Chromosome Abnormalities

Understanding Chromosome Abnormalities

• Chromosome abnormalities involve changes in the normal structure or number of chromosomes
• These alterations can lead to various health conditions or disorders
• Numerical abnormalities change the number of chromosomes. Trisomy, having three copies of a chromosome instead of the usual two, is an example
• Structural abnormalities involve changes to the chromosome's structure, such as duplications, deletions, inversions, or translocations
• Abnormalities can stem from errors during cell division processes like meiosis or mitosis
• Failure of chromosomes to separate properly during cell division can lead to numerical abnormalities
• Structural abnormalities can result from chromosomal breakage or rearrangement

Chromosomes in Humans

• Human somatic cells are all body cells excluding gametes (sperm and egg cells)
• Humans possess 23 pairs of homologous chromosomes
• One chromosome in each pair originates from each parent
• This arrangement ensures genetic diversity and proper inheritance
• Somatic cells contain a total of 46 chromosomes
• Of the 23 pairs:
  • 22 pairs are autosomal chromosomes (non-sex chromosomes), carrying genes for various traits like hair color
  • One pair consists of sex chromosomes, determining the biological sex of an individual: XX chromosomes for females; XY chromosomes for males

Chromosome Appearance

• Chromosomes appearance depends on the phase of the cell cycle
• The cell cycle comprises a series of events somatic cells undergo from formation until division into two identical daughter cells
• The cell cycle includes two main phases:
  • Interphase (G1, S, G2): Here, the cell readies for division by growing and replicating its DNA
  • Mitosis: This is when the cell divides, producing two genetically identical daughter cells

Chromosome Count in Interphase

• Early interphase:
  • Each chromosome is unreplicated and consists of a single copy of genetic information called chromatin
  • Chromosome count: 46
  • Chromatid count: 46 (each chromosome has a single chromatid)
• Late interphase (just before mitosis begins)
  • Chromosomes are replicated, with each chromosome consisting of two identical chromatids joined at the centromere
  • Chromosome count: 46
  • Chromatid count: 92 (each chromosome now has two chromatids)

Chromosome Count After Mitosis

• Following mitosis, each of the two daughter cells receives one chromatid from each chromosome
• This results in 46 chromosomes in each daughter cell
• This ensures that daughter cells are genetically identical to the original parent cell

Chromosome Abnormalities

• Chromosome abnormalities can occur in almost all body cells
• They can be either:
  • Congenital abnormalities: Present from birth, often causing developmental or physical differences in individuals
  • Somatically acquired abnormalities: Occur later in life in a subset of cells and are often associated with cancer and aging (these abnormalities are clonal, meaning they arise from a single cell)

Detection of Chromosome Abnormalities

• Historically, chromosomal anomalies could only be detected with light microscopy, limiting detection to only large abnormalities
• Modern technologies, like fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (aCGH), allow for the detection of submicroscopic deletions, duplications, or rearrangements of chromosomal material
• Smaller copy number variants (CNVs) can now be detected, providing more detailed insights into genetic disorders
• As a result, distinguishing chromosomal abnormalities from monogenic (single-gene) disorders has become more challenging
• 65% to 85% of the population have hyper copy number variants (genetic variations where the number of copies of certain genes is greater than normal) that are 100 kilobase pairs or larger; larger variants are rarer

Classification of Chromosome Abnormalities by Origin

• Congenital abnormalities: Present at birth and may be inherited from one or both parents or arise de novo (new mutations) They can lead to genetic syndromes and are often visible at birth
• Somatically acquired abnormalities: Occur later in life and are usually clonal (originating from a single cell) They are not inherited and often arise due to environmental factors like radiation, toxins, or viral infections; these abnormalities are associated with cancers and certain aging-related diseases

Classification of Chromosome Abnormalities by Type

• Numerical Chromosome Abnormalities:
  • Involve changes in the number of chromosomes
  • Trisomy (three copies of a chromosome instead of two), such as Down syndrome (trisomy 21)
  • Monosomy (one copy of a chromosome instead of two), such as Turner syndrome (monosomy X)
  • Often caused by errors in meiosis or mitosis, leading to chromosome nondisjunction
  • Always clinically evident, causing physical or developmental symptoms
• Structural Chromosome Abnormalities:
  • Involve changes in the physical structure of chromosomes
  • Duplications: An extra copy of a chromosome segment is present
  • Deletions: A part of the chromosome is missing
  • Inversions: A chromosome segment is reversed end to end
  • Translocations: A chromosome segment is transferred to a different chromosome
• Balanced structural abnormalities usually do not cause clinical symptoms, as there is no loss or gain of genetic material, but they can still lead to reproductive issues or genetic imbalances in offspring
• Unbalanced structural abnormalities can lead to developmental and physical issues, depending on the size and location of the abnormality
• Structural abnormalities can be passed from one generation to the next, depending on the nature of the rearrangement

Detection Methods for Chromosomal Abnormalities

• Larger chromosomal abnormalities (such as trisomies or large deletions) can often be detected with light microscopy
• Smaller deletions and duplications require more advanced methods such as:
  • Molecular cytogenetics, including fluorescence in situ hybridization (FISH), which allows for the visualization of specific genetic material on chromosomes
  • DNA analysis techniques, such as array comparative genomic hybridization (aCGH), which can detect even small chromosomal changes that might not be visible under a microscope

