Genomics & Genetics

Because your family tree is more than just awkward Christmas dinners

Primary Care Genomics Family History Red Flag Recognition

Executive Summary

Quick navigation and key statistics

1 in 250

Familial Hypercholesterolaemia prevalence

5-10%

Cancers with hereditary component

1 in 40

Ashkenazi Jewish BRCA carrier rate

50%

Lifetime breast cancer risk with BRCA1

Downloads

path: GENOMIC MEDICINE (GENETICS)

Web Resources

Genomics Education Programme (HEE)
Main NHS genomics hub; courses, guides, case learning
Genomics in Primary Care (HEE)
GP-specific: family history, testing, referral, conversations
Genomics 101 Courses (HEE)
30-minute courses: genes, testing, family history
Genomics in the NHS e-Learning (e-LfH)
Structured NHS modules for everyday clinical care
Wales Genomics Toolkit
GP-friendly: when to think about genetics in practice
North West GMSA — Primary Care
Identification, referral, risk communication for GPs
South West Genomics — Primary Care Resources
Case examples and referral guidance for clinicians
East Genomics Education Platform
Free modules: hereditary cancer, cardiac, carrier testing
North Thames Genomics Training Catalogue
Large catalogue of genomics CPD for clinicians
RCGP Genomics Toolkit
RCGP-endorsed GP competency framework
NHS Genomic Medicine Service
National test directory & referral pathways
HEART UK — FH Resources
FH tools and cascade testing support
Macmillan Genomics Toolkit (Cancer)
Genomics in oncology; hereditary cancer testing overview

Brainy Bites: Essential Genomics Wisdom

The stuff seasoned GPs wish someone had told them sooner

🌳 The Three-Generation Rule

Always take a three-generation family history for cancer or cardiac concerns. Ask: "Tell me about your parents, grandparents, siblings, and children — any serious illnesses?"

💡 GPS: Grandparents, Parents, Siblings

💛 FH Screening Success

Cascade testing for familial hypercholesterolaemia prevents 76% of premature deaths. One diagnosis can save an entire family tree.

💬 "Your cholesterol is very high despite your healthy lifestyle. This might run in your family — we should test your relatives too."

⬇️ Autosomal Dominant Pattern

50% risk to each child, affects multiple generations, both sexes equally. Classic examples: FH, Huntington's, adult PKD.

💡 VERTICAL transmission — goes down the family tree

➡️ Autosomal Recessive Clues

Consanguinity, skips generations, siblings affected but not parents. Think CF, haemochromatosis, sickle cell.

💡 HORIZONTAL transmission — affects siblings in one generation

↘️ X-Linked Red Flags

Only males affected, transmitted through unaffected females, no male-to-male transmission. DMD, haemophilia, Fragile X.

💡 DIAGONAL transmission — uncle to nephew via carrier sister

✅ Genetic Testing Consent

Discuss: implications for family, insurance concerns, right not to know, psychological impact, no treatment available for some conditions.

💬 "Before we test, let's talk about what a positive result would mean for you and your family..."

🔑 Family History IS a Genetic Test

A well-drawn three-generation pedigree is your most powerful genomic tool. It costs nothing, takes 3 minutes, and can save a life. Ask about: age of onset, bilateral disease, multiple primaries, and consanguinity.

💡 GPS: Grandparents, Parents, Siblings — three generations, three questions

🎯 EARLY — Genetic Red Flag Mnemonic

Early onset (<50), Affected relatives (≥2 first-degree), Rare/unusual tumour type, Lateral/bilateral disease, Young relative with same condition. One tick = consider; three ticks = refer to genetics.

💡 One EARLY flag = think genetics. Three flags = refer.

⚠️ Penetrance vs Expressivity — Don't Mix Them Up

Penetrance = does the gene cause disease at all? (BRCA1 is ~70% penetrant for breast cancer). Expressivity = how severely? (NF1 varies from café-au-lait spots to plexiform neurofibromas). A patient with no symptoms can still carry and pass on the gene.

💡 Think: Penetrance = Present/Absent. Expressivity = how BAD.

💡 Autosomal Dominant Clue in AKT Questions

If the question shows an affected parent in EVERY generation and ~50% offspring affected → autosomal dominant. Skips generations with unaffected carrier parents producing affected children → autosomal recessive. Male-to-male transmission RULES OUT X-linked.

💡 Every gen = Dominant | Skips gens = Recessive | Males only = X-linked

📋 The 6-Question Family History Script

Ask: (1) Has anyone had [condition]? (2) At what age? (3) How many relatives? (4) Which side — mum or dad? (5) Are your parents related? (6) Any unexplained infant deaths or miscarriages? These six questions unlock most hereditary risk.

