Genetic Disease and Chromosomal Abnormalities

Learning Objectives

  • At the end of this lecture the student should be able to:
    • Describe a chromosome and interpret a karyotype.
    • List the types of chromosomal abnormalities.
    • Explain what is meant by aneuploidy, polyploidy, robertsonian translocation, reciprocal translocation.
    • Understand the genetic basis and consequences of autosomal and sex chromosomal abnormalities.
    • Discuss the genetic basis of selected chromosomal disorders.
    • Explain different mechanisms involved in Down syndrome and demonstrate the relevance of these for recurrence risk.
    • Discuss advances in prenatal diagnosis.

Types of Genetic Diseases

  • Chromosomal abnormalities
  • Mendelian inherited single gene disorders
  • Complex multifactorial disorders
  • Other types of genetic disorders

Cellular Components Related to Chromosomes

  • Cell: Basic unit of life.
  • Nucleus: Organelle that contains chromosomes.
  • Chromosome: Structure within the cell nucleus that carries genetic information.
  • Chromatid: One-half of a duplicated chromosome.
  • Telomere: The end of a chromosome, which protects it from deterioration.
  • Centromere: The region of a chromosome where the two sister chromatids join.
  • p arm: The shorter arm of a chromosome.
  • q arm: The longer arm of a chromosome.

Cytogenetic Diagnosis

  • Cytogenetic testing is defined as the examination of the structure and number of chromosomes to identify chromosomal abnormalities.

Techniques in Cytogenetics

  • Karyotype: The complete set of chromosomes in an individual; used to assess chromosomal abnormalities.
  • G banding: A method used to stain chromosomes to produce a visible karyotype.
  • Fluorescence in situ hybridization (FISH): A molecular cytogenetic technique that uses fluorescent probes to detect and localize specific DNA sequences on chromosomes.
  • Array Comparative Genome Hybridization (CGH): A technique used to analyze the copy number variations across the entire genome.

Applications of Cytogenetic Techniques

  • Chromosomal abnormalities detection.
  • Identification of microdeletions.
  • Cancer diagnostics.

Karyotype Preparation

  • Karyotype preparation involves:
    • Actively dividing cells are necessary for chromosome analysis.
    • Requires culturing cells in the lab for analysis.
    • Chromosomes are arranged into a karyotype for structural or numerical abnormalities survey.

Normal Human Karyotype

  • Normal male karyotype: 46, XY.
  • Human gametes are haploid, containing 23 chromosomes.
  • All human somatic cells are diploid, containing 23 pairs of homologous chromosomes: 22 pairs of autosomes and 1 pair of sex chromosomes.

Morphological Classification of Chromosomes

  • Metacentric: Centromere is in the middle.
  • Submetacentric: Centromere is slightly off-center.
  • Acrocentric: Centromere is located near one end of the chromosome.
  • Designations of arms: Short arm (p) and Long arm (q).

Chromosomal Location of a Gene

  • Example: The X chromosome can be mapped with bands indicating specific regions (e.g., Xq23).

Chromosomal Abnormalities

Causes

  • Errors of fertilization or cell division can lead to chromosomal abnormalities, which are categorized into:
    • Numerical abnormalities: Changes in the number of chromosomes (e.g., trisomy, monosomy).
    • Structural abnormalities: Changes in the structure of chromosomes (e.g., deletions, duplications).

Examples of Structural Abnormalities

  • Deletions: Loss of a chromosome segment.
    • E.g., Cri du chat syndrome (deletion at 5p15).
    • E.g., Wolf-Hirschhorn syndrome (deletion at 4p16).
  • Inversions: Two breaks result in a segment being inverted.
  • Duplications: Extra segment of DNA is present.

Specific Genetic Disorders

Cri du Chat Syndrome (5p-)

  • Karyotype: 46, XX, del 5p15.
  • Characteristics include:
    • Distinctive high-pitched cry (cat-like sound).
    • Intellectual disability and developmental delays.
    • Microcephaly (small head size).
    • Distinctive facial features such as widely spaced eyes and low-set ears.

Wolf-Hirschhorn Syndrome (46, XY, del 4p16)

  • Notable features include:
    • Characteristic facial appearance (widely spaced eyes, prominent nose).
    • Delayed growth and development along with intellectual disability.
    • Seizures are common.

22q Deletion Syndrome (also known as DiGeorge syndrome, VCFS)

  • Karyotype appears normal (microdeletion <5Mb).
  • Common features include:
    • Underdeveloped chin, low-set ears, wide-set eyes, and small mouth.
    • Associated health issues include heart defects, immune system issues, and potential behavioral disorders such as ADHD.

Copy Number Variation (CNV)

  • CNV refers to variations in the number of copies of a particular segment of DNA among individuals.
  • CNVs can range from benign to pathogenic based on their gene content and occurrence.
  • Typically, large duplications/deletions visible under a microscope have significant effects.
  • The ClinVar database is essential for interpreting CNVs.

