L12 Genetics Investigating specific genetic disorders

Overview

This lecture has two parts. The first introduces “rare” genetic disorders and walks through the Specific Genetic Disorder Assignment: its structure, required headings, word limits and the research-appraisal and referencing skills (evidence hierarchy, primary vs review papers, citation, plagiarism, generative AI use) needed to write it well. The second is the science background for Tutorial 4: HFE-related Hereditary Haemochromatosis (HFE-HHC), covering its clinical picture, genetics, the hepcidin-ferroportin axis that normally controls iron absorption, how the C282Y mutation disrupts it, and why the disease shows incomplete penetrance.

Rare disorders and the genetics-diagnosis framework

• EU policy defines a disorder as rare when it affects less than 1 in 2000 people.
• Over 7000 rare disorders are known, with more discovered constantly (examples: Cystic Fibrosis, Huntington’s disease).
• An estimated 300 million people worldwide live with a rare disorder.
• 72% of rare disorders are genetic in origin, so are present throughout life even if symptoms appear later.
• About 50% of people affected by rare disorders are children.
• Overall mortality before age 5 is 30%, and few treatments exist.

Diseases with a genetic component fall into three groups, which feed into a common diagnostic pathway:

1. Monogenic - “rare” disorders (the focus of this assignment).
2. Polygenic - e.g. diabetes, autism, obesity.
3. Cancer.
   All three lead to identifying the genetic defect(s) and pathophysiology, which then splits into two applications:

• Diagnostics (e.g. haemochromatosis, CF carrier/affected screening, inherited cancer) → preventative medicine.
• Pharmacogenomics (e.g. mutation-specific CF treatment, targeted cancer therapies) → genetics-informed personalised/precision medicine.

Genetic diagnosis benefits patients through a biomarker-guided pipeline: patients are tested with biomarker diagnostics, which identifies which therapy subgroup they fall into, so each patient receives the treatment matched to them rather than a one-size-fits-all drug.

The Specific Genetic Disorder Assignment

Small groups of 3-5 investigate one assigned genetic disorder, to show they can find literature on a disorder, understand the genetic terminology used to describe it, and critically evaluate current research. Six disorders are assigned across the class:

#	Disorder
1	Familial Hypercholesterolaemia (LDLR)
2	Hypertrophic cardiomyopathy (MYBPC3)
3	Marfan Syndrome
4	Duchenne Muscular Dystrophy
5	Long QT syndrome type 1
6	Huntington’s disease

For disorders #1 and #2, the write-up must focus on the specific gene indicated (LDLR or MYBPC3 respectively).

There are two assessed components:

1. Individual written summary, submitted through Moodle by 7 pm Sunday 14 September 2025 (the course-schedule slide separately lists 15 September as the report due date; the transcript does not reconcile the two). Group discussion is allowed but the final written work must be the student’s own; graded by the tutor.
2. 10-minute group oral presentation with visual aids (e.g. PowerPoint) to the tutorial group; a simplified, illustrated version of the report where each person covers one slide on their research paper and briefly cites the source of any diagram/material on each slide (e.g. “Figure from N Engl J Med 358:291”). Presenting is a terms requirement.

The written summary is ~1100 words (800-1100 word range), with a per-section limit; references, figure legends, tables and the AI-use statement do not count toward the total. Figures are encouraged. Required headings, and what each must cover:

• Clinical features (150-250 words): disease presentation; prognosis with and without treatment; available treatments; anything relevant to the NZ population (e.g. differing prevalence in Māori or Polynesian peoples, or environmental effects such as UV exposure).
• Genes involved (100-200 words): which gene(s) are involved (if several loci/genes exist, focus on the most common but list examples); whether there is locus and/or allelic heterogeneity, illustrated with the student’s own disorder; the inheritance pattern, and whether heterozygotes are affected; the type(s) of mutation involved.
• Genetic diagnosis and testing (200-250 words): how the disorder is diagnosed, with a genetic focus but noting other diagnostic methods; availability and uptake of prenatal diagnosis, newborn screening, carrier testing or mutation testing; the effect of a diagnosis on family members; 2-3 advantages of testing asymptomatic individuals; whether a specific genotype predicts the phenotype.
• Research, in two parts: Current research (120-175 words) on developments that might change future management (gene therapy, prenatal diagnosis, carrier detection, treatments available overseas/in trials but not yet in NZ); and Research paper (120-175 words) summarising one recent primary genetics research paper (not a review), covering its aim, methods, main findings and likely impact on future understanding or treatment.