💡 6Qs = Condition, Age, Number, Side, Consanguinity, Losses

🚨 Never Diagnose from Direct-to-Consumer Tests

Patients increasingly bring 23andMe or AncestryDNA results to surgery. These are NOT clinical-grade diagnostics. Acknowledge findings, do NOT act on these results alone. Refer to clinical genetics if results flag a serious variant. Explain testing limitations kindly.

💬 "These tests can flag things that aren't actually a risk — let's look at this together and I can refer you if needed."

🩸 BRCA Referral Triggers

Refer if: breast cancer <40, ovarian cancer any age, male breast cancer, triple-negative breast cancer <60, bilateral breast cancer, Ashkenazi Jewish ancestry with breast/ovarian cancer.

💡 YOUNG OVARY: Young breast, Ovarian any age, Unusual (male/triple-negative), Not one side, Genetic background (Ashkenazi)

💊 Pharmacogenomics Is Here Now

CYP2C19 variants affect clopidogrel activation — poor metabolisers get less antiplatelet effect. TPMT variants affect thiopurine toxicity — ALWAYS check TPMT before azathioprine. You may encounter genomic data in discharge letters — flag for specialist review, don't ignore it.

💡 TPMT before Azathioprine — this is mandatory. Skipping it is negligent.

💬 What to Say When Results Are Uncertain

Try: "We've found a change in a gene that might increase risk, but we can't be certain. The genetics team are best placed to explain what this means for you and your family. Would you like me to refer you?" — Non-directive, honest, action-oriented.

💬 VUS = "Variant of Uncertain Significance" — always refer, never reassure or alarm alone

🆕 2026 NHS Genomic Register

NHS now maintains national register for BRCA/Lynch syndrome carriers. Automatic screening invitations sent. Always ask: "Has anyone in your family been told they have a genetic mutation?"

💬 Update family history at every relevant review — it can trigger system alerts automatically

🧬 The Basics of Genetics

Key terminology every GP should know — the foundation everything else builds on

📚 Basic Genetic Terminology

Start here — understanding these concepts makes every other genomics topic click

A gene is the basic unit of genetic information — think of it as a single instruction in the body's instruction manual.

Genes are made up of DNA (deoxyribonucleic acid)
DNA is used to make an RNA product — which is either directly functional itself, or acts as a template to build a protein
Proteins do almost everything in the body: they form structures, act as enzymes, carry signals, and defend against infection
A change (mutation) in a gene can alter the protein it produces — sometimes with significant consequences for health

💡 Simple analogy: Think of DNA as a recipe book. Each gene is one recipe. RNA is the chef's notes copied from the recipe. The protein is the finished dish. A mistake in the recipe (mutation) can produce a dish that looks or tastes wrong — that's what causes genetic disease.

Chromosomes are the protein strands around which DNA (and hence genes) is anchored — like thread wound around a spool.

Each human somatic cell (body cell) contains 23 pairs of homologous (matching) chromosomes — 46 chromosomes in total
Each pair contains one chromosome inherited from mum and one from dad
22 pairs are autosomes (non-sex chromosomes)
1 pair is the sex chromosome pair:
- Female genotype: XX
- Male genotype: XY

🎓 AKT Tip: When a question mentions chromosome number — 46 = normal somatic cell (diploid). 47 = trisomy (e.g. Down syndrome = trisomy 21, Klinefelter = 47,XXY). 45 = monosomy (e.g. Turner syndrome = 45,X).

Somatic cells (body cells)

All cells except sperm and eggs.

Diploid — contain 46 chromosomes (23 pairs). Every cell in your skin, liver, brain etc. has a complete double set.

Germ cells (sperm & eggs)

Sperm cells and ova (eggs) only.

Haploid — contain only 23 chromosomes (no pairs). One from each pair, ready to combine with the other parent's contribution.

When sperm and egg fuse at fertilisation, the resulting cell (zygote) has the full 46 chromosomes again — 23 from mum, 23 from dad
This halving and recombining is what enables genetic diversity across generations — every child is genetically unique

💡 Why it matters in GP practice: This is why inherited conditions follow predictable patterns. A parent with one faulty autosomal dominant gene passes it to 50% of children — because each child gets only one chromosome from each pair. Germ cell division (meiosis) is also where non-disjunction errors happen, producing trisomies like Down syndrome.

Penetrance

Does the gene cause disease at all?

The proportion of people who carry a gene variant who actually develop the condition.

Example: BRCA1 has ~70% penetrance for breast cancer — so ~30% of carriers never develop it despite having the mutation.

Expressivity

How severe is the disease?

The extent to which the gene variant manifests — i.e. how severely and in what ways the condition presents, even between people who both have it.

Example: Marfan syndrome — some patients only have arachnodactyly (long fingers); others have life-threatening aortic aneurysm. Same gene, very different severity.

