Genetic Pathology: Introduction to Genetics

Genetic Pathology Outline

• NFNF1612 is a course on Genetic Pathology.
• The course content includes: basic introduction to genetics, genetic expression and mutation, genetic inheritance patterns, Mendelian disorders, cytogenetic disorders, multifactorial disorders.
• Genetics is the study of heredity and its components include DNA, Genes, and Chromosomes.

What is "Genetics"?

• Genetics is the study of heredity.
• Important components include: DNA, Genes, Chromosomes.
• DNA is the double helix structure containing genetic instructions; Genes are segments of DNA that carry specific instructions to make proteins; Chromosomes are thread-like structures in the nucleus that carry genes.

Human Genome

• The human genome is the complete set of all genes present in humans.
• Normal human karyotype is 46, XY (Male) and 46, XX (Female).

Genes

• Genes contain coding and non-coding sequences.
• Coding sequences produce proteins.
• Non-coding sequences include promoter/enhancer sequences that regulate gene expression.
• Alleles are different forms of a gene. Dominant alleles express even if only one copy is present. Recessive alleles only show if both copies are present. Codominant alleles affect the phenotype equally when both are present.

Gene Expression

• Genes critically affect homeostasis. (homeostasis is the process of maintaining a stable internal environment by adjusting the bodily functions).
• This is done through protein expression (like enzymes and receptors).
• Gene expression involves the process of DNA transcription to produce mRNA, followed by mRNA translation to form a protein. Proteins carry out most cellular functions.

DNA Mutations

• Mutations are permanent changes in genetic components.
• Germ cell mutations are passed to offspring and cause heritable diseases.
• Somatic cell mutations do not cause hereditary diseases but are linked to diseases like cancer and congenital malformations.
• Three types of DNA mutations are genome mutations, chromosome mutations, and gene mutations.
  • Genome mutations involve whole chromosome loss or gain.
  • Chromosome mutations are rearrangements in genetic material, leading to structural chromosome changes.
  • Gene mutations are submicroscopic alterations in DNA sequences (genes).

Types of Gene Mutations

• Gene mutations can be point mutations (single base changes) – such as substitution, transition, transversion, nonsense mutation, missense mutation, silent mutation; or frame-shift mutations (insertions or deletions), trinucleotide repeats.
• Mutations can occur in the coding areas (affect proteins) or non-coding areas of a gene (regulate gene activity).

Sickle Cell Anemia

• Sickle cell anemia is a disease where the structure of hemoglobin (Hb) is abnormal.
• Mutations in the HBB gene primarily affect the beta-globin chain, leading to the production of hemoglobin S.
• These structural changes cause the red blood cells to sickle, which can lead to health complications.

β⁰-thalassemia

• β⁰-thalassemia is linked to premature termination within the β-globin gene translation.
• This results in shorter β-globin peptides leading to rapid degradation.
• The absence of functioning β-globin chains reduces functional hemoglobin, leading to reduced mature red blood cell production and associated health issues.

Tay-Sachs Disease

• Tay-Sachs disease involves mutations in the HEXA gene, which codes for the enzyme β-hexosaminidase A.
• This enzyme is crucial for breaking down GM2 ganglioside.
• Reduced or absent enzyme activity causes a buildup of GM2 ganglioside, leading to toxic accumulation and neuronal damage.

Modes of Genetic Inheritance

• Genetic inheritance patterns include autosomal recessive, autosomal dominant, X-linked recessive, X-linked dominant, Y-linked, codominance, and Mitochondrial DNA inheritance.
• Examples: Huntington disease, cystic fibrosis, Fragile X syndrome, Haemophilia, and Leber hereditary optic neuropathy.

Cytogenetic Disorders

• Cytogenetic disorders result from changes in chromosome numbers or structure.
• Examples include Down syndrome, 22q11.2 deletion syndrome, Klinefelter syndrome, and Turner syndrome.

Numerical Abnormalities

• Numerical abnormalities include: haploid (n), diploid (2n), euploid (2n, 3n,), polyploid (>2n), aneuploidy (2n-1, 2n+1, 2n+2, 2n-3), monosomy (2n-1), and trisomy (2n+1).

Structural Abnormalities

• Specific locations of genes on a chromosome are very important.
• Chromosomal breakage can lead to loss or rearrangement of genetic material.
• Common structural abnormalities include translocations, inversions, deletions, and ring chromosomes.

Polygenic Disorders (Multifactorial Disorders)

• Polygenic or multifactorial disorders result from interactions between several genes and environmental factors.
• An example is Diabetes mellitus, which can have genetic and lifestyle factors contributing to the development of the disorder.

Polymorphism

• Polymorphisms are variations in the genomic DNA sequence among individuals.

Reduced Penetrance

• Reduced penetrance means that a gene can be present but may not always cause a detectable phenotype.

Variable Expressivity

• Variable expressivity means that the severity of a phenotype can vary among individuals even when carrying the same genetic mutation.