The research paper must be from 2024 or 2025, must be a genuine research paper (not a review), and its methods must have a genetics focus. Students should find a suitable paper before leaving next week’s tutorial, and partners within a group must each choose a different paper.

Appraising and citing genetics literature

The hierarchy of evidence (bottom to top, weakest to strongest): animal and laboratory studies (no humans involved) → case reports/series, narrative reviews, expert opinion, editorials (no formal design) → observational studies, comprising case-control studies (retrospective, looking back for risk factors) and cohort studies (prospective, following an exposed group for outcomes) → randomised controlled trials (prospective, testing a treatment) → meta-analyses/systematic reviews and clinical practice guidelines (secondary, pre-appraised/filtered evidence) at the top. Case-control, cohort and RCT studies together are “primary studies”.

For the assignment’s research-paper requirement specifically: RCTs, cohort studies, case-control studies and animal/laboratory studies are acceptable; meta-analyses/systematic reviews and clinical practice guidelines are not (they are reviews, not original research); case reports/series and narrative reviews are borderline.

A primary research paper differs from a review article in four ways:

• Content: a research paper presents new experimental/observational data; a review summarises, synthesises and critiques existing research.
• Purpose: a research paper advances knowledge with novel findings; a review gives a comprehensive overview of a field.
• Structure: a research paper follows IMRAD (Introduction, Methods, Results, Discussion) and is usually longer/detailed; a review is organised thematically or methodologically and varies in length.
• Contribution: a research paper adds original findings to the field; a review helps identify gaps and guide future research.

Citation practice: citation gives credit, supports an argument, and directs readers to sources; almost all statements need one. The two exceptions are common knowledge (e.g. “oxygen is essential for human respiration”) and the writer’s own observations/reflections (e.g. “based on our analysis, the new drug reduced symptoms more effectively than the placebo”). Direct quotes must use quotation marks. The lecture illustrates this with an uncited overstatement, “Trikafta is the most effective drug for all types of cystic fibrosis and cures the disease entirely,” contrasted with a properly hedged and cited version, “Trikafta is highly effective in treating cystic fibrosis patients with at least one F508del mutation in the CFTR gene, significantly improving lung function and quality of life, but it is not a cure for the disease (1).”

Avoiding plagiarism: understand the material being written about; reference correctly; allow enough time; reference sources while note-taking, not only at the end; know the referencing style used in the subject; be discriminating about sources, especially online ones. A reference is required when: copying work word-for-word (with quotation marks); paraphrasing or summarising someone else’s work; using someone else’s ideas; or using facts that are not common knowledge. If unsure, reference it. Unauthorised collaboration is working with others on an individually assessed task requiring individual answers; discussing ideas is fine, but answers must be written individually.

Generative AI may be used for research only, and carefully: it can hallucinate and invent citations, and students must be able to verify the source of any information in their assignment. The report must end with a reference list and a statement of how AI tools (e.g. ChatGPT, Grammarly, QuillBot) were used, if at all (e.g. grammar checking, rephrasing).

Hereditary Haemochromatosis (HFE-HHC)

Learning outcomes for this material (Tutorial 4/5): distinguish genetic screening from genetic testing; distinguish diagnostic, predictive and carrier genetic testing; understand the process of investigating a suspected genetic disorder and the people involved (family, GP, clinical geneticist, lead maternity carer, diagnostic laboratories); recognise that “genetic tests” can include clinical examination, metabolite assays and imaging, not only nucleic-acid analysis; know the laboratory techniques used and their advantages/limitations; know the parameters governing population genetic screening programmes; recognise the major features of Cystic Fibrosis and Hereditary Haemochromatosis and how genetic analysis is used in each.

Clinical features: iron overload with late onset, typically presenting in middle-aged men (30-40+) and later in women, who are protected by menstrual blood loss. Features include fatigue, joint pain/arthritis, “bronze diabetes”, cirrhosis and heart failure. By organ system: skin (bronze/grey discolouration), skeletal (arthritis, joint pain), heart (arrhythmia, failure), liver (cirrhosis, cancer, failure), pancreas (diabetes mellitus). Treatment is venesection (regular blood donation/phlebotomy) until iron levels normalise.