Mechanisms of Structural Chromosome Aberrations

• Structural chromosome abnormalities occur due to chromosome breakage followed by abnormal realignment
• Causes include:
  • Spontaneous mutations
  • Exposure to ionizing radiation
  • Chemical exposure (e.g., alkylating agents)
  • Viral infections
• Outcomes of chromosomal abnormalities:
  • Balanced abnormalities: No loss or gain in chromosomal material after recombination; Genetic material remains intact, usually with no clinical relevance
  • Unbalanced abnormalities: Involve gain or loss of chromosomal segments which have clinically significant effects and can lead to birth defects, developmental disorders, or genetic diseases

Chromosomal Structure & Normal Function

• Humans have 46 chromosomes, consisting of 22 autosomal pairs and one pair of sex chromosomes
• Chromosome numbering:
  • Chromosome 1 = Largest
  • Chromosome 22 = Smallest
  • Sex Chromosomes: Males = X and Y ; Females = Two X chromosomes
• Reciprocal translocations occur when two chromosomes exchange segments of genetic material.
• Balanced Reciprocal Translocation: No chromosomal material is lost or gained and most carriers are asymptomatic Balanced
• Unbalanced Reciprocal Translocation: One chromosome contains too much material from another, leading to excess genetic material; The other chromosome loses material, resulting in gene deficiency

Effects on Fertility

• Balanced translocation carriers may struggle with infertility, recurrent miscarriage, or birth defects in offspring due to unbalanced inheritance
• Inheritance possibilities:
  • Child inherits normal chromosomes, making them healthy
  • Child inherits balanced translocation, also making them healthy
  • Child inherits unbalanced translocation, potentially causing birth defects or disorders

Types of Structural Chromosomal Changes

• Translocations
• Inversions
• Duplications
• Deletions

Aneuploidy & Structural Abnormalities

• Aneuploidy: abnormal number of chromosomes
  • Down Syndrome (Trisomy 21): extra chromosome 21
  • Turner Syndrome (45, X): missing one X chromosome

Specific Structural Chromosomal Abnormalities

• Deletions: a segment of a chromosome is missing; example is Cri-du-Chat (5p Minus Syndrome): deletion of the short arm of chromosome 5
• Duplications: a segment of a chromosome is duplicated, leading to excess genetic material; example is Chromosome 1q21.1 Duplication Syndrome: extra copies of certain genes in the long arm of chromosome 1
• Inversions: a chromosome segment breaks off, reverses its orientation, and reattaches; can alter gene expression
• Translocations: a portion of one chromosome swaps places with a part of another non-homologous chromosome; can result in gene fusions that drive disease states

Philadelphia Chromosome & Leukemia

• Chromosome 22 acquires a portion of chromosome 9, resulting in a fusion between the BCR gene (Chr 22) and ABL gene (Chr 9)
• Drives uncontrolled cell division, leading to Chronic Myeloid Leukemia (CML)

Chromosomal Structural Changes

• Structural chromosome abnormalities involve alterations in the structure of the chromosomes
• These abnormalities can include: Translocations, inversions, duplications & deletions

Balanced and Unbalanced Inheritance:

• Balanced inheritance: The total amount of chromosomal material remains the same, with no extra or missing parts, which usually does not result in clinical symptoms
• Unbalanced inheritance: The child inherits either too much or too little chromosomal material, leading to clinical issues like developmental delays, congenital malformations, or other disorders

Inversions

• A segment of the chromosome breaks off, flips, and reattaches
• Can affect how genes are expressed or lead to problems during the formation of gametes (eggs or sperm)
• If the inversion is inherited from a parent, it can cause difficulty in chromosome pairing during meiosis, which may lead to abnormal gametes and unbalanced inheritance

Chromosomal Structures

• Understanding how chromosomal abnormalities are named (e.g., using specific terminology for the location and nature of the alteration) is important for precise diagnosis, communication, and treatment

Translocations

• Involve the rearrangement of parts of chromosomes, where a segment of one chromosome breaks off and attaches to another chromosome
• Reciprocal translocations: Two chromosomes exchange pieces, and the overall genetic material stays balanced, though it may still cause issues in fertility or health
• Insertional translocations: A piece of chromosomal material from one chromosome is inserted into another chromosome, which can lead to more complex inheritance patterns

Insertional Translocation Example

• A chromosomal segment from chromosome 3 is inserted into chromosome 5
• In a healthy person: even though the segments are not in the correct order, the person generally has the correct number of genes, so they may not show any symptoms of the translocation
• Issues arise during reproduction because of how these chromosomes pair up during fertilization

Effects of Insertional Translocations

• Most carriers of insertional translocations are healthy because they still have the correct number of genes despite the rearrangement
• Issues can arise when they have children due to the nature of how chromosomes are inherited
• Offspring with two healthy chromosomes: If the parent carrying the insertional translocation passes on two healthy chromosomes (without the inserted segment), the child will be healthy because they receive the correct amount and type of chromosomal material
• Unbalanced inheritance due to extra segment: If the parent with the translocation passes on the chromosome with the extra segment along with a normal chromosome, the child will inherit too much chromosomal material, which is known as unbalanced inheritance and could lead to health problems such as developmental delays, intellectual disabilities, or growth problems
• Unbalanced inheritance due to missing segment: If the parent with the translocation passes on the chromosome with the shortened chromosome (missing the segment) and a normal chromosome, the child will inherit too little chromosomal material, which is also unbalanced inheritance; can result in problems similar to those caused by extra material, including developmental delays and other health issues
• Risk for the offspring: the risk for a child inheriting unbalanced inheritance from a parent carrying an insertional translocation is 50% (one in two) because each parent contributes one chromosome to the child’s genetic makeup; the larger the insertion (i.e., the more chromosomal material is inserted), the greater the risk for more significant health problems or even miscarriage