Prevention — Genetic Disorders, Screening and Gene Therapy

Q1.1 — Trend description (2 marks)

The risk of Down syndrome increases with maternal age in a non-linear (approximately exponential) pattern. At age 20 the risk is approximately 0.7 per 1000 live births, rising slowly to 1.1 per 1000 at age 30 [1], then increasing steeply to approximately 10 per 1000 at age 40 and 19 per 1000 at age 45 — a roughly 27-fold increase from age 20 to 45 [1].

Q1.2 — Estimate at age 38 (1 mark)

Approximately 5–7 per 1000 live births at age 38 (by interpolation between the age 35 value of 2.5 and age 40 value of 10, biased toward 40). Accept any value in the range 4–8 with supporting reasoning. [1]

Q1.3 — Biological mechanism (3 marks)

Women are born with all their primary oocytes already arrested at prophase I of meiosis [1]. These oocytes remain in meiotic arrest for decades — at age 40, oocytes have been paused for up to 40 years. During this extended arrest, the molecular structures responsible for chromosomal alignment and segregation (cohesin proteins holding sister chromatids together) degrade [1]. This increases the likelihood that chromosome 21 homologues fail to separate correctly (non-disjunction) when meiosis resumes at ovulation, producing an n+1 egg that gives rise to a trisomy 21 zygote upon fertilisation [1].

Q1.4 — Appropriate first test (2 marks)

NIPT should be offered first [1]. It can be performed from 10 weeks gestation, carries no procedural miscarriage risk (non-invasive — analyses cell-free fetal DNA in maternal blood), and is appropriate as a first-line screening tool to identify high-risk pregnancies. If the NIPT result is positive, amniocentesis would then be offered for definitive diagnosis. At age 37 (advanced maternal age), NIPT is commonly offered routinely in Australia [1].

Q2 — Cause-and-effect chain

Effect 1: The delta-F508 mutation causes the CFTR protein to misfold; it is recognised by quality-control pathways and destroyed before it reaches the cell surface.

Effect 2: Without functional CFTR in the membrane, chloride ions cannot be transported out of epithelial cells.

Effect 3: Two organs/consequences (any two of): (1) Lungs — thick mucus traps bacteria, leading to chronic lung infections (Pseudomonas aeruginosa, Staphylococcus aureus) and progressive lung damage; (2) Pancreas — mucus blocks pancreatic ducts, preventing digestive enzymes from reaching the small intestine (malabsorption, failure to thrive); (3) Reproductive tract — in males, the vas deferens is blocked by mucus, causing infertility.

Overall (2 marks): CF is autosomal recessive because one functional CFTR allele (in a carrier) produces enough chloride channel protein to prevent the disease phenotype — the single working allele is sufficient for adequate ion transport. Only individuals homozygous for loss-of-function mutations (or compound heterozygotes) produce no functional CFTR and thus develop the disease [1]. This explains carrier status: heterozygous individuals are phenotypically normal but can pass the mutant allele to offspring [1].

Q3 — Diagram critique (6 marks)

3.1 Error 1: The mother is labelled "affected" (fully shaded). Correction: A female with haemophilia A must be homozygous X^hX^h to be affected. A female who has only one X^h allele is a carrier (X^HX^h), not affected. She should be shown as a half-shaded circle (carrier symbol). [1+1]

3.2 Error 2: Both daughters are shown as affected (fully shaded). Correction: Daughters of a carrier mother and an unaffected father inherit either X^H or X^h from their mother and X^H from their father, giving X^HX^H (normal) or X^HX^h (carrier). Neither daughter receives X^hY — daughters cannot be affected unless their father is also affected. They should be shown as half-shaded (carriers) or unshaded (normal). [1+1]

3.3 Error 3: The caption and diagram incorrectly show the son as unaffected and state that "sons are protected by their Y chromosome." Correction: Males have only one X chromosome; a son who inherits X^h from his carrier mother has no second X to compensate, so he is affected (X^hY). The son should be shown as fully shaded and the caption corrected. [1+1]

Q4.1 — Fetal haemoglobin strategy (3 marks)

Sickle-cell disease is caused by a point mutation in the HBB gene encoding the beta-globin subunit of adult haemoglobin (HbA); the glutamic acid → valine substitution produces HbS, which polymerises when deoxygenated, distorting red blood cells into a sickle shape [1]. Fetal haemoglobin (HbF) uses gamma-globin chains (HBG1/HBG2) instead of beta-globin and does not polymerise with HbS [1]. By using CRISPR-Cas9 to disrupt the BCL11A repressor gene in the patient's blood stem cells, HbF production is reactivated, producing red blood cells that contain enough HbF to prevent sickling — effectively compensating for the defective HbA [1].

Q4.2 — Heritable effects (2 marks)

No, the therapy would not prevent the patient's children from inheriting sickle-cell disease [1]. Casgevy edits the patient's blood stem cells — somatic cells that do not contribute to gamete formation. The patient's sperm or egg cells still carry the original HBB mutation and would transmit it to offspring at the usual Mendelian probability. Only germline editing (modifying eggs, sperm or embryos) would produce heritable changes, and this is banned in most countries due to ethical and safety concerns about altering future generations [1].

Q4.3 — Ethical concern (1 mark)

Any one of: Access equity — at AUD $3.5 million without PBS listing, only extremely wealthy individuals could afford the treatment, creating a two-tiered system where genetics-based illness can be treated for the rich but not for most Australians; OR healthcare resource allocation — the cost of treating one patient could fund a much greater total health benefit if distributed across other interventions. [1]