How to remember the difference

PPenetrance = Present or absent — does the person get the disease at all? (Yes/No)
EExpressivity = Expression severity — if they do get it, how bad is it? (Mild/Moderate/Severe)

⚠️ Why this matters clinically: A patient with no symptoms can still carry a gene and pass it on to their children (incomplete penetrance). Two siblings with the same BRCA1 mutation may have very different cancer risks in practice due to other genetic and environmental modifiers (variable expressivity). Never reassure a carrier that they're "fine" based on current symptoms alone.

Genotype: The genetic make-up of an individual — the specific gene variants they carry. This is fixed at conception and doesn't change.
Phenotype: The observable characteristics or clinical features that result from the genotype interacting with the environment — what you see in the patient.
The same genotype can produce different phenotypes in different people (this is expressivity)
Different genotypes can sometimes produce similar phenotypes — this is why genetic testing is needed to distinguish conditions that look alike clinically

💡 Simple analogy: Genotype is your genes (the code). Phenotype is what you look like and how you present (the output). Expressivity and penetrance explain why the same code doesn't always produce the same output.

Allele: One version of a gene. Because chromosomes come in pairs, every person has two alleles for each gene — one from each parent.
Dominant allele: Only one copy is needed to express the trait or cause disease. The dominant allele "overrides" the other. Written with a capital letter (e.g. A).
Recessive allele: Two copies are needed (one from each parent) to express the trait or cause disease. Written with a lower-case letter (e.g. a).
Homozygous: Both alleles are the same (e.g. AA or aa)
Heterozygous: The two alleles are different (e.g. Aa) — this person is often a carrier of a recessive condition

🎓 AKT Tip: Autosomal dominant = one faulty allele causes disease (heterozygous affected). Autosomal recessive = need two faulty alleles (homozygous affected). Carrier = heterozygous for a recessive gene — unaffected themselves but can pass it on. This maps directly to pedigree patterns.

1️⃣ Data-Gathering, Family History & Pedigrees

Your most powerful diagnostic tool — costs nothing, reveals everything

📋 Taking a Three-Generation Genetic Family History

Structure for gathering information that may transform your clinical management

💬 Script: "I'd like to ask you about your family's health history — it helps me spot whether there might be anything hereditary we should know about. It's just a few quick questions..."

1. Has anyone in your family had [condition]? — cast wide: mention cancer, heart disease, stroke, developmental delay, recurrent miscarriage
2. At what age were they diagnosed? — onset before 50 years is always significant for most conditions
3. How many relatives were affected? — ≥2 first-degree relatives = significant; ≥3 = strongly consider genetics referral
4. Which side of the family — maternal or paternal? — affects inheritance pattern interpretation significantly
5. Are your parents related to each other? — consanguinity (cousins, close relatives) raises autosomal recessive risk substantially
6. Any unexplained infant deaths, stillbirths, or miscarriages? — recurrent pregnancy loss may have chromosomal or genetic cause

Mnemonic: FAMILY TREE

FFirst-degree relatives — parents, siblings, children
AAge of onset — younger = more concerning
MMultiple affected — pattern recognition
IInheritance pattern — vertical / horizontal / diagonal
LLaterality — bilateral disease more suspicious
YYoung onset — cancer <50 years always flags

Physical Findings That Should Trigger a Genetic Thought Process

📋 Dysmorphic Features

Epicanthic folds, single palmar crease — Down syndrome
Webbed neck, short stature — Turner syndrome
Arm span > height, arachnodactyly — Marfan syndrome
Café-au-lait spots ≥6, >5mm (pre-pubertal) — NF1
Lisch nodules on iris (slit-lamp) — NF1
Ash-leaf macules (Wood's lamp) — Tuberous sclerosis

📋 Systemic Clues

Corneal arcus <45 years — Familial hypercholesterolaemia
Tendon xanthomata / xanthelasma — FH
Lens dislocation — Marfan syndrome or homocystinuria
Small testes + tall male — Klinefelter syndrome
Bronze skin + liver disease + diabetes — Haemochromatosis
Haemarthrosis in young male — Haemophilia

🎓 AKT Tip: Physical exam findings in AKT scenarios are often the only clue to a genetic diagnosis. Learn the classic phenotypes above — they appear frequently as single best answer questions.

🚩 Genetic Red Flags — "EARLY" Mnemonic

EEarly onset — cancer, MI, or other serious disease before age 50
AAffected relatives — ≥2 first-degree relatives with same condition
RRare tumour type — male breast cancer, ovarian clear cell, medullary thyroid
LLateral / bilateral — bilateral breast, bilateral renal tumours, bilateral retinoblastoma
YYoung relative — same cancer in a young relative (nephew/niece <40)

⚠️ Additional flags: Multisystem disease (multiple organ involvement), developmental delay + dysmorphic features, recurrent miscarriages ≥3, unexplained infant deaths, consanguinity, or any patient where the diagnosis "doesn't add up."