Genetics: caused by mutation in the HFE gene, usually homozygous p.C282Y (Cys282Tyr), sometimes with p.H63D (His63Asp) or other variants; collectively these Northern-European-associated variants are called “Celtic” mutations. Inheritance is autosomal recessive. In NZ Caucasians, homozygote frequency is about 1:200; more broadly, homozygote frequency is 1/200-1/250, but clinical penetrance is low. Carrier frequency in Northern Europeans is about 1/7-1/10 for p.C282Y and about 1/4 for p.H63D, so it is a common genotype with a low percentage of clinical effect (and diagnosis). A carrier-frequency map of Europe shows the highest rates in Ireland, the UK and Scandinavia. Both biochemical and genetic predictive testing are available; genetic testing costs the health system about $100.

Pathophysiology - the hepcidin/ferroportin axis: systemic iron homeostasis is controlled mainly by this axis.

• Normal state: iron enters the plasma through open ferroportin channels on gut enterocytes and from macrophage iron stores, binding transferrin (Tf). Hepcidin, made by the liver, is present at low levels and does not block ferroportin, so the gate stays open (very low hepcidin, gate fully open, is also seen physiologically in iron-deficient patients).
• Infection, inflammation, or iron overload: the liver secretes high levels of hepcidin, which closes the ferroportin gate, stopping iron absorption from the gut and stopping iron release from macrophages and the liver. Serum iron and transferrin saturation fall.
• In HFE-related haemochromatosis: the defective HFE protein fails to trigger adequate hepcidin production, so lifelong low hepcidin leaves ferroportin permanently open, causing excessive iron absorption from the gut despite already-adequate iron stores.

Molecular mechanism: normal HFE protein prevents ubiquitination and proteasomal degradation of the BMP (bone morphogenetic protein) receptor type I, Alk3, increasing its surface expression on hepatocytes; this raises BMP/SMAD signalling (via R-SMAD/SMAD4) into the nucleus, activating transcription of the hepcidin gene, so that rising iron levels normally trigger more hepcidin. With HFE mutations, this signalling is impaired: Alk3 surface expression and downstream signalling fall, hepcidin transcription and production drop, and ferroportin remains active, so dietary iron absorption continues unchecked, driving iron overload.

Incomplete penetrance: penetrance rises with age and is higher in men. Progression is staged: genetic predisposition (stage 0) is present in essentially all C282Y homozygotes (~1:200 of the population); biochemical expression (stages 1-2, rising transferrin saturation followed by rising serum ferritin) occurs in 40-75% of homozygotes; clinical disease (stages 3-4) occurs in only 2% of women and 30% of men. Clinical complications include liver cancer, cardiomyopathy, diabetes, cirrhosis, hypogonadism, osteoarthropathy and chronic fatigue; the liver can progress from normal to cirrhosis to hepatocellular carcinoma.

Self-test

1. Define what makes a disorder “rare” under the EU policy definition, and give two statistics illustrating the global burden of rare disorders.
2. Describe the three categories of genetic disease and the two downstream applications (with an example disorder each) that identifying a genetic defect can lead to.
3. Outline the personalised-medicine benefit pipeline: how does biomarker diagnostics change what treatment a patient receives?
4. List the two assessed components of the Specific Genetic Disorder Assignment, including their format and the rule about individual vs group work.
5. List the four required headings of the written assignment and state one thing each heading must cover.
6. What two constraints (beyond being a primary research paper) apply to the article summarised in the “Research paper” sub-section?
7. Distinguish a primary research paper from a review article in terms of content and structure.
8. Which levels of the evidence hierarchy are acceptable as the assignment’s “research paper,” and which are not?
9. When must a statement in the assignment be referenced, and what are the two exceptions?
10. Describe how generative AI may and may not be used in preparing the assignment, and what must be disclosed about its use.
11. Describe the clinical presentation of hereditary haemochromatosis, including why onset differs between men and women.
12. Describe the genetics of HFE-related hereditary haemochromatosis: the gene, its key mutations, the inheritance pattern, and the relevant carrier/homozygote frequencies.
13. Describe how the hepcidin-ferroportin axis normally regulates iron absorption, and how this changes during infection, inflammation or iron overload.
14. Explain the molecular mechanism by which the C282Y mutation reduces hepcidin production and leads to iron overload.
15. What is incomplete penetrance, and what proportion of C282Y homozygotes show biochemical versus clinical expression of haemochromatosis?
16. What is the standard treatment for haemochromatosis?
17. A 45-year-old Northern European man presents with fatigue, joint pain and bronzed skin and is found to be C282Y homozygous. His 30-year-old sister is also C282Y homozygous but has no symptoms. Using penetrance and the hepcidin-ferroportin mechanism, explain why she might currently be asymptomatic, and what testing would be appropriate to monitor her.

