Investigate the causes and effects of named genetic diseases on humans, including cystic fibrosis, sickle cell anaemia and Huntington's disease, and analyse pedigrees showing their inheritance

What this dot point is asking

NESA wants you to describe the cause, inheritance pattern and effects of named genetic disorders, and to read pedigrees identifying them. Cystic fibrosis, sickle cell anaemia and Huntington's disease are the three most commonly examined.

The answer

Cystic fibrosis (autosomal recessive)

Gene and mutation

CFTR (cystic fibrosis transmembrane conductance regulator), chromosome 7. The most common mutation is $\Delta F508$, a three-base-pair deletion that removes phenylalanine at position 508 of the CFTR protein.

Inheritance

Autosomal recessive. Two unaffected carrier parents ($Cc \times Cc$) have a 25 percent chance of an affected child. Carrier frequency in Australians of Northern European ancestry is approximately 1 in 25.

Pathophysiology

CFTR is a chloride channel in the apical membrane of epithelial cells. Loss of function reduces chloride and water secretion onto epithelial surfaces, producing thick viscous mucus. The mucus obstructs:

• Lungs. Mucus traps bacteria (Pseudomonas aeruginosa, Staphylococcus aureus), causing recurrent infection, inflammation and progressive lung damage.
• Pancreas. Blocked ducts prevent digestive enzyme delivery to the intestine, causing malabsorption and failure to thrive.
• Sweat glands. Excessive salt loss (the basis of the sweat chloride test).
• Reproductive tract. Congenital bilateral absence of the vas deferens in males causes infertility.

Treatment. Airway clearance physiotherapy, inhaled antibiotics, pancreatic enzyme replacement, high-calorie diet, and CFTR modulator drugs (e.g. ivacaftor for G551D, elexacaftor/tezacaftor/ivacaftor for $\Delta F508$). Lung transplant for end-stage disease. Gene therapy and gene editing (CRISPR) are in trial.

Sickle cell anaemia (autosomal recessive)

Gene and mutation

HBB (beta-globin) on chromosome 11. A single point mutation (GAG to GTG) changes glutamate to valine at position 6 of the beta-globin chain (the HbS allele).

Inheritance

Autosomal recessive. Homozygotes ($ss$) have sickle cell disease; heterozygotes ($Ss$) have sickle cell trait, which is largely asymptomatic but offers partial protection against malaria. This heterozygote advantage explains why the HbS allele reaches frequencies of 10 to 15 percent in West, Central and East Africa.

Pathophysiology

Mutant haemoglobin (HbS) polymerises under low oxygen tension, deforming red blood cells into rigid sickle shapes. Sickle cells:

• Block capillaries, causing painful vaso-occlusive crises and tissue infarction.
• Are destroyed prematurely, causing haemolytic anaemia.
• Predispose to bacterial infection (functional asplenia) and stroke.

Treatment. Hydration, pain relief during crises, hydroxyurea (boosts fetal haemoglobin), blood transfusions, prophylactic antibiotics. Allogeneic bone marrow transplant is curative. CRISPR-based gene therapy (Casgevy, approved 2023) edits the BCL11A gene to reactivate fetal haemoglobin and effectively cures the disease.

Huntington's disease (autosomal dominant)

Gene and mutation

HTT (huntingtin), chromosome 4. The mutation is an expanded CAG trinucleotide repeat in exon 1. Fewer than 27 repeats is normal; 36 or more causes disease. The expanded repeat encodes a long polyglutamine tract that makes the huntingtin protein toxic to neurons.

Inheritance

Autosomal dominant. One affected heterozygote parent ($Hh$) has a 50 percent chance per child of passing the affected allele. The repeat can expand further when transmitted, particularly through the father (anticipation): each generation may have earlier onset.

Pathophysiology

Mutant huntingtin causes selective neurodegeneration in the basal ganglia (caudate, putamen) and cortex. Symptoms include:

• Motor. Chorea (involuntary jerky movements), dystonia, later rigidity.
• Cognitive. Executive dysfunction, dementia.
• Psychiatric. Depression, irritability, psychosis.