🚨 Rule of thumb: 1 EARLY flag = consider genetics; 3+ EARLY flags = refer to genetics. When in doubt, refer — it's never wrong to ask.

Use plain language: "Genes are like instruction books in your cells" — not "alleles and loci"
Explain inheritance simply: "You got half your genes from mum, half from dad — so there's a 1-in-2 chance each child could inherit this"
Discuss probability, not certainty: "This increases your risk, but doesn't guarantee you'll get it"
Non-directive counselling: Present options without pushing a particular choice. Say "some people choose..." not "you should..."
VUS — variant of uncertain significance: "We've found a gene change we don't fully understand yet. The genetics team are experts at interpreting this."
Cultural sensitivity: In South Asian and Middle Eastern communities, carrier status can affect marriage prospects — approach with empathy; offer privacy.

💬 Script: "Your family history suggests there might be an inherited component. This doesn't mean you'll definitely develop the condition, but it does mean we should keep a closer eye on things. Would you like me to refer you to a genetics specialist?"

📊 Constructing a Pedigree — Symbol Reference

Standard NSGC nomenclature — used in AKT questions, genetics referrals, and clinical records

Start with the patient (proband): Mark with an arrow, place in the middle of the page
Work upwards: Add parents, then grandparents
Work sideways: Add siblings, then aunts/uncles and cousins
Work downwards: Add children if applicable
Label each person: Age (or age at death), relevant diagnoses, carrier status if known
Note ethnic background: Especially if relevant to condition (e.g., Ashkenazi Jewish for BRCA)

🎓 AKT Exam Tip: You'll be shown pedigrees and asked to identify inheritance patterns. Practice recognising: vertical transmission (autosomal dominant), horizontal transmission (autosomal recessive), and diagonal transmission (X-linked). Male-to-male transmission rules out X-linked.

Symbol	Name	Meaning & Clinical Note
◯	Female (unaffected)	Empty circle. No disease/trait present.
⚫	Female (affected)	Filled circle. Has the disease/trait being studied.
□	Male (unaffected)	Empty square. No disease/trait present.
■	Male (affected)	Filled square. Has the disease/trait.
◇	Unknown sex (unaffected)	Diamond. Used when sex is unknown or not disclosed; also used for early pregnancy.
◆	Unknown sex (affected)	Filled diamond. Unknown sex with condition.

Symbol	Name	Meaning & Clinical Note
◍	Female carrier (obligate)	Circle with central dot. Carries one copy of autosomal recessive gene — unaffected but can pass on. Obligate = deduced from pedigree structure (e.g. unaffected mother of two affected sons in X-linked).
▤	Male carrier (obligate)	Square with central dot. Usually denotes autosomal recessive carrier male. Rare for X-linked.
⚦	Female carrier (half-filled)	Half-shaded circle. Used in X-linked recessive — carrier female has one functional X-linked gene copy. Clinically important: may have mild symptoms (e.g. carrier females in DMD can develop cardiomyopathy).
⚥	Male mosaic (half-filled)	Half-shaded square. Mosaicism — individual has two cell populations. E.g. Turner mosaic (45X/46XX). Features may be milder.

🎓 AKT Tip: "Obligate carrier" is a key concept — a person who must carry the mutation based on pedigree structure, even if untested. The unaffected mother of two haemophilia boys is an obligate carrier.

Symbol	Name	Meaning & Clinical Note
✟	Deceased female	Circle with diagonal line through it. Always record age at death and cause — critical for genetic risk assessment. Age notation: "d.47 Ca breast"
⊠	Deceased male	Square with diagonal line. Document cause of death where known — vital for cancer syndrome pedigrees.
△	Pregnancy (unknown sex)	Triangle. Gestational age noted inside (e.g. "20wk"). Used for ongoing pregnancies where sex not yet known.
▲	Pregnancy (affected)	Filled triangle. Pregnancy with condition identified prenatally.
SB	Stillbirth	"SB" written below symbol. Gestational age noted. Record whether karyotype was performed.
m	Miscarriage	Small dot with "m" label. Important for recurrent pregnancy loss assessment (≥3 = refer to genetics).
TOP	Termination of pregnancy	"TOP" below symbol. Distinguish from spontaneous miscarriage. Note genetic indication if any.

