Sickle cell heterozygous advantage: HbA/HbS carriers are largely asymptomatic but have partial protection against severe Plasmodium falciparum malaria. This balancing selection explains why the HbS allele remains at high frequency (~8–25%) in malaria-endemic regions of sub-Saharan Africa, the Mediterranean, Middle East, and India.

PKU — early treatment prevents disability: Neonatal screening (heel-prick Guthrie test / tandem mass spectrometry) detects PKU on days 2–5. Starting a low-phenylalanine diet within days of birth completely prevents intellectual disability. PKU is the textbook example of a treatable Mendelian disorder — the phenotype is controlled even though the genotype cannot be changed.

Haemophilia A — historical and clinical significance: Queen Victoria was a carrier ($X^H$ $X^h$). She passed the F8 recessive allele to multiple European royal families, producing affected males across three generations. This historical pedigree is the definitive real-world example of X-linked recessive criss-cross inheritance. Modern treatment involves prophylactic factor VIII concentrate infusions.

Down syndrome and maternal age: The risk of trisomy 21 increases sharply with maternal age. At age 20, risk is ~1 in 1500; at age 35, ~1 in 270; at age 45, ~1 in 35. This is because human oocytes are arrested in meiosis I prophase since fetal development — prolonged arrest degrades cohesin proteins that hold chromosomes together, increasing non-disjunction risk.

Turner syndrome clinical management: Affected individuals require growth hormone treatment for short stature and oestrogen replacement therapy for pubertal development. Fertility treatment with donor eggs is possible but biological fertility is not achievable due to streak gonads. Regular cardiac monitoring is needed for associated cardiovascular defects (bicuspid aortic valve, coarctation of aorta).

Klinefelter syndrome clinical management: Testosterone replacement therapy from puberty reduces feminising features and improves quality of life. Assisted reproduction with testicular sperm extraction (TESE) is possible in some Klinefelter males who have residual spermatogenesis.

Thalassemia prevention: Carrier screening of couples in high-prevalence regions (Mediterranean, South Asia, Southeast Asia) followed by prenatal diagnosis (chorionic villus sampling at 10–12 weeks or amniocentesis at 15–18 weeks) is used to prevent thalassemia major births. Bone marrow transplantation is the only curative treatment currently available.

Familial Down syndrome: Approximately 4% of Down syndrome cases are due to Robertsonian translocation (chromosome 14;21 fusion), not standard trisomy 21. In this form, a phenotypically normal parent carries a balanced translocation. Risk of Down syndrome in offspring is 10–15% for female carriers. This form is heritable and not associated with maternal age.