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).

Worked example

A couple of Northern European ancestry have one child with cystic fibrosis and one unaffected child. Neither parent has CF. Genetic testing of the parents identifies the $\Delta F508$ variant in both.

Analysis.

• Both parents are heterozygous carriers ($Cc$).
• Each pregnancy: 25 percent CF, 50 percent carrier, 25 percent unaffected non-carrier.
• Unaffected sibling: two-thirds chance of being a carrier ($Cc$), one-third chance of being non-carrier ($CC$), conditional on being unaffected.
• Future pregnancies: 25 percent chance of CF each time.

Options. Preimplantation genetic diagnosis (PGD), prenatal testing by chorionic villus sampling, or natural conception with neonatal screening. Genetic counselling is essential.

Common traps

Confusing carriers and affected individuals. Carriers of recessive disease (CF, sickle cell) are heterozygous and unaffected. Dominant disease (HD) has no carriers in this sense; heterozygotes are affected.

Saying Huntington's is "later onset because of the dominant allele." Onset depends on the polyglutamine tract length and protein aggregation rate, not the dominant inheritance pattern itself.

Forgetting heterozygote advantage in sickle cell. The HbS allele frequency is high in malarial regions because $Ss$ carriers resist Plasmodium falciparum.

Calling cystic fibrosis "a lung disease." It is a multi-system disease affecting lungs, pancreas, gut, sweat glands and reproductive tract.

In one sentence

Cystic fibrosis (autosomal recessive, CFTR), sickle cell anaemia (autosomal recessive, HBB) and Huntington's disease (autosomal dominant, HTT) illustrate the three main Mendelian inheritance patterns, with pedigrees diagnosed by tracing generational appearance, carrier patterns and sex ratios of affected individuals.