5. Despite the large number of unique mutations described in the LDL-R gene that cause familial
hypercholesterolemia, certain mutations are found in high frequency in specific populations, e.g., the
9.5 kb 3′ deletion is found in 35% of Finnish patients. This is an example of:
a. Variable expressivity
b. Allelic heterogeneity
c. Founder effect
d. Locus heterogeneity
Population Genetics Concept
Founder effect occurs when a small group establishes a new population, carrying limited genetic diversity. Rare alleles in founders become common in descendants due to drift, explaining elevated disease frequencies in isolated groups like Finns, Ashkenazi Jews, or Amish .
Option Analysis
- a. Variable expressivity: Incorrect; describes varying phenotype severity among genotype carriers, not mutation frequency patterns.
- b. Allelic heterogeneity: Incorrect; refers to different mutations at same locus causing same disease (true for LDL-R FH), but doesn’t explain population-specific prevalence .
- c. Founder effect: Correct; specific 9.5 kb deletion at 35% in Finns traces to common ancestor, amplified by isolation .
- d. Locus heterogeneity: Incorrect; different genes causing same phenotype (e.g., FH via LDLR/APOB/PCSK9), not single gene variants.
CSIR NET Relevance
Tests population genetics vs molecular pathology distinctions. Formula: founder effect increases allele frequency \( p’ = \frac{k}{2N} \) where k=mutant alleles in founders, N=founder number. Examples: Tay-Sachs (Ashkenazi), Ellis-van Creveld (Amish) .