Symbol	Name	Meaning & Clinical Note
□ — ◯	Partnership line	Horizontal line connecting two individuals. Indicates a reproductive couple (married or not).
□ ═ ◯	Consanguineous union	Double horizontal line. Related couple (e.g. cousins). Increases risk of autosomal recessive disorders — very important in genetics history. Always ask sensitively.
□ - - ◯	Non-paternity / donor	Dashed line. Sperm/egg donor or disputed paternity. Handle sensitively — affects risk calculations.
\| (vertical)	Line of descent	Vertical line from couple to offspring.
⎯	Sibship line	Horizontal line from which siblings hang. Numbered left to right by birth order. Eldest child always on the left.
[ □ ]	Adopted individual	Brackets around symbol. Use genetic family for risk assessment — not adoptive family.
➔ □	Proband (index case)	Arrow pointing to the affected individual who first presented. Label with "P". This is the starting point of the pedigree.

⚠️ Generation Labelling: Generations are numbered I (top/oldest) downward with Roman numerals. Individuals within each generation are numbered left to right (e.g. III-2 = 3rd generation, 2nd individual). This is the standard in genetics referrals.

Symbol	Name	Meaning & Clinical Note
◔	Variable expression	Partially shaded symbol. Individual carries the gene but shows only some features. Common in NF1 and Marfan syndrome.
⌀	No offspring / infertile	Line through or specific notation. Relevant when tracing transmission through childless generations.
2 (inside)	Twins — dizygotic	Two symbols hanging from a single descent point, connected by a V-line. DZ twins share 50% DNA on average — same genetic risk as siblings.
\| (inner)	Twins — monozygotic	Horizontal bar connecting the two descent lines. MZ twins share 100% DNA — if one affected, same genetic risk in other. Discordance = environmental/epigenetic factors.
?	Uncertain diagnosis	Question mark above/beside individual. Reported or suspected diagnosis, not confirmed. Note source (patient report, medical records, death certificate).
Dx.XX	Age at diagnosis notation	Written below symbol (e.g. "Dx.47 Ca breast"). Essential for familial cancer risk — age of onset determines referral threshold.

🧠 How to Read a Pedigree — "GASI" Mnemonic

GGenerations — How many generations affected? Every generation = dominant. Skipped generation = recessive.
AAffected ratio — What proportion of offspring are affected? ~50% = dominant; ~25% = recessive.
SSex bias — Mainly males affected, carrier females? Think X-linked recessive (haemophilia, DMD). Both sexes = autosomal.
IIndex case — Find the proband (arrow). Work outwards to deduce carrier parents from the offspring pattern.

🎓 AKT Exam Tip: In AKT pedigree questions: (1) look for male-to-male transmission first — if present, rules out X-linked; (2) if only males affected with carrier females → X-linked recessive; (3) if parents are cousins → think autosomal recessive; (4) if the condition worsens each generation → think anticipation (e.g. myotonic dystrophy, Huntington's).

✓ GP Tip: You don't need to draw a perfect pedigree in every consultation. The goal is to spot the pattern. Even a quick mental check — "Is this condition turning up in multiple relatives, at young ages, bilaterally?" — is clinical genomics in action.

2️⃣ Inheritance Patterns & Investigations

The six patterns every GP must recognise — heavily tested in AKT

Understanding Inheritance Patterns

Pattern	Key Pedigree Features	Risk to Offspring	GP Examples
Autosomal Dominant	Every generation affected; both sexes equally; affected parent always present; male-to-male transmission possible	50% of offspring of affected parent	FH, ADPKD, Huntington's, NF1, Marfan, Myotonic dystrophy
Autosomal Recessive	Skips generations; both sexes affected; parents often unaffected carriers; consanguinity increases risk	25% if both parents are carriers	CF, Haemochromatosis, Sickle cell, Thalassaemia, PKU, Wilson's disease
X-linked Recessive	Mainly males affected; carrier females usually unaffected; NO male-to-male transmission; all daughters of affected males are carriers	50% sons of carrier mother affected; 50% daughters are carriers	Haemophilia A/B, Duchenne/Becker MD, G6PD deficiency, Fragile X
X-linked Dominant	Both sexes affected; affected father passes to ALL daughters (not sons); more severe in males (often lethal)	50% daughters of carrier mother; all daughters of affected father	Rett syndrome, Incontinentia pigmenti, X-linked hypophosphataemia
Mitochondrial	Maternal inheritance ONLY — all children of affected mother at risk; fathers NEVER pass on; variable penetrance (heteroplasmy)	All offspring of affected mother at risk (variable severity)	MELAS, Leber hereditary optic neuropathy (LHON), MERRF
Multifactorial	No clear Mendelian pattern; multiple relatives with mildly elevated risk; influenced by environment	Population risk + familial increment (usually 2–5x)	Type 2 diabetes, CAD, hypertension, asthma, common cancers

