I. Clinical Genealogical (Pedigree) Method
Definition
- A fundamental method in medical genetics used to study how traits and diseases are transmitted through generations.
- Involves constructing a pedigree (family tree) that records medical history of several generations.
Purpose
- Identify the mode of inheritance (AD, AR, X-linked, mitochondrial).
- Predict recurrence risk for relatives.
- Support diagnosis of hereditary diseases.
- Guide genetic counseling and prenatal testing.
Procedure
- 1. Data collection → detailed family history (3–4 generations).
- 2. Pedigree construction → standardized symbols (squares = males, circles = females, filled = affected, half-filled = carrier, line through = deceased).
- 3. Analysis → pattern of inheritance, age of onset, penetrance, expressivity.
II. Types of Inheritance of Monogenic Defects
Monogenic defects = diseases caused by mutations in a single gene locus. They follow Mendelian inheritance patterns.
1. Autosomal Dominant (AD) Inheritance
Definition: A single mutant allele on an autosome is enough to cause disease, regardless of the second allele.
Key Features
- Vertical transmission → disease appears in every generation.
- Affected individuals usually have one affected parent.
- Males and females equally affected (autosomal).
- 50% risk of transmission from affected parent to offspring.
- Unaffected individuals do not transmit disease.
- Often due to structural protein defects or receptor/signaling mutations.
Examples
- Marfan syndrome (FBN1 mutation → defective fibrillin).
- Huntington disease (HTT gene, CAG repeat expansion).
- Familial hypercholesterolemia (LDLR mutation → high LDL cholesterol).
- Achondroplasia (FGFR3 gain-of-function mutation).
Special Concepts
- Variable expressivity → same mutation causes different severity (e.g., Marfan).
- Reduced penetrance → some carriers do not show phenotype (e.g., retinoblastoma).
- New mutations → many AD diseases arise de novo (e.g., achondroplasia).
2. Autosomal Recessive (AR) Inheritance
Definition: Disease occurs only if both alleles are mutated; carriers (heterozygotes) are unaffected.
Key Features
- Horizontal pattern → disease often appears among siblings, but parents are unaffected.
- Parents usually carriers (heterozygotes).
- 25% risk of affected child if both parents are carriers.
- Males and females equally affected.
- More common with consanguinity (related parents).
- Usually involves enzyme deficiencies or metabolic disorders.
Examples
- Cystic fibrosis (CFTR mutation → chloride transport defect).
- Phenylketonuria (PAH mutation → impaired phenylalanine metabolism).
- Tay-Sachs disease (HEXA mutation → hexosaminidase deficiency).
- Sickle cell anemia (HBB mutation → hemoglobin polymerization).
Special Concepts
- Carrier advantage: Heterozygotes may have survival benefit.
- Example: Sickle cell trait protects against malaria.
- Founder effect: Certain AR mutations common in specific populations (e.g., Tay-Sachs in Ashkenazi Jews).