In-Depth Notes on Chromosomal Abnormalities

Introduction to Medical Sciences
  • Subject: Genetics and Chromosomal Abnormalities
  • Presented by: Dr. Sunayna Best, Clinical Genetics ST6, LTHT
Key Objectives
  • Understand the anatomy of a normal metaphase chromosome
  • Recognize what a normal karyotype looks like and identify abnormalities
  • Comprehend the main types of chromosomal abnormalities and their origins:
    • Aneuploidies: Triploidy, Monoploidy
    • Microdeletions
    • Translocations
  • Learn the genetic findings and classical features of various syndromes:
    • Aneuploidy Syndromes:
    • Down’s syndrome
    • Edwards’ syndrome
    • Patau’s syndrome
    • Klinefelter syndrome
    • Turner syndrome
    • Microdeletion Syndromes:
    • Di George syndrome
    • Prader-Willi syndrome
    • Translocation-Related Diseases:
    • Chronic myeloid leukaemia
    • Recurrent miscarriage due to balanced translocation
Anatomy of a Chromosome
  • Composed of:
    • P arm (short arm)
    • Q arm (long arm)
    • Centromere (the central region)
    • Telomeres (ends of the chromosome)
  • Karyotyping analyzes chromosome size, banding patterns, and centromere positioning.
  • Chromosome 1 (Metacentric), Chromosome 4 (Submetacentric), Chromosome 14 (Acrocentric)
Karyotype and Chromosome Banding
  • Karyotypes display the number and structure of chromosomes.
  • Chromosome banding helps identify structural abnormalities by visualizing band patterns.
Chromosomal Abnormalities
  • Aneuploidy:
    • Abnormal number of copies of chromosomes:
    • Monosomy: Loss of one chromosome (e.g., total = 45)
    • Trisomy: Gain of an extra chromosome (e.g., total = 47)
    • Polyploidy: Gain of extra sets of chromosomes (e.g., triploid = 69)
Specific Genetic Syndromes

  • Down Syndrome: Trisomy 21

    • Karyotype: 47,XY,+21
    • Features: Characteristic facial features, mild to moderate intellectual disability, congenital heart disease

  • Edwards Syndrome: Trisomy 18

    • Karyotype: 47,XY,+18
    • Features: Intrauterine growth restriction, overlapping fingers, rocker-bottom feet

  • Patau Syndrome: Trisomy 13

    • Karyotype: 47,XY,+13
    • Features: Intrauterine growth restriction, and cleft lip/palate

  • Klinefelter Syndrome: 47, XXY

    • Features: Tall stature, infertility, normal intellect

  • Turner Syndrome: Monosomy X (45, XO)

    • Features: Infertility, short stature, webbed neck
Microdeletions and Microduplications

  • Di George Syndrome: 22q11.2 microdeletion

    • Features: Congenital heart defects, intellectual disability, psychiatric disorders

  • Prader-Willi Syndrome: 15q11.2-q13 deletion

    • Features: Low tone at birth, short stature, challenging behaviors
Translocations
  • Translocation Types:
    • Reciprocal: Exchange segments between two chromosomes
    • Robertsonian: Fusing of acrocentric chromosomes (e.g., 13, 14, 21)
  • Chronic Myeloid Leukaemia: Caused by a reciprocal translocation between chromosomes 9 and 22, resulting in a fusion oncogene (BCR::ABL) leading to abnormal cell growth.
Summary of Key Stressors
  • Karyotype can detect:
    • Abnormal chromosome number, location, and amounts (missing or additional segments)
    • Limitations: only visible changes above a resolution of ~5Mb
Screening Techniques
  • Combined Test: A screening for Down's syndrome, Edwards' syndrome, and Patau's syndrome conducted between weeks 10 and 14, combining ultrasound and blood tests to assess risk based on nuchal translucency and maternal age.