Mnemonic: "DAME X-M" — the 6 inheritance patterns

DDominant (autosomal) — every generation, 50% risk, FH/Huntington's/Marfan
AAutosomal recessive — skips generations, 25%, consanguinity clue, CF/Haemochromatosis
MMultifactorial — environment + genes, common diseases, risk increases with family history
EEpigenetic — imprinting: Prader-Willi (paternal del) vs Angelman (maternal del) — same region, different phenotype
XX-linked (recessive/dominant) — males mainly affected, no male-to-male, carrier females
MMitochondrial — mum only passes it on; all children of affected mother at risk

⚠️ AKT Pitfall: Genomic imprinting (e.g. Prader-Willi, Angelman syndrome) produces different phenotypes depending on whether the abnormal gene comes from mum or dad — this is NOT classic Mendelian inheritance. Anticipation (worsening severity each generation, e.g. myotonic dystrophy, Huntington's) also doesn't fit simple patterns. Both are AKT favourites.

🔬 Investigations: What a GP Can Arrange vs What Needs Referral

Tests You Can Arrange Directly in Primary Care

Test	Condition Screened For	When to Do
Fasting lipid profile (TC, LDL-C, HDL-C, TG)	Familial Hypercholesterolaemia	TC >7.5 mmol/L, premature CVD, FH family history
Fasting glucose / HbA1c	MODY (maturity-onset diabetes of the young)	Young, slim, mild diabetes with strong family history
Fasting transferrin saturation + ferritin	Hereditary Haemochromatosis	Unexplained fatigue, arthralgia, abnormal LFTs, FH of haemochromatosis
Renal USS	ADPKD screening	First-degree relatives of confirmed ADPKD — from age 18-20
FBC + haemoglobin electrophoresis	Haemoglobinopathy (sickle cell, thalassaemia)	MCV <80 fL, relevant ethnicity, pregnancy
Alpha-fetoprotein	Liver surveillance in haemochromatosis	Established haemochromatosis with hepatic involvement
CK level	Duchenne/Becker MD screening	Any boy with delayed walking, frequent falls, difficulty climbing stairs

Tests That Require Genetics Referral

Test Type	Purpose	Who to Refer
Diagnostic genetic testing	Confirm suspected genetic diagnosis in symptomatic patient	Refer to genetics — do not test without counselling
Predictive testing	Test well relatives at risk (e.g. Huntington's, BRCA)	Refer — requires pre-test genetic counselling. NEVER test for Huntington's in primary care.
Carrier testing	Identify carrier status for AR/X-linked conditions	Refer, especially in pregnancy planning
Prenatal testing (CVS / amniocentesis)	Diagnose chromosomal / genetic conditions in foetus	Refer to obstetrics / fetal medicine
BRCA / Lynch / FAP gene testing	Cancer predisposition syndromes	Refer to regional clinical genetics service
Chromosomal microarray / WES	Unexplained developmental delay + dysmorphic features	Refer to paediatric genetics

⚠️ NEVER test for Huntington's in primary care: Predictive testing requires extensive pre-test counselling, psychological assessment, and post-test support. Always refer to specialist genetics service. Testing children for adult-onset conditions is generally not done until they can consent as adults.

🏴󠁧󠁢󠁧󠁮󠁦󠁿 NHS National Screening Programmes with Genetic Components

Newborn bloodspot (Guthrie card — day 5): 9 conditions: PKU, CF, congenital hypothyroidism, MCADD, sickle cell disease, MSUD, IVA, GA1, HCU. Mnemonic: "PKU CHaT MSUD IVA GA1 HCU"
Antenatal Down syndrome screening: Combined test (10–13+6 weeks) — nuchal translucency + beta-hCG + PAPP-A. High risk → offer CVS or amniocentesis. NIPT now offered for high-risk pregnancies.
Antenatal haemoglobinopathy screening: Sickle cell and thalassaemia screening offered to all pregnant women. Partners screened if woman is carrier.
Familial breast cancer (NICE NG151): Offer BRCA risk assessment using Manchester score or Tyrer-Cuzick to women with ≥10% 10-year risk.
Bowel cancer screening (FIT test 50–74): Lynch syndrome families may need earlier colonoscopy from age 25 (specialist-led).

✓ GP Tip: Parents often ask GPs to explain newborn bloodspot results. Learn the 9 screened conditions — they appear in AKT questions and SCA scenarios. Key point: a positive result means increased risk and needs specialist referral, not a confirmed diagnosis.

