15. Cytogenetics

Cytogenetics Overview

• Cytogenetics is the study of chromosomes and their abnormalities.

• Key topics covered in today's lecture:

  • Cytogenetic Nomenclature

  • Chromosome Banding

  • Polyploidy and Aneuploidy

  • Diseases associated with extra autosomes or sex chromosomes

  • Translocations and rearrangements

Importance of Chromosome Abnormalities

• Chromosome abnormalities contribute to a significant fraction of genetic diseases.

• Occurrence: Approximately 1 in every 150 live births.

• Leading causes of pregnancy loss and intellectual disabilities.

• Noteworthy statistics:

  • 50% of first-trimester spontaneous abortions show chromosome abnormalities.

  • 20% of second-trimester spontaneous abortions show chromosome abnormalities.

  • Triploidy (69 chromosomes) is common at conception, often leading to early pregnancy loss due to dispermy (fertilization of an egg by two sperm).

Cytogenetic Nomenclature

• Karyotype: An ordered display of chromosomes categorized by size and the position of the centromere.

  • Banding karyotype of a normal male arranged from largest to smallest.

  • Chromosome Designations: e.g., 46, XY for normal male, 46, XX for normal female.

Chromosome Structures

• Chromosome structure determined by size & centromere position:

  • Metacentric: Centromere located in the middle.

  • Submetacentric: Centromere located between the middle & tip.

  • Acrocentric: Centromere near the tip. (13, 14, 15, 21, 22)

  • Telomere: The tip of each chromosome

    • p: short arm

    • q: long arm

Chromosome Banding Techniques

• Developed in the 1970s for detecting structural changes:

  • Q bands: Quinacrine stain (similar to G-bands).

  • G bands: Giemsa stain (A and T base-rich regions).

  • R bands: G/C base staining.

  • C bands: Constitutive heterochromatin, with a focus on centromeric regions.

  • NOR bands: Stains nucleolar organizing regions.

Chromosomal Abnormalities in Karyotypes

• Chromosomal anomalies and their descriptions:

  • 47, XX, +21: Female with trisomy 21 (Down syndrome).

  • 46, XY, del(4)(p14): Male with distal deletion on chromosome 4.

  • 46, XX, dup(5)(p14p15.3): Female with chromosome 5 duplication.

Fluorescence In Situ Hybridization (FISH)

• Uses fluorescently-labeled tags on DNA probes that hybridize to complementary DNA in chromosomes.

• Enables detection of specific genes and potential deletions in chromosomes.

• Example: Centromere-hybridizing probes for chromosome 17 in cases of 17p deletion.

Comparative Genomic Hybridization (CGH)

• Technique to detect large scale losses or duplications of chromosome regions.

• Used in cancer cells.

• More sensitive than FISH.

Chromosome Abnormalities and Incidence

• Types of abnormalities include:

  • Euploid: Exact multiple of the haploid number.

  • Polyploid: Extra complete set of chromosomes.

  • Aneuploid: Missing or additional individual chromosomes, including monosomy and trisomy.

    • Nondisjunction during meiosis = common cause of aneuploidy.

• Generalizations regarding chromosome abnormalities

  1. Associated with developmental delay (both mental and physical) in children and possibly severe mental disabilities in older persons.

  2. Alterations in facial features. Usually, patients with the same disorder have similarities in facial features.

  3. Delay in growth is common in autosomal syndromes.

  4. Congenital malformations are common, especially heart defects.

Genetic Syndromes Associated with Chromosome Abnormalities

• Trisomy 21 (Down syndrome): Most common autosomal aneuploid condition, incidence 1 in 700-1000 live births.

  • Delay in physical growth, distinct facial traits, congenital heart defects.

  • Caused by nondisjunction during meiosis

  • Regarded as new mutations

• Trisomy 18 (Edwards syndrome): Prevalence 1 in 6000 live births; characterized by severe clinical symptoms and low survival rates.

  • Prenatal growth deficiency, characteristic hand and face abnormalities.

• Trisomy 13 (Patau syndrome): Incidence of 1 in 10,000 births, often leading to early infant mortality.

  • Oral and facial clefts, microphthalmia (small eyes), and polydactyly.

• Cri-du-chat Syndrome: deletion of the short arm of chromosome 5

  • Severe mental impairment, microcephaly (small head), distinctive cry.

• Wolf-Hirshhorn Syndrome: deletion of the distal short arm of chromosome 4

Sex Chromosome Abnormalities

• Types and phenotypes include:

  • Turner Syndrome (45, X0): Female, short stature, webbed neck, congenital heart defects.

  • Klinefelter Syndrome (47, XXY): Taller stature, learning disabilities, gynecomastia.

  • Trisomy X (47, XXX): Variable presentation with potential sterility and mild disabilities.

Chromosomal Abnormalities & Rearrangements

• Balanced: a chromosome rearrangement that does not produce a loss or gain of chromosome material.

• Unbalanced: a chromosome rearrangement that causes a gain or loss of chromosome material.

• Translocations: the interchange of genetic material between nonhomologous chromosomes.

  • Reciprocal: two different chromosomes exchange segments of DNA, resulting in 2 derivative chromosomes having altered genetic material without any net loss.

  • Robertsonian: a type of chromosomal translocation that occurs when 2 acrocentric chromosomes fuse at their centromeres, resulting in a single chromosome and the loss of the short arms of the involved chromosomes.

• Chromosome Deletions: caused by a chromosome break and subsequent loss of genetic material.

  • Terminal Deletion: a single chromosome break leading to a loss that includes the chromosome’s tip.

  • Interstitial Deletion: when two breaks occur and the material between the breaks is lost.

• Chromosomal Duplications: often seen in the offspring of persons who carry a reciprocal translocation.

• Ring Chromosomes: form when deletions occur at both tips of a chromosome. The remaining chromosome ends fuse to form a ring.

• Chromosomal Inversions: the result of two breaks on a chromosome followed by the reinsertion of the intervening fragments at the original site, but in an inverted order.

  • Pericentric Inversion: the inversion includes the centromere.

  • Paracentric Inversion: the inversion does not include the centromere.

Cancer Cytogenetics

• Philadelphia Chromosome: reciprocal translocation in hematopoietic cells that occurs in bone marrow cells and can produce chronic myelogenous leukemia (CML). Chromosome 9 and 22

• Burkitt Lymphoma: reciprocal translocation that occurs in B cell lymphocytes involving MYC gene altering immunoglobulin loci. Chromosome 8 and 14