Answers

Reveal answers

1. A disorder is “rare” if it affects fewer than 1 in 2000 people (EU definition). Globally, an estimated 300 million people live with a rare disorder, and 30% of those affected die before age 5.
2. Monogenic (“rare”) disorders, polygenic disorders (e.g. diabetes, autism, obesity) and cancer all lead to identifying the genetic defect and pathophysiology. This splits into diagnostics (e.g. haemochromatosis, CF screening, inherited cancer) leading to preventative medicine, and pharmacogenomics (e.g. mutation-specific CF treatment, targeted cancer therapy) leading to genetics-informed personalised/precision medicine.
3. Patients are tested with biomarker diagnostics, which sorts them into subgroups; each subgroup then receives the therapy matched to it, so each patient gets an individualised treatment rather than a generic drug.
4. (1) An individual written summary submitted via Moodle, which must be the student’s own final work even though the topic can be discussed with colleagues; (2) a 10-minute group oral presentation with visual aids to the tutorial group, which is a terms requirement.
5. Clinical features (disease presentation, prognosis with/without treatment, treatments, NZ-relevant information); Genes involved (gene(s), heterogeneity, inheritance pattern, mutation type); Genetic diagnosis and testing (diagnostic methods, availability of prenatal/newborn/carrier/mutation testing, effect on family, advantages of testing asymptomatic people, genotype-phenotype prediction); Research (current research directions, plus a summary of one recent primary research paper).
6. It must be from 2024 or 2025, and its methods must have a genetics focus (as well as being a genuine research paper, not a review).
7. A research paper presents new experimental/observational data and follows the IMRAD structure (Introduction, Methods, Results, Discussion), usually at length; a review summarises and critiques existing research, is organised thematically, and varies in length. A research paper adds original findings; a review helps identify gaps and guide future research.
8. Acceptable: randomised controlled trials, cohort studies, case-control studies, and animal/laboratory studies. Not acceptable: meta-analyses/systematic reviews and clinical practice guidelines (these are secondary/filtered evidence, not original research). Case reports/series and narrative reviews are borderline.
9. Almost all statements need a reference. Exceptions: common knowledge (e.g. “oxygen is essential for human respiration”) and the writer’s own observations/reflections.
10. AI may be used for research only, and carefully, because it can hallucinate and fabricate citations; every fact used must be independently verifiable. The report must end with a reference list and a statement disclosing whether AI tools were used and, if so, how (e.g. grammar checking, rephrasing).
11. Iron overload causes fatigue, joint pain/arthritis, bronze skin discolouration, cirrhosis and heart failure, plus pancreatic diabetes. Men typically present earlier (30-40+) than women, who are protected by iron loss through menstruation and so present later.
12. It is caused by mutation in the HFE gene, usually homozygous p.C282Y, sometimes with p.H63D (together called “Celtic” mutations). Inheritance is autosomal recessive. In NZ Caucasians, homozygote frequency is about 1:200; carrier frequency in Northern Europeans is about 1/7-1/10 for C282Y and 1/4 for H63D.
13. Normally, iron enters plasma through open ferroportin channels on gut enterocytes and from macrophage stores, bound to transferrin; hepcidin (from the liver) is low and does not block ferroportin. During infection, inflammation or iron overload, the liver raises hepcidin, which closes ferroportin, stopping gut absorption and macrophage/liver iron release, so serum iron and transferrin saturation fall.
14. Normal HFE protects the BMP receptor Alk3 from degradation, keeping it expressed on hepatocytes and driving BMP/SMAD signalling that activates hepcidin gene transcription. The C282Y mutation impairs this signalling, so Alk3 expression and hepcidin transcription fall; with chronically low hepcidin, ferroportin stays open and iron continues to be absorbed unchecked, causing overload.
15. Incomplete penetrance means not every person with the genotype develops disease. About 40-75% of C282Y homozygotes show biochemical expression (raised transferrin saturation, then ferritin), but only 30% of men and 2% of women progress to clinical disease; penetrance rises with age and is higher in men.
16. Venesection (regular phlebotomy/blood donation) to remove excess iron, continued until iron levels normalise.
17. She is C282Y homozygous but, like most homozygotes, may not yet have progressed past the genetic-predisposition or early biochemical-expression stage: her hepcidin deficiency means ferroportin stays open and she is slowly accumulating iron, but clinical disease occurs in only 2% of women (versus 30% of men) partly because menstrual blood loss delays iron accumulation, and penetrance generally increases with age. She should have biochemical monitoring (transferrin saturation and serum ferritin) to track progression from biochemical to clinical expression, alongside her genetic test result.