Genetics and Molecular Pathology
Mendelian and non-Mendelian inheritance
Know autosomal dominant (vertical transmission, variable penetrance, e.g. Marfan, Huntington, familial hypercholesterolaemia), autosomal recessive (horizontal pattern, consanguinity, e.g. cystic fibrosis, phenylketonuria), X-linked recessive (males affected, carrier females, e.g. Duchenne, haemophilia), and X-linked dominant patterns. Understand imprinting (Prader-Willi versus Angelman), mitochondrial inheritance (maternal transmission, heteroplasmy), and trinucleotide repeat disorders (anticipation, e.g. fragile X, Huntington).
Cytogenetics and mutations
Know aneuploidy (trisomy 21, 18, 13), translocations (Philadelphia chromosome t(9;22) BCR-ABL), deletions (22q11 DiGeorge), and inversions. Mutation types include missense, nonsense, frameshift, and splice-site. Distinguish germline from somatic mutations and their implications for inheritance versus tumour development.
Molecular diagnostics
Understand PCR, Sanger sequencing, next-generation sequencing, FISH, and microarray. Know the two-hit hypothesis for tumour suppressors and the concept of driver versus passenger mutations. Pharmacogenomics (e.g. thiopurine methyltransferase and azathioprine toxicity) and prenatal screening (combined first-trimester screening, cell-free DNA) are testable.
Traps
Do not assume a family history is absent in autosomal recessive disease. Penetrance and expressivity differ: penetrance is whether a phenotype appears; expressivity is its severity. A translocation may be balanced and phenotypically silent but cause disease through gene disruption or abnormal gametes.
Rule of thumb
For inheritance questions, draw the pedigree pattern first: vertical = dominant, horizontal with unaffected parents = recessive, male-only with carrier females = X-linked recessive. For tumour genetics, ask whether the mutation is germline (familial, earlier onset, bilateral) or somatic (sporadic, unilateral).