3️⃣ Differential Diagnosis Frameworks

Distinguishing genetic from sporadic disease

Familial vs Sporadic Cancer

Feature	Sporadic Cancer	Familial Cancer Syndrome
Age of onset	Usually >50 years	Often <50 years (especially <40 for breast cancer)
Number affected	Isolated case	Multiple relatives (≥3 close relatives)
Laterality	Unilateral	Often bilateral (e.g. both breasts, both kidneys)
Multiple primaries	Rare	Common (e.g. breast + ovarian, colon + endometrial)
Rare cancers	Uncommon	May include rare types (male breast, ovarian, pancreatic)
Inheritance pattern	None	Often autosomal dominant (vertical transmission)

🧬 BRCA-Associated Cancers: Breast (female and male), ovarian, prostate, pancreatic. Think BRCA if: breast cancer <40, ovarian cancer any age, male breast cancer, triple-negative breast cancer <60, Ashkenazi Jewish ancestry with breast/ovarian cancer.

🧬 Lynch Syndrome (HNPCC): Colorectal, endometrial, ovarian, gastric, small bowel, urinary tract, brain. Think Lynch if: colorectal cancer <50, multiple Lynch-associated cancers in same person, ≥3 relatives with Lynch-associated cancers across 2 generations.

5-Step GP Framework for Suspected Genetic Conditions

Identify genetic red flags: Use the EARLY mnemonic — early onset, multiple affected relatives, rare tumour type, bilateral disease, young relative affected
Take detailed three-generation family history: The 6 key questions — document all affected relatives with ages and diagnoses
Consider inheritance pattern: GASI — generations, affected ratio, sex bias, index case. DAME X-M for the 6 patterns.
Assess risk level: Use validated tools — Manchester score (breast/ovarian cancer), QRISK3 (cardiovascular), Simon Broome criteria (FH)
Decide — investigate vs refer: FH, haemochromatosis → investigate in primary care. BRCA, Lynch, Huntington's, developmental delay → refer to genetics.

✓ You CAN manage in primary care: FH screening (lipid profile + cascade), haemochromatosis (iron studies + venesection referral), ADPKD family screening (renal USS), sickle cell routine management (penicillin prophylaxis + folic acid).

⚠️ You SHOULD refer to genetics: Cancer predisposition syndromes (BRCA, Lynch), Huntington's disease, unexplained developmental delay + dysmorphic features, recurrent pregnancy loss with suspected chromosomal cause, requests for predictive testing.

Assessing Genetic Risk

Population risk: Baseline risk for the general population (e.g., 1 in 8 women develop breast cancer)
Familial risk: Increased risk due to family history without an identified mutation (e.g., 2–3x population risk)
High genetic risk: Known pathogenic mutation (e.g., BRCA1 = 50–70% lifetime breast cancer risk)

Recurrence Risk Estimates

Autosomal dominant: 50% risk to each child if one parent is affected
Autosomal recessive: 25% risk to each child if both parents are carriers
X-linked recessive: 50% of sons affected if mother is a carrier; 50% of daughters are carriers
Multifactorial: Risk increases with number of affected relatives and severity of condition

🧮 Risk Calculation Tools: Use validated calculators — Manchester score (breast/ovarian cancer), QRISK3 (cardiovascular), Simon Broome criteria (FH). Don't rely on memory for complex risk calculations.

Referral to Regional Genetic Services

Cancer predisposition: Family history meeting NICE criteria for BRCA/Lynch/FAP testing
Predictive testing: At-risk relatives of someone with a known mutation (e.g., Huntington's, BRCA)
Diagnostic uncertainty: Unexplained constellation of features suggesting a genetic syndrome
Reproductive concerns: Recurrent pregnancy loss, consanguinity with concerns, known carrier status
Paediatric genetics: Developmental delay + dysmorphic features, suspected metabolic disorder

📋 Information to Include in Referral: Three-generation pedigree, relevant test results (lipids, imaging, pathology reports), ethnic background, patient's specific concerns and questions, urgency (routine vs urgent based on NICE criteria)

💬 Setting Expectations: "The genetics team will review your family history in detail and may offer genetic testing if appropriate. They'll also discuss what the results might mean for you and your family. The appointment usually takes about an hour, and you can bring a family member for support."

8️⃣ Referral Pathways & Practice Systems

When to refer, who to refer to, and what to include in the letter

🏠 Genetic Referral Decision Pathway

Use this flowchart for any patient with a possible genetic condition or significant family history

Patient with possible genetic condition
or significant family history

↓

❓ Does the patient meet ANY referral criteria?
(see criteria list below)

↓

YES

↓

📋 Refer to Regional Clinical Genetics Service

Include in referral:
✓ Three-generation pedigree or detailed family history
✓ Proband's diagnosis (confirmed, suspected, or at risk)
✓ Ages and diagnoses of affected relatives
✓ Ethnicity
✓ Consanguinity if present
✓ Any prior genetic test results
✓ Specific clinical concern (not just "family history")
✓ Urgency level

↓

🕐 Await genetics appointment
Inform patient: ~1hr appointment; can bring family member; non-directive counselling; testing may or may not be offered

↓

📈 Manage in Primary Care

✓ Monitor — recheck if family history changes
✓ Update records with relevant coding (SNOMED)
✓ Arrange appropriate surveillance (e.g. annual eGFR for ADPKD; lipid targets for FH)
✓ Consider cascade screening for FH, haemochromatosis
✓ Advise patient to update you if new diagnoses in family

↓

🔄 Safety-net: "If anyone in your family develops a new cancer or serious illness, please let us know — it might change our assessment."

