Cytogenetics 10/28 & 10/30: Structural Chromosome Abnormalities & Chromosomal Disorders

Cytogenetics is the branch of genetics that studies chromosomes, their structure, and abnormalities.
Focus on structural abnormalities and chromosomal disorders, particularly
- Numerical abnormalities
- Structural abnormalities

Chromosomes can be classified into two main categories:
- Autosomal chromosomes: 22 pairs of chromosomes not related to sex determination.
- Sex chromosomes: Chromosomes that determine an individual's sex (e.g., XX for females, XY for males).
X-Chromosome inactivation: A phenomenon wherein one of the two X chromosomes in females is randomly inactivated to balance gene dosage between males and females.

Mitotic division: The process by which a single cell divides into two identical daughter cells.
Meiotic division: A type of cell division that reduces the chromosome number by half, resulting in gametes (sperm and eggs).
Chromosome segregation: The process during cell division by which chromosomes are distributed into daughter cells.
Gametogenesis: The formation of gametes through meiosis.

Numeric Abnormalities:
- Aneuploidy: The presence of an abnormal number of chromosomes in a cell (e.g., trisomy, monosomy).
- Polyploidy: The condition of a cell having more than two paired (homologous) sets of chromosomes.
Structural Abnormalities:
- Deletion: A portion of a chromosome is lost.
- Duplication: A section of a chromosome is duplicated.
- Inversion: A segment of a chromosome is reversed end to end.
- Translocation: A segment of one chromosome is transferred to another non-homologous chromosome.

Histological stain: Used for staining chromosomes to analyze their structure under a microscope.
Molecular cytogenetics: Techniques used to study the structure and function of chromosomes at the molecular level.

Trisomy: Presence of an extra chromosome (e.g., Down syndrome is caused by trisomy 21).
Monosomy: Absence of one chromosome from the pair (e.g., Turner syndrome which is characterized by a lack of one X chromosome).
Mosaicism: A condition where genetically different cells are present in the same individual.

Chromosome Deletion:
- Definition: A deletion occurs when a chromosome loses a segment due to breakage.
- Deletions can lead to partial monosomy (loss of one chromosome copy).
- Clinical examples:
  - Cri-du-chat Syndrome: Caused by deletion on chromosome 5 (46,XX,del(5p)). Symptoms include:
    - High-pitched cry resembling a cat's cry.
    - Severe mental retardation and facial anomalies.
    - Occurs in about 1 in 25,000 to 50,000 live births.
  - DiGeorge Syndrome: Resulting from deletion on chromosome 22 (46, XY, del(22(q11))). Symptoms include:
    - Craniofacial anomalies, heart defects, and mental retardation.
    - Detection rates – 1 in 2000 to 4000 live births.

Prader-Willi Syndrome and Angelman Syndrome:
- Both conditions arise from deletions on chromosome 15.
- The outcome depends on the parent from whom the deletion is inherited:
  - Prader-Willi Syndrome: deletion inherited from the father.
  - Angelman Syndrome: deletion inherited from the mother.

Definition: Inversions are intra-chromosomal structural rearrangements where segments of chromosomes are reversed.
Characteristics:
- No loss of genetic information but results in rearrangement of the gene sequence.
- Can lead to reproductive issues due to improper alignment during meiosis.
- Types:
  - Paracentric inversion: does not include the centromere.
  - Pericentric inversion: includes the centromere.
Clinical implications: Carriers can experience recurrent pregnancy loss due to disruptions during gamete formation.

Definition: Translocation involves interchange of chromosomal segments between two non-homologous chromosomes.
Types of Translocations:
- Reciprocal translocation: two chromosomes exchange segments.
- Robertsonian translocation: fusion involving acrocentric chromosomes, reducing total chromosome number by one.
Clinical Case: Down Syndrome: Rhiannon's case illustrates how a translocation can lead to Down syndrome, particularly involving chromosome 14 and 21, inherited through family history which includes miscarriages.

Isochromosomes: Chromosomes with identical arms formed due to meiotic errors leading to unbalanced genetic information. Commonly associated with tumors.
Ring Chromosomes: Formed when telomeres are lost leading to a circular structure. May cause multiple clinical issues.

A comprehensive understanding of chromosome abnormalities involves knowing both numerical (e.g., polyploidy, aneuploidy) and structural (e.g., deletion, duplication, inversion, translocation).
The phenotypic consequences of chromosome abnormalities depend on:
- Specific nature of the abnormality (numerical or structural).
- Type of genomic imbalance involved.
- Specific genes affected by the abnormality.

Examines the implications of potential chromosomal abnormalities in pregnancies, highlighting family history, reproductive problems, and the complexity of karyotyping in the assessment of congenital conditions.