Medical Genetics and Human Disease Mechanisms
From mechanism to phenotype
Disease logic
Human disease can result from loss of function, gain of function, dominant negative effects, haploinsufficiency, altered dosage, repeat expansion, mitochondrial dysfunction, or regulatory disruption. Genotype-phenotype interpretation requires connecting molecular mechanism to tissue specificity, penetrance, and expressivity.
Which mechanism best describes a mutation that reduces the amount of functional protein below a critical threshold?
Haploinsufficiency occurs when one functional copy is insufficient for normal function.
Correct answer: Haploinsufficiency
Differentiate penetrance from expressivity.
They measure different aspects of genotype-phenotype correspondence.
Correct answer: Penetrance is the proportion of carriers who show the phenotype; expressivity is the severity or range of phenotype among affected individuals.
Cancer genetics
Somatic evolution
Cancer is a somatic evolutionary process driven by accumulating mutations, copy-number changes, epigenetic reprogramming, and selection within tissues. Driver mutations confer fitness advantages, while passenger mutations accumulate neutrally or near-neutrally. Tumor heterogeneity complicates diagnosis and therapy.
Inherited vs somatic disease genetics
Germline disease
- Present in all cells or inherited predisposition
- Often affects family segregation and recurrence risk
Somatic disease
- Arises during life in a subset of cells
- Common in cancer and mosaic disorders
What best describes a driver mutation in cancer?
Driver mutations confer a growth or survival advantage to the clone.
Correct answer: A mutation that increases clonal fitness
Why can the same pathogenic variant show variable expressivity across patients?
Disease expression is multi-factorial even for single-gene disorders.
Correct answer: Because modifier genes, environment, stochastic developmental effects, and epigenetic background can alter phenotype.
Clinical translation
Modern diagnostics often combine sequencing, copy-number analysis, RNA studies, and functional assays to resolve variants of uncertain significance.