Referral Criteria & Practice Systems

Refer to Regional Clinical Genetics When ANY of These Apply:

🚨 ≥2 first-degree relatives with same cancer, especially <50 years
🚨 Cancer at unusually young age (<40 for most cancers)
🚨 Male breast cancer (any age)
🚨 Bilateral or multifocal tumours
🚨 ≥3 recurrent miscarriages
🚨 Developmental delay + dysmorphic features
🚨 Suspected chromosomal syndrome
🚨 Patient requesting predictive testing (e.g. at-risk for Huntington's)
🚨 Unusual disease in young patient (cardiomyopathy <40, unexplained arrhythmia)
🚨 Consanguinity + family history of recessive disease
🚨 Known carrier status in close relative needing discussion
🚨 Ovarian cancer at any age
🚨 Colorectal cancer <50 or meeting Amsterdam criteria for Lynch

✅ What to Include in a Genetics Referral Letter

Reason for referral — specific clinical concern, not just "family history" or "patient concerned"
Three-generation pedigree or detailed family history with ages, diagnoses, and relationships. Include ages at diagnosis and age/cause of death for deceased relatives.
Proband's diagnosis — confirmed, suspected, or at-risk only
Ethnicity — relevant for carrier frequency and variant interpretation (e.g. Ashkenazi Jewish, Mediterranean, African-Caribbean)
Consanguinity — essential to document if present
Previous testing — any prior genetic test results, pathology reports, death certificates if available
Patient's specific concerns — what they want to know and why they're asking now
Urgency — routine vs urgent (e.g. cancer diagnosis requiring prompt risk assessment)

💻 Practice Systems — Recording Genetic Information

Code family history clearly using SNOMED/Read codes — enables population-level risk flagging and decision support
Add relevant family history to patient summaries — don't bury it in encounter notes where it won't be seen at future appointments
Flag first-degree relatives for cascade screening (e.g. FH, Lynch) — proactive, not reactive
Set up surveillance recall — ADPKD (annual eGFR + urine ACR), FH (annual lipid review, LDL-C target), sickle cell (annual review), Down syndrome (annual TFTs)
NHS Genomic Register (2026): BRCA/Lynch carriers enrolled automatically receive screening invitations. Update family history at every relevant review.
Safety-net systems: If you identify a genetic risk but the patient declines referral, document this clearly and set a review date

💡 System Tip: When a patient is diagnosed with FH, add a task or alert to contact first-degree relatives for cascade testing. One diagnosis = potentially 5-10 relatives who need testing. This is where proactive GP systems save lives.

Recognising Inherited Disease Patterns

Suspect genetic syndrome when multiple organ systems are affected:

Neurofibromatosis type 1 (NF1): Café-au-lait spots ≥6 (≥5mm pre-pubertal) + neurofibromas + Lisch nodules + axillary/inguinal freckling + optic glioma
Tuberous sclerosis: Seizures + learning disability + skin lesions (ash-leaf spots, shagreen patches, facial angiofibromas) + cardiac rhabdomyomas + renal angiomyolipomas
Marfan syndrome: Tall stature + arachnodactyly + lens dislocation + aortic root dilatation + pectus deformity + positive wrist/thumb signs
Von Hippel-Lindau (VHL): Retinal angiomas + cerebellar haemangioblastomas + renal cell carcinoma + phaeochromocytoma + pancreatic cysts

⚠️ Red Flag: Developmental delay + dysmorphic features + congenital anomalies = refer to clinical genetics for chromosomal microarray or whole exome sequencing. Don't just refer to community paediatrics alone.

Penetrance = proportion of people with mutation who develop disease. Variable expression = different severity/features in different family members with same mutation.

NF1: 100% penetrance but hugely variable expression — some have only café-au-lait spots, others have disfiguring tumours and complications
BRCA1/2: High but incomplete penetrance — not everyone with mutation develops cancer (50-70% lifetime risk for breast cancer)
Huntington's disease: 100% penetrance if you live long enough, but age of onset varies. Anticipation (earlier onset in successive generations, especially with paternal inheritance)
Myotonic dystrophy: Classic example of anticipation — mild myotonia in grandparent, moderate in parent, severe congenital form in grandchild

💬 Explaining to Patients: "Having the gene change doesn't guarantee you'll get the condition, but it does increase your risk significantly. We can't predict exