Basics of Medical Genetics Chromosomal Abnormalities

Dr Heba Kassem (Ph.D., M.D.)

By

Learning Objectives
1. 2. 3. 4. 5. 6. 7. Acknowledge the impact of genetic disease Classification of genetic disorders Determine methods of chromosomal analysis Define Karyotype and ideogram Classify chromosomal abnormalities List examples of numerical chromosomal disorders Determine types of structural chromosomal abnormalities

Genetic Disorders in different age groups

Spontaneous Miscarriage Neonatal Period Childhood Adulthood

Types of Genetic Disease

Single Gene Disorders Multifactorial/ Polygenic Disorders Chromosomal Disorders Mitochondrial Disorders Somatic Cell Genetic Disorders

Methods of chromosome analysis

Cytogenetics Molecular cytogenetics

Structure of chromosomes

Karyotype

Systematised arrangement of chromosomes: Size/position of centromere/banding pattern

Ideogram

Molecular Cytogenetics

Chromosomal Disorders
Numerical Structural

Causes of chromosomal abnormalities

Misrepair of broken chromosomes Improper recombination following crossing over during meiosis Mal-segregation of chromosomes during mitosis and meiosis

Chromosomal segregation

Numerical Abnormalities 1. Polyploidy

Simple multiple of a haploid chrom. Set
Triploidy (69 chromosomes, with XXX,XXY,XYY) Tetraploidy (92 chromosomes) (XXXX, XXYY)

Causes Lethal and results in spontaneous abortion

Triploidy (Partial Vesicular Mole)

Partial mole occurs when the extra set of chromosomes is of paternal origin

Numerical Abnormalities 2. Aneuploidy

Not involve the whole chromosome set (extra or loss of one or more chromosme)
Trisomy (autosomes:21, 13, 18; sex ch: XXX, XXY, XYY) Monosomy (sex chromosomes: XO)

Causes:
Nondisjunction Anaphase lag

Clinical Examples of Aneuploidy

Trisomy 21 Down Syd

Trisomy 13 Patau

Trisomy 18 Edwards Syd

Aneuploidy affecting the sex chromosomes

Turner Syd 45,XO Kleinfelter Syd, 47,XXY

Numerical Abnormalities 3. Mixoploidy

Two or more genetically different cell lineages within the same individual
Mosaicism: The genetically different cell lineages arise from the same zygote Chimerism: Genetically different cell lineages derived from 2 zygotes.

Mosaicism

Structural Abnormalities
Causes: misrepair of chromosome breaks or recombination between non homologous chromosomes.

Deletion: loss of part of chromosome

Terminal

Interstitial

Ring

Duplication: gain of a chromosome part Two breaks and unequal sister chromatid exchange or unequal exchange between two homologous chromosomes

Structural Abnormalities
Inversion: reversal of the order of chromatin between two breaks

Isochromosome: Horizontal Division of the centromere resulting in extra copy of an arm and loss of the other arm of the chromosome affected.

Structural Abnormalities
Translocation:
Robertsonian translocation (acrocentric chromosomes)

Reciprocal translocation (metacentric/submetacentric)

Translocation

Effect of balanced translocation

Normal Chromosomes

Balanced translocation 14/21 carrier

Possible gametes Outcome

Structural Abnormalities
Chromosomal fragile sites
X chromosome

Fragile site

 Chromosomal breakage syndrome

Visible lesions in metaphase chromosomes Defect in DNA repair Increased risk to cancer

Effect of Chromosomal Abnormalities

Unbalanced: abnormal phenotype Balanced: abnormal gametes resulting in offspring with unbalanced chromosomal

Indications of chromosomal analysis

Couples presenting with infertility Miscarriage Abnormal livebirths: multiple congenital abnormalities Unexplained Mental Retardation

X-Chromosome Inactivation
Lyon Hypothesis One X chromosome is active in the cells of the females due to dosage compensation Random inactivation Females are actually mosaics