-scale genomic data from cytogenetic studies. These methods offer high sensitivity for microdeletions undetectable by conventional approaches and non-invasive options like NIPT, minimizing procedural risks. However, they cannot visualize overall chromosome morphology or pairing during , and their higher costs limit accessibility in resource-constrained settings.

and

Naming Conventions

The International System for Human Cytogenomic Nomenclature (ISCN) provides a standardized framework for describing human chromosome complements and abnormalities, ensuring consistent communication across cytogenetic and genomic analyses. Originating from the Conference in 1960, which proposed the initial system for numbering and classifying human mitotic chromosomes into seven groups (A-G) based on size and morphology, the nomenclature has evolved through subsequent international conferences in (1963), (1966), and (1971 and 1975) to incorporate banding techniques and structural details. This progression culminated in the formal ISCN publications, with the first edition in 1978, and periodic updates reflecting advances in cytogenomics; the most recent edition, ISCN 2024, integrates nomenclature for emerging technologies like genome mapping while merging rules for numerical and structural findings into a unified chapter for clarity. Numerical abnormalities are denoted by specifying the total chromosome count, followed by the sex chromosome constitution, and then the abnormality using a plus (+) or minus (-) sign with the chromosome number. For instance, trisomy 21 is represented as 47,XX,+21, indicating 47 chromosomes with an extra chromosome 21 in a female karyotype, while monosomy X (Turner syndrome) is 45,X, denoting 45 chromosomes with a single X. In cases of polyploidy or aneuploidy ranges, tildes () indicate approximations, such as 92,XXYY,,tet(+21), for near-tetrasomy. Structural abnormalities follow a format that identifies the involved chromosomes, the type of rearrangement, and breakpoints using (p for short, for long) and band notations. Translocations are abbreviated as t, with format t(chromosome1;chromosome2)(band1;breakpoint1;band2;breakpoint2); for example, the in chronic myeloid leukemia is t(9;22)(q34;q11.2), specifying a reciprocal exchange between the long arms of chromosomes 9 and 22 at those bands. Deletions use del, as in del(5)(p15), indicating loss of material from the short of at band p15; inversions are inv, duplications dup, and derivative chromosomes der for unbalanced products. The 2024 edition refines and recombinant notations to better handle complex insertions and fusions, using double colons (::) in mapping contexts for breakage events. Mosaicism, where multiple cell lines coexist, is indicated by "mos" followed by slash-separated karyotypes in brackets denoting cell counts, such as mos 47,XY,+21/46,XY, representing 20 cells with trisomy 21 and 10 normal cells in a male. Sex chromosomes are symbolized as X and Y, with undisclosed gender in prenatal cases using U, as in 46,U. Special cases include marker chromosomes (mar) for unidentified small supernumerary elements, rings (r) as r(18) for a circular , and isochromosomes (i) like i(X)(q10) for a mirrored long arm of X. These notations prioritize simplicity and ambiguity avoidance, evolving from the system's group-based classification to the band-resolution precision of modern ISCN.

Examples of Common Abnormalities

Common chromosomal abnormalities are selected for illustration based on their relative frequency in clinical populations, allowing demonstration of the International System for Human Cytogenomic Nomenclature (ISCN) for precise description. These examples encompass numerical and structural variants across autosomes and , as well as , reflecting patterns observed in prenatal and postnatal cytogenetic analyses. Autosomal numerical abnormalities include trisomy 21, the most prevalent , denoted as 47,XX,+21 in females or 47,XY,+21 in males, indicating an extra chromosome 21. A common structural autosomal variant is the 22q11.2 deletion, represented as del(22)(q11.2), signifying loss of material at the q11.2 band on the long arm of ; this notation highlights interstitial deletions detectable in routine karyotyping. Sex chromosome aneuploidies frequently involve extra or missing X chromosomes. Klinefelter syndrome typically presents as 47,XXY, with an additional X chromosome in males, accounting for over 90% of cases. Turner syndrome is denoted by 45,X, reflecting monosomy X due to absence of one sex chromosome. Triple X syndrome, or 47,XXX, indicates an extra X in females and is a recognized numerical variant in population studies. Structural rearrangements often appear balanced in carriers. A balanced reciprocal translocation between 14 and 21 is notated as 46,XX,t(14;21) or 46,XY,t(14;21), preserving total genetic material but altering chromosome structure. Robertsonian translocations, common fusions of acrocentric , are exemplified by 45,XX,der(14;21)(q10;q10), where the derivative chromosome joins the long arms at centromeric regions q10, resulting in 45 chromosomes overall. Polyploidy, though rarer and often lethal, includes triploidy denoted as 69,XXX (or 69,XXY), representing three full sets of chromosomes, frequently identified in early pregnancy losses. In clinical cytogenetic laboratories, ISCN notation integrates seamlessly into reports to ensure unambiguous communication of findings, facilitating accurate genetic counseling and further testing. For instance, a full karyotype description might combine sex chromosomes, total count, and abnormality symbols as in the examples above, adhering to ISCN guidelines for consistency across global labs.