Translocations in Genetics

Reciprocal Translocation

  • Occurs when chromosomes break and exchange segments.
  • Example: The Philadelphia chromosome, associated with chronic myeloid leukemia (CML).
  • Karyotype representation: t(9;22)(q34.1;q11.2).

Robertsonian Translocation

  • A specific translocation between two acrocentric chromosomes.
  • Risk of aneuploid offspring (e.g., 45,XX,rob(13;14)(q10;q10)).

Outcomes of Unusual Chromosomal Arrangements

  • Possible outcomes for a child born to a parent with chromosomal rearrangement include:
    • Normal chromosome arrangement.
    • Inheritance of the same rearrangement.
    • Developmental delays or health problems.
    • Higher risk of miscarriage.

Numerical Abnormalities

Definitions

  • Polyploidy: A change in chromosome number that is an exact multiple of the haploid number.
    • Example: Triploidy (3n = 69).
  • Aneuploidy: Chromosome number is not an exact multiple of the haploid number, commonly due to nondisjunction during meiosis.
    • Trisomy: Extra copy of a specific chromosome, which can lead to conditions like Down syndrome (Trisomy 21).
    • Monosomy: Loss of one chromosome, such as in Turner syndrome.

Autosomal Aneuploidies

  • Fatal in the case of autosomal monosomies.
  • Notable trisomies include:
    • Trisomy 21 (Down syndrome).
    • Trisomy 18 (Edward syndrome).
    • Trisomy 13 (Patau syndrome).
  • Common features include growth restriction, intellectual disability, and congenital anomalies.
  • Incidence of aneuploidy increases with maternal age.

Down Syndrome (DS)

  • Intellectual disability: IQ typically ranges from 25 to 50.
  • By age 40, full Alzheimer's disease pathology observed in individuals with DS.
  • Common phenotypic traits:
    • Single transverse palmar crease, epicanthal folds.

Genetic Basis of Down Syndrome

  • Karyotype shows three copies of chromosome 21 in ~95% of cases: 47, XX/XY, +21.
  • Recurrence risk in future pregnancies is around 1%, irrespective of parental age.
  • Robertsonian translocations account for ~4% of cases.

Molecular Pathogenesis of Down Syndrome

  • DS is a disorder of gene dosage, with critical regions identified at 21q22 responsible for features associated with intellectual disability.
  • Variability in DS phenotypes is thought to result from genetic, epigenetic, and gene-environment interactions.
  • APP gene is implicated in amyloid production related to increased Alzheimer's risk.

Maternal Age Effect on Chromosomal Abnormalities

  • As maternal age increases, the risk for trisomy increases significantly (e.g., 1 in 250 at age 35, 1 in 30 at age 40).

Gametogenesis Differences

  • Males: Commences at puberty, completing mitosis cycle rapidly.
  • Females: Primary oocytes are arrested in meiosis I until puberty, and some remain dormant for decades.

Prenatal Screening and Diagnosis

  • First trimester screening (11-14 weeks): Nuchal translucency scan and maternal serum markers; detects ~85% DS cases.
  • Second trimester screening: Anomaly scan and quad tests.
  • Invasive methods (First trimester: CVS; Second trimester: Amniocentesis) used for definitive diagnosis.

New Technologies in Prenatal Testing

  • Cell-free DNA analysis allows for detecting extra chromosome copies in maternal blood.
  • New microdeletion panels are available for comprehensive risk assessment.

Specific Chromosomal Abnormalities

Edward Syndrome

  • Incidence: ~1 in 5000 births, with high mortality rates in infancy and profound developmental delays.
  • Karyotype representation: 47, XY, +18.

Patau Syndrome

  • Incidence: ~1 in 8-12 thousand births, severe psychomotor developmental delays with a high rate of extra digits.
  • Karyotype representation: 47, XX, +13.

Abnormalities of Sex Chromosomes

  • More common than autosomal abnormalities with better tolerance for imbalances.
  • Lyonization: Random inactivation of one X chromosome in females, leading to the formation of Barr bodies.

Turner Syndrome (45,X)

  • Common features include short stature, broad chest, and coarctation of the aorta.
  • Incidence of ~1 in 2000.

Klinefelter Syndrome (47, XXY)

  • Incidence of ~1 in 1000 males, characterized by hypogonadism and tall stature, commonly diagnosed due to infertility.

Summary of Chromosomal Abnormalities

Structural Abnormalities

  • Deletions.
  • Duplications.
  • Microdeletions/microduplications.
  • Inversions.
  • Ring chromosomes.

Numerical Abnormalities

  • Polyploidy.
  • Aneuploidy.
  • Trisomy.
  • Monosomy.