Chromosomes

Chromosomes consist of chromatin, a complex of DNA and histone proteins. They exist in a highly condensed state during mitosis and meiosis, making them visible under a light microscope during metaphase. A standard human karyotype consists of 22 pairs of autosomes and 1 pair of sex chromosomes (XX in females, XY in males). Each chromosome has a short arm (p, for 'petit') and a long arm (q), separated by a primary constriction called the centromere. The position of the centromere classifies chromosomes as metacentric (middle), submetacentric (offset), or acrocentric (near one end). Acrocentric chromosomes (13, 14, 15, 21, 22) have 'satellites' containing ribosomal RNA genes. Telomeres are protective caps at the ends of chromosomes that prevent degradation and fusion. During the cell cycle, chromosomes replicate into two sister chromatids. Errors during meiosis, such as non-disjunction, lead to aneuploidy (e.g., Trisomy 21). Structural abnormalities include translocations, deletions, inversions, and duplications. Balanced translocations may not affect the individual but increase the risk of unbalanced offspring. Understanding chromosomal arrangement is pivotal for prenatal screening and diagnosing hematological malignancies.

The physical organization of chromosomes is crucial for gene regulation and inheritance. DNA is wound around histone octamers (H2A, H2B, H3, H4) to form nucleosomes. The further coiling of nucleosomes into 30nm fibers and loops allows 2 meters of DNA to fit into a microscopic nucleus. During the S-phase, DNA replicates. In mitosis, sister chromatids are pulled apart to opposite poles. Meiosis involves two divisions: Meiosis I (separation of homologous chromosomes) and Meiosis II (separation of sister chromatids). Meiosis I includes recombination (crossing over), which generates genetic diversity. Errors in these processes result in chromosomal disorders. Numerical abnormalities (aneuploidy) usually arise from non-disjunction. Structural abnormalities arise from chromosome breakage followed by faulty repair. For example, a Robertsonian translocation involves the fusion of the long arms of two acrocentric chromosomes and the loss of the short arms, which is clinically significant in Down's syndrome (roughly 4% of cases).

Chromosomal disorders are a major cause of congenital disabilities and miscarriage. Trisomy 21 (Down's syndrome) is the most common. Others include Trisomy 18 (Edwards) and Trisomy 13 (Patau). Sex chromosome aneuploidies like 45,X (Turner syndrome) and 47,XXY (Klinefelter syndrome) present with growth and fertility issues. Microdeletion syndromes (e.g., 22q11.2 deletion/DiGeorge syndrome) require specialized testing like FISH or CGH microarray. In adult medicine, chromosomal translocations are hallmarks of many cancers, such as the t(9;22) translocation in CML. Clinicians must identify 'red flags' such as dysmorphic features, developmental delay, or recurrent pregnancy loss, which warrant chromosomal investigation.

1. G-banded Karyotype: To look for numerical and large structural changes. 2. Fluorescence In Situ Hybridisation (FISH): To detect specific microdeletions or translocations. 3. Array Comparative Genomic Hybridization (aCGH): The first-line test for developmental delay to detect submicroscopic gains or losses. 4. QF-PCR: Rapid test for Trisomy 13, 18, and 21 during pregnancy.

Management is multidisciplinary. For Trisomy 21, this includes screening for cardiac defects (AVSD), thyroid dysfunction, and hearing loss. For Turner Syndrome, growth hormone and estrogen replacement are used. Genetic counseling is vital for families to discuss recurrence risks, especially in cases of balanced translocations. Definitive 'cure' for chromosomal numbers is not possible; treatment focuses on managing associated complications.