Genetic Diseases: Classification and Mechanisms

1. Concept:

• Genetic disease: A disease in which genetic factors (genes) play a significant role in its pathogenesis.

• Note: In many cases, genetic diseases arise from complex interactions between genetic factors and environmental factors.

2. Classification of Genetic Diseases:

• 2.1 Classification based on genetic factors:

• a. Single-gene disorders: Caused by mutations in a single gene.

• 5 types of single-gene disorders:

• Autosomal dominant/recessive inheritance:

• Autosomal dominant inheritance:

• The disease is more severe and appears earlier in homozygous dominant individuals (AA).

• Occurs in both males and females at equal rates.

• Pedigree chart is vertical, the disease can occur in multiple generations, except for exceptions such as new mutations, low penetrance,…

• Autosomal recessive inheritance:

• Pedigree chart is horizontal, not continuous across generations.

• Healthy parents, affected child => Aa x Aa, the probability of each child being affected is 25%.

• Both parents affected => the probability of each child being affected is 100%.

• Consanguineous marriage increases the risk of disease occurrence.

• X-linked dominant/recessive inheritance:

• X-linked dominant inheritance:

• The disease is more common in females than males.

• Pedigree chart is vertical, continuous across generations, with diagonal inheritance.

• Affected father, healthy mother => all daughters affected to varying degrees, all sons are normal.

• Healthy father, affected mother => 50% of children (sons/daughters) are affected.

• X-linked recessive inheritance:

• The disease is more common in males than females.

• Pedigree chart is horizontal, intermittent across generations, with diagonal inheritance.

• Y-linked inheritance:

• Inherited directly from father to son.

• b. Chromosomal disorders: Caused by abnormalities in the number or structure of chromosomes.

• Example: Down syndrome (46, XX/XY, +21)

• c. Multifactorial disorders: Caused by the interaction of multiple affected genes with environmental factors, mostly common diseases and birth defects.

• Example: Cleft palate, congenital heart defects.

• d. Diseases caused by somatic mutations:

• Example: Cancer.

• 2.2 Classification based on the weight of environmental and genetic factors:

• 100% genetic: The disease depends solely on genetic factors.

• Mostly genetic, less environmental: Genetic factors play the main role, environmental factors have minimal impact.

• Less genetic, mostly environmental: Environmental factors play the main role, genetics have minimal impact.

• Mostly environmental: The disease is primarily caused by environmental factors.

• 100% environmental: The disease is entirely caused by environmental factors.

3. Mechanisms of Genetic Diseases:

• 3.1 Abnormalities in chromosome number and structure:

• Balanced structural rearrangements: Translocations within the same chromosome, inversions.

• Unbalanced structural rearrangements: Deletions, duplications, isochromosomes, ring chromosomes, marker chromosomes,…

• 3.2 Gene mutations:

• Genomic imprinting:

• The same gene mutation can have different disease phenotypes depending on whether the mutated allele is inherited from the father or mother.

• Only observed in species with imprinting.

• Over 90 genes in humans are reported to be involved in genomic imprinting.

• Usually, these are enzyme genes.

• Uniparental disomy (UPD):

• Two chromosomes of the same pair are both inherited from either the father or the mother.

• Caused by rescue from trisomy or monosomy.

• Common diseases associated with genomic imprinting:

• UPD

• Microdeletions

• Mutations in the specific gene affected by genomic imprinting.

• Examples:

• Prader-Willi syndrome: Deletion of 15q11 – 15q13, lack of genes from father, lack of appetite control, constant feeling of hunger.

• Angelman syndrome: Deletion of 15q11 – 15q13, lack of genes from mother, happy facial expression and excited behavior.

• 3.3 Pseudodominant inheritance:

• Inheritance of genes located on the homologous regions of the X and Y chromosomes.

• 3.4 Contiguous gene syndromes:

• The occurrence of multiple single-gene disorders in the same patient due to the impact of several adjacent genes.

4. Some common genetic diseases:

• Cri-du-chat syndrome: 46, XX/XY, 5p-

• Hemophilia: Caused by mutations in the FVIII gene (clotting factor VIII) on the X chromosome.

• Achondroplasia:

• Prevalence: 1/25,000.

• Cause: Mutation in the FGFR3 gene on chromosome 4.

• Manifestation: Abnormalities in cartilage formation -> dwarfism, large head, flat nose, prominent forehead, kyphosis.

• Normal IQ.

• Children are born normally.

• Homozygous dominant: Death in infancy.

• Sickle cell anemia:

• Prevalence: 1/5,000 – 1/500.

• Cause: Mutation in the HBB gene (encoding beta-globin), codon 6 replaces A with T -> replaces glutamic acid with valine.

• Manifestation: Sickle-shaped red blood cells in low oxygen environments, hindering blood flow, leading to clumping and mass lysis.

• Symptoms: Anemia, pain, fatigue, shortness of breath, cold extremities, pale skin,…

• Hypophosphatemic rickets:

• Prevalence: 1/2,000.

• Cause: Mutation in the PHEX gene on the X chromosome.

• Consequence: Reduced phosphate absorption in the kidneys, hypophosphatemia, disturbed osteoblast activity.

• Trinucleotide repeats:

• Normal: 5 – 30 repeats.

• High number of repeats:

• Intracellular aggregation:

• Transcriptional silencing: Repeats in the 5’UTR region

• Abnormal length of pre-RNA or RNA dysfunction.

• Examples:

• Fragile X syndrome: CGG repeats >= 200 times, increased methylation of FMR1, inhibiting transcription of this gene.

• Huntington’s disease: CAG repeats >= 40 times.

Notes:

• Information on prevalence, cause, and manifestation may vary depending on the source of reference and research.

• Genetic diseases can impact the health, life, and reproduction of individuals and families.

• Consult with a healthcare professional for appropriate advice and support.