Clinical Significance

Associated Conditions and Syndromes

Chromosome abnormalities often lead to syndromes by disrupting , where an extra or missing copy of genetic material alters the expression levels of multiple genes, resulting in developmental and physiological imbalances. This imbalance can cause a cascade of effects, including impaired cellular function, organ malformation, and increased susceptibility to certain diseases, as seen in various aneuploidies and structural variants. For instance, trisomies typically result in overexpression of genes on the affected , contributing to characteristic phenotypic features across affected individuals. Among autosomal trisomies, , caused by trisomy 21, is associated with , characteristic facial features such as upslanting palpebral fissures, and congenital heart defects like atrioventricular septal defects in approximately 40-50% of cases. (trisomy 18) presents with severe developmental delays, , clenched fists, rocker-bottom feet, and life-threatening heart and kidney malformations, with most affected infants not surviving beyond the first year. Similarly, (trisomy 13) manifests with cleft lip and palate, , , and profound , often accompanied by brain and heart anomalies that lead to high early mortality. Structural abnormalities, such as deletions, also produce distinct syndromes through , where the loss of one gene copy impairs normal development. Cri-du-chat syndrome, resulting from a deletion on the short arm of (5p-), features a high-pitched, cat-like cry in infancy, , , and moderate to severe . DiGeorge syndrome, due to a microdeletion at 22q11.2, is characterized by thymic hypoplasia leading to immune deficiency, conotruncal heart defects such as , from parathyroid involvement, and palatal abnormalities. Sex chromosome abnormalities similarly affect gene dosage, particularly of X-linked genes escaping inactivation. Turner syndrome (45,X) in females results in short stature, gonadal dysgenesis causing and lack of secondary sexual characteristics, , and increased risk of aortic coarctation and . (47,XXY) in males leads to with small testes and low testosterone, tall stature, , and learning difficulties, often with preserved fertility in milder cases but common. Mosaicism, where only some cells carry the abnormality, can lead to variable phenotypic severity depending on the proportion and distribution of affected cells. In mosaic Down syndrome, individuals may exhibit milder and fewer physical features compared to full trisomy 21, with outcomes influenced by the percentage of trisomic cells in critical tissues like the . Epidemiologically, has an incidence of approximately 1 in 700 live births, with risk strongly correlated to —for example, rising from about 1 in 1,500 at age 25 to 1 in 100 at age 40 due to increased meiotic . Incidences for Edwards and Patau syndromes are lower, at roughly 1 in 5,000 and 1 in 5,000-10,000 live births, respectively, also linked to maternal age. Recent research highlights how epigenetic modifiers, such as patterns altered by the extra chromosome, can influence the penetrance and expressivity of these syndromes, potentially modulating symptom severity beyond simple effects in conditions like .

Management and Genetic Counseling

Management of chromosome abnormalities typically involves a multidisciplinary approach tailored to the specific type and severity of the abnormality, focusing on and supportive care to improve . For instance, in cases of ( 21), which often includes congenital heart defects in approximately 40-50% of affected individuals, surgical interventions such as repair are commonly performed to address structural cardiac issues, with favorable outcomes and low mortality rates when managed early. Early intervention therapies, including physical, occupational, and speech-language therapies, are recommended for infants and young children with chromosomal disorders like to enhance developmental milestones, with programs starting as early as birth under frameworks like those from the U.S. . These therapies can significantly mitigate delays in motor skills, communication, and cognition, often coordinated by teams comprising pediatricians, geneticists, cardiologists, and therapists. Reproductive options for carriers of balanced chromosomal rearrangements or families with a history of abnormalities include (PGD), now termed preimplantation genetic testing for structural rearrangements (PGT-SR), which allows screening of embryos during in vitro fertilization (IVF) to select those without the abnormality before implantation. This technique has been effective in reducing the transmission risk of conditions like reciprocal translocations, with success rates for healthy live births comparable to standard IVF when embryos are euploid. Alternatives such as sperm or from unaffected donors provide another avenue for families at high risk, bypassing the need for carrier screening in gametes. Genetic counseling plays a central role in supporting individuals and families affected by chromosome abnormalities, beginning with a comprehensive risk assessment that incorporates family pedigree analysis, personal medical history, and probabilistic modeling of recurrence risks based on the abnormality type—for example, a 10-15% empiric risk for unbalanced offspring in carriers of Robertsonian translocations. Counselors facilitate informed consent for diagnostic testing by explaining options like karyotyping or chromosomal microarray, ensuring patients understand benefits, limitations, and potential psychological impacts. Post-diagnosis, counseling extends to emotional support, resource referral, and long-term planning, helping families navigate decisions about family building or care management. As of 2025, advancements in gene editing technologies offer emerging potential for addressing certain genetic disorders linked to chromosomal abnormalities, though clinical applications remain limited to monogenic conditions analogous to structural variants. Experimental approaches, such as CRISPR-mediated chromosome elimination, show promise in preclinical models for correcting by targeting supernumerary chromosomes, but human trials for monosomies like (45,X) are still in early research phases focused on to supplement missing gene products rather than full chromosomal restoration. These developments highlight the technology's potential but underscore challenges like off-target effects and delivery efficiency in somatic cells. Ethical considerations in management and counseling for chromosome abnormalities include the implications of selective termination following prenatal , where nondirective counseling aims to respect while addressing potential or stigmatization of disabilities. Uncertainties in mosaicism, where only a of cells carry the abnormality, complicate prognostic counseling and , as variability in phenotypic expression can lead to incomplete risk information and ethical dilemmas around testing accuracy. Counselors must navigate , especially in familial implications, and promote equitable access to options without exacerbating social disparities. Support resources for affected families include organizations like the Rare Chromosome Disorder Support Group (Unique), which provides international networking, educational materials, and advocacy for over 100 rare chromosomal conditions. Chromosome Disorder Outreach, Inc., offers peer support, newsletters, and family connections for those with deletions, duplications, or other structural variants. Specialized registries, such as those under the National Organization for Rare Disorders (NORD), facilitate research participation and connect families to clinical trials, while groups like Support Organization for Trisomy (SOFT) focus on 13, 18, and related disorders with annual conferences and care guides.

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