Chromosome Aberrations

• Structural chromosome aberrations arise through chromosome breakage followed by abnormal realignment, either spontaneously or due to factors like ionizing radiation, chemicals (e.g., alkylating agents), or viral infections.

Balanced vs. Unbalanced Structural Abnormalities

• Balanced structural abnormalities involve no loss or gain of chromosomal material after recombination.
• They typically have no clinical relevance unless the process disrupts a gene, causing a dominant loss or gain of function.
• Unbalanced chromosome abnormalities involve a gain or loss of chromosome segments, making them clinically relevant.
• Structurally altered chromosomes are called derivative chromosomes.

Reciprocal Translocations

• Reciprocal translocations occur when two chromosomes swap pieces of chromosomal material.
• This is a balanced chromosomal translocation because no chromosomal material is lost or gained.
• Most individuals with balanced reciprocal translocations are healthy.
• Families may be identified with balanced reciprocal translocations due to investigations following a family history of infertility, recurrent miscarriage, or the birth of a child with birth defects and/or learning difficulties.
• Problems can arise for balanced translocation carriers during egg or sperm production, as four chromosomes must pair up.
• Unbalanced versions of the chromosomes can be passed on, resulting in offspring having too much of one chromosome and too little of the other.
• The larger the imbalance, the more likely a miscarriage will result; smaller imbalances may lead to a baby with birth defects and learning difficulties.
• Risk depends on the specific translocation, and genetic specialists can help determine individual risk needs.

Types of Structural Chromosome Abnormalities

• Structural changes include translocations, inversions, duplications, and deletions.
• Aneuploidy refers to having an abnormal number of chromosomes (additional or missing).
• Down syndrome (Trisomy 21) involves an extra chromosome 21.
• Turner Syndrome involves only one sex chromosome (a single X).
• Deletions involve a missing chunk of a chromosome, such as in Cri du Chat (5p minus) syndrome, where the tip of chromosome 5's short arm is missing.
• Duplication means a chromosome has a duplicate segment.
• Inversions involve a part of a chromosome breaking off and reattaching in reverse order.
• Translocations involve a part of one chromosome breaking off and attaching to another non-homologous chromosome.
• Philadelphia chromosome is a translocation example where chromosome 22 has a piece of chromosome 9, leading to a fusion between the BCR gene (from chromosome 22) and the ABL gene (from chromosome 9).
• The presence of the ABL-BCR fusion gene leads to uncontrolled cell division, resulting in leukemia.

Chromosome Abnormalities Overview

• Chromosome abnormalities involve changes in the normal structure or number of chromosomes, potentially leading to health conditions or disorders.
• Numerical abnormalities involve changes in the number of chromosomes, like trisomy or monosomy.
• Structural abnormalities involve changes in the chromosome's structure, such as duplications, deletions, inversions, or translocations.
• Abnormalities can occur due to errors in cell division processes like meiosis or mitosis.
• Structural abnormalities can result from chromosomal breakage or rearrangement.

Human Chromosome Structure

• Human somatic cells have 23 pairs of homologous chromosomes, totaling 46 chromosomes.
• One chromosome in each pair comes from each parent.
• 22 pairs are autosomal chromosomes, carrying genes for various traits.
• 1 pair is the sex chromosomes, determining biological sex (XX for females, XY for males).

Chromosome Appearance in the Cell Cycle

• Chromosomes vary in appearance depending on the phase of the cell cycle.
• The cell cycle consists of interphase (cell growth and DNA replication) and mitosis (cell division).
• In early interphase, each chromosome is unreplicated, consisting of a single chromatid (46 chromosomes, 46 chromatids).
• In late interphase, chromosomes are replicated, with each chromosome consisting of two identical chromatids joined at the centromere (46 chromosomes, 92 chromatids).
• After mitosis, each daughter cell receives one chromatid from each chromosome, resulting in 46 chromosomes in each daughter cell.

Chromosome Abnormalities: General Information

• Chromosome abnormalities can be congenital (present from birth) or somatically acquired (occurring later in life).
• Congenital abnormalities often cause developmental or physical differences.
• Somatically acquired abnormalities are often associated with cancer and aging and are clonal.
• Historically, detection relied on light microscopy, but modern technologies like FISH and aCGH allow detection of submicroscopic abnormalities.
• 65% to 85% of the population have hyper copy number variants, larger variants are rarer.

Classification of Chromosome Abnormalities by Origin

• Congenital abnormalities are present at birth and may be inherited or arise de novo, often leading to genetic syndromes.
• Somatically acquired abnormalities occur later in life, are clonal, and often arise from environmental factors, associated with cancers and aging-related diseases.

Classification of Chromosome Abnormalities by Type

• Numerical abnormalities involve changes in chromosome number, such as trisomy or monosomy, caused by errors in meiosis or mitosis (nondisjunction).
• Numerical abnormalities are always clinically evident and usually de novo.
• Structural abnormalities involve changes in the physical structure of chromosomes, including duplications, deletions, inversions, and translocations.
• Balanced structural abnormalities usually do not cause clinical symptoms but can lead to reproductive issues.
• Unbalanced structural abnormalities can lead to developmental and physical issues, depending on the size and location of the abnormality.
• Balanced structural abnormalities do not cause clinical symptoms because the genetic material is not lost or duplicated, so the person has the usual amount of genetic material, but they can cause reproductive problems.
• Balanced structural abnormalities can cause miscarriages or an increased risk of passing on unbalanced chromosome arrangements to offspring, potentially leading to developmental or physical problems in their children.
• Unbalanced structural abnormalities often cause developmental or physical issues because there is either too much or too little genetic material, which can disrupt normal gene function.
• The symptoms depend on the size of the genetic change and the specific genes involved.
• Structural abnormalities can be passed from one generation to the next.

Detection Methods for Chromosomal Abnormalities

• Larger chromosomal abnormalities can often be detected with light microscopy.
• Smaller deletions and duplications require molecular cytogenetics (FISH) or DNA analysis techniques (aCGH).