Biology • Year 12 • Module 8 • Lesson 7
Genetic Diseases: CF, PKU, Huntington's Disease, Type 1 Diabetes
Apply the gene–protein–phenotype framework to real data, cause–effect reasoning, and unfamiliar genetic disease scenarios.
1. Interpret diagnostic data — sweat chloride testing for CF
The sweat chloride test measures the concentration of chloride ions (Cl−) in sweat. In CF, CFTR cannot reabsorb Cl− from sweat ducts, so sweat chloride concentration is elevated. The table below shows sweat chloride results for five patients (P1–P5) and their subsequent genetic results. 8 marks
| Patient | Sweat Cl− (mmol/L) | Diagnostic category | Genotype (CFTR alleles) | Clinical notes |
|---|---|---|---|---|
| P1 | 8 | Normal (<30) | CC (two normal alleles) | No respiratory symptoms |
| P2 | 24 | Normal (<30) | Cc (carrier) | No symptoms; tested after sibling CF diagnosis |
| P3 | 41 | Intermediate (30–59) | Cc (carrier, atypical) | Mild recurrent respiratory infections |
| P4 | 78 | Positive (≥60) | cc (two mutant alleles) | Classic CF — chronic Pseudomonas colonisation |
| P5 | 85 | Positive (≥60) | cc (two mutant alleles, compound heterozygous) | CF with pancreatic insufficiency |
1.1 Describe the relationship between CFTR genotype and sweat chloride concentration shown in the table. 2 marks
1.2 Using your knowledge of CFTR function, explain why sweat chloride is elevated in patients with CF (P4 and P5) but not in the carrier (P2). 3 marks
1.3 P5 is described as “compound heterozygous” — meaning they carry two different mutant CFTR alleles (e.g. F508del + G551D) rather than two copies of the same mutation. Predict whether P5’s sweat chloride result would be higher or lower than P4’s, and justify your prediction. 3 marks
2. Graph interpretation — CAG repeat length and age of onset in Huntington’s disease
The figure below shows data from a cohort study of 523 individuals with confirmed Huntington’s disease, plotting CAG repeat length in the HTT gene against the age at which motor symptoms first appeared. Each point represents one patient. The curve shows the best-fit regression line. 9 marks
Figure 2.1. Relationship between CAG repeat length and age of motor symptom onset in 523 patients with confirmed Huntington’s disease. Dashed line = best-fit regression. Data pattern after Langbehn et al. (2004), Clinical Genetics, 65(4): 267–277.
2.1 Describe the overall relationship between CAG repeat length and age of onset shown in the figure. Include approximate values from the graph in your description. 2 marks
2.2 Using your knowledge of the mechanism of Huntington’s disease, explain why longer CAG repeat lengths produce an earlier age of onset. 3 marks
2.3 A person has 38 CAG repeats in the HTT gene (in the “reduced penetrance” range of 36–39). Use the graph and lesson content to explain why this individual’s prognosis is uncertain. 2 marks
2.4 The phenomenon of “anticipation” describes the tendency for CAG repeats to expand further during transmission, particularly from fathers. Using the graph, predict what this would mean for the age of onset in the next generation compared to the parent with 50 repeats. 2 marks
3. Cause-and-effect chain — untreated PKU from birth to neurological outcome
The boxes on the left show the causes in the PKU pathway. In each empty right-hand box, write the effect that follows. The final box is your overall outcome. 5 marks
| Cause (given) | → | Effect (you write) |
|---|---|---|
| Mutation in both PAH alleles (autosomal recessive) | → | |
| Phenylalanine hydroxylase is non-functional | → | |
| Phenylalanine cannot be converted to tyrosine in the liver | → | |
| Elevated phenylalanine crosses the blood–brain barrier | → | |
| Overall outcome if untreated from birth (write one sentence): | ||
4. Apply to an unfamiliar scenario — familial hypercholesterolaemia (FH)
Familial hypercholesterolaemia (FH) is a genetic disease caused by mutations in the LDLR gene (encoding the LDL receptor protein on liver cell membranes). Normally LDL receptors bind LDL cholesterol (“bad cholesterol”) and internalise it for degradation. In FH, non-functional LDL receptors cause LDL to accumulate in the blood, depositing in artery walls and causing premature cardiovascular disease. Heterozygous FH (one mutant allele) causes moderately elevated LDL and cardiovascular disease from middle age. Homozygous FH (two mutant alleles) causes severely elevated LDL and cardiovascular disease in childhood. FH affects approximately 1 in 250 Australians and is significantly underdiagnosed. 8 marks
4.1 State the complete gene–protein–phenotype pathway for FH. 2 marks
4.2 Is FH a loss-of-function or gain-of-function mutation? Justify your answer. 2 marks
4.3 The description states that heterozygous individuals are affected (one mutant allele causes disease). Does this make FH autosomal recessive or autosomal dominant? Justify using lesson content. 2 marks
4.4 Explain why FH is classified as a genetic disease rather than an environmental one, even though diet (high saturated fat, high cholesterol) also elevates LDL in the general population. 2 marks
Q1.1 — Sweat chloride and genotype relationship
There is a positive relationship between the number of mutant CFTR alleles and sweat chloride concentration. Individuals with two normal alleles (CC) have the lowest sweat chloride (e.g. P1 = 8 mmol/L, below 30). Carriers (Cc) have intermediate values (P2 = 24 mmol/L normal, P3 = 41 mmol/L borderline). Individuals with two mutant alleles (cc) have the highest values (P4 = 78, P5 = 85 mmol/L), both in the diagnostic-positive range (≥60 mmol/L).