Symptoms typically begin between ages 30 and 50, after most affected individuals have already had children, which is why the allele persists in populations. Death typically 15 to 20 years after onset, often from pneumonia.

Treatment. No disease-modifying therapy. Symptomatic management with tetrabenazine for chorea, antipsychotics, antidepressants. Antisense oligonucleotide trials (tominersen) target huntingtin mRNA.

Pedigree analysis for these conditions

Autosomal recessive pedigree (cystic fibrosis, sickle cell).

• Trait often skips generations (unaffected carriers).
• Both sexes affected equally.
• Two unaffected parents can have affected children.
• Consanguinity raises risk.
• Affected child cross $Cc \times Cc$: 25 percent affected, 50 percent carriers, 25 percent unaffected non-carriers.

Autosomal dominant pedigree (Huntington's).

• Trait appears in every generation.
• Roughly 50 percent of offspring of an affected parent are affected.
• Both sexes affected equally.
• Affected father can transmit to son (rules out X-linked).
• New mutations are uncommon; almost all cases have an affected parent.

Punnett squares (autosomal recessive carriers).

Ratio 1 CC : 2 Cc : 1 cc (25 percent affected, 50 percent carrier, 25 percent homozygous unaffected).

Examples in context

Example 1. Cystic fibrosis carrier screening in NSW pregnancy planning. Around 1 in 25 Australians of European ancestry is a heterozygous carrier (Aa) of a CFTR mutation, mostly F508del. RANZCOG guidelines since 2018 recommend reproductive carrier screening for all couples planning pregnancy. If both partners are heterozygous, their probability of an affected (aa) child is 1 in 4 per pregnancy. The NSW pre-pregnancy carrier screening program now includes CFTR alongside SMA and Fragile X. Detected carrier couples are offered options including PGT-M (preimplantation genetic testing during IVF) to select unaffected embryos, prenatal testing, or accepting the recurrence risk. The pedigree pattern - two unaffected carrier parents with an affected child - is the autosomal recessive signature.

Example 2. Huntington's disease predictive testing at Royal Melbourne Hospital. Huntington's disease is autosomal dominant, so an affected parent has a 50 percent chance of passing the expanded HTT allele to each child. The Royal Melbourne Hospital Predictive Testing Program offers presymptomatic genetic testing to adult children of affected parents, including extensive pre-test counselling (typically three sessions over months) to ensure informed consent. The test counts CAG repeats: under 27 normal, 27 to 35 intermediate, 36 to 39 reduced penetrance, 40 or more fully penetrant. Roughly 15 percent of eligible at-risk individuals choose to test. Those who test positive face complex life decisions including reproductive choices, career and insurance, all underpinned by the predictable autosomal dominant pedigree pattern (every generation affected).

Try this

Q1. Identify the inheritance pattern and chromosome location of (a) cystic fibrosis, (b) sickle cell anaemia, (c) Huntington's disease. [3 marks]

• Cue. (a) Autosomal recessive, CFTR on chromosome 7. (b) Autosomal recessive, HBB on chromosome 11. (c) Autosomal dominant, HTT on chromosome 4.

Q2. Two heterozygous CFTR carriers (Aa) have three children. Calculate (a) the probability that all three are unaffected, (b) the probability that at least one is affected. [3 marks]

• Cue. (a) (3/4) cubed = 27/64. (b) 1 - 27/64 = 37/64.

Q3. Compare the molecular and clinical features of cystic fibrosis and Huntington's disease. (a) Identify the gene and mutation type for each. (b) Describe the typical age of symptom onset. (c) Justify why genetic counselling differs between the two disorders. [2+2+3 marks]

• Cue. (a) CFTR three-base deletion (F508del); HTT CAG repeat expansion. (b) CF symptoms from infancy; HD typically 35-50 years. (c) HD predictive testing reveals future inevitable disease in an asymptomatic adult, raising different ethical issues than CF carrier testing.