Q1.2 — Why sweat chloride is elevated in CF but not in carriers (3 marks)
CFTR normally reabsorbs Cl− from sweat ducts back into the body after Cl− has been secreted [1]. In P4 and P5 (cc), no functional CFTR protein is present — Cl− cannot be reabsorbed from the sweat duct and remains in sweat, producing elevated sweat chloride concentration [1]. In P2 (Cc carrier), one functional CFTR allele produces enough CFTR protein to maintain adequate Cl− reabsorption from the sweat duct, so sweat chloride remains within the normal range [1].
Q1.3 — Compound heterozygous sweat chloride prediction (3 marks)
P5’s result (85 mmol/L) is similar to or slightly higher than P4’s (78 mmol/L) but both are in the diagnostic-positive range, so the difference is clinically small [1]. Compound heterozygous individuals carry two different CFTR mutations, both of which abolish CFTR function; sweat chloride elevation depends on the absence of functional CFTR protein, not on which specific mutations are present [1]. If one of the two mutations in P5 causes a partially functional protein (e.g. G551D affects gating rather than folding), sweat chloride might actually be slightly lower than in a classic F508del/F508del patient — but in this dataset P5’s result is higher, suggesting both mutations cause near-complete loss of function [1]. Accept any justified prediction that the result would be positive (≥60 mmol/L) and explains the absence of functional CFTR.
Q2.1 — Graph trend description (2 marks)
There is a strong negative (inverse) relationship: as CAG repeat length increases, age of motor symptom onset decreases [1]. At approximately 38–42 repeats, onset is around 55–70 years; at 48 repeats, onset is approximately 35–45 years (marked on graph at ~40 years); at 60–66+ repeats, onset may occur in childhood or adolescence (juveniles <10 years) [1].
Q2.2 — Mechanism explaining longer repeat → earlier onset (3 marks)
Longer CAG repeats produce a mutant huntingtin protein with a longer polyglutamine (polyQ) tract [1]. The longer the polyQ tract, the more readily the protein misfolds and forms toxic aggregates, and the more rapidly these aggregates accumulate in striatal neurons [1]. Because neuronal death is progressive — and symptoms only appear once enough neurons have been lost — a faster rate of aggregate accumulation (from longer repeats) reaches the threshold of detectable damage sooner, producing an earlier onset [1].
Q2.3 — Uncertain prognosis at 38 repeats (2 marks)
With 38 repeats (in the 36–39 “reduced penetrance” range), the individual sits above the threshold for disease-causing alleles but below the fully penetrant range (40+ repeats) [1]. Some individuals with 36–39 repeats develop HD symptoms (at a late age, based on graph regression extrapolation past 70 years), and some may die of other causes before symptoms appear; penetrance is therefore incomplete, making it genuinely uncertain whether or not this individual will develop the disease in their lifetime [1].
Q2.4 — Anticipation and age of onset prediction (2 marks)
If a parent has 50 CAG repeats and the repeat expands (particularly during paternal transmission) to, say, 55–60 repeats in the next generation, the graph predicts an earlier onset — shifting from approximately 30 years (parent with 50 repeats) to approximately 15–20 years or younger in the offspring [1]. This means the child of the affected parent would develop symptoms earlier in life, and potentially in adolescence rather than mid-adulthood, consistent with the phenomenon of anticipation [1].
Q3 — PKU cause–effect chain
Row 1 effect: Phenylalanine hydroxylase enzyme is non-functional (zero enzyme activity). Row 2 effect: Phenylalanine cannot be converted to tyrosine in the liver. Row 3 effect: Phenylalanine accumulates to toxic levels in blood and tissues. Row 4 effect: Phenylalanine disrupts amino acid transport across the blood–brain barrier and impairs myelin synthesis — neurons are damaged. Overall outcome: Untreated PKU results in progressive intellectual disability, seizures, and behavioural problems due to phenylalanine neurotoxicity during critical brain development.
Q4.1 — FH gene–protein–phenotype pathway (2 marks)
Gene: LDLR (LDL receptor gene) → mutated allele(s) produce a non-functional or absent LDL receptor protein on liver cell membranes [1] → LDL cholesterol cannot be internalised and degraded by liver cells → LDL accumulates in blood → deposits in arterial walls → premature cardiovascular disease (phenotype) [1].
Q4.2 — Loss-of-function or gain-of-function (2 marks)
FH is a loss-of-function mutation [1]. The mutant LDL receptor simply fails to perform its normal role (binding and internalising LDL); it does not acquire a new toxic activity. This is the same mechanism as CF (absent CFTR channel function) and PKU (absent PAH enzyme activity), in contrast to Huntington’s disease where the mutant protein acquires a new toxic action [1].
Q4.3 — FH is autosomal dominant (2 marks)
FH is autosomal dominant [1]. In the lesson, autosomal dominance means one copy of a mutated allele is sufficient to cause disease — the heterozygous form (Cc) of FH causes disease, so the mutant allele is dominant over the normal allele. This contrasts with autosomal recessive conditions (CF, PKU) where one functional allele is sufficient to prevent the disease in carriers [1].
Q4.4 — FH as genetic rather than environmental disease (2 marks)
FH is classified as a genetic disease because the primary cause is an inherited mutation in the LDLR gene that is present from conception regardless of diet — individuals with homozygous FH develop severe cardiovascular disease in childhood even on a normal diet [1]. While diet can modulate LDL levels in the general population, dietary LDL elevation is a physiological response to intake; in FH the LDL receptor mechanism itself is broken. The disease is non-infectious, inherited from parents, and present from birth, meeting the definition of a genetic disease. Diet is a modifier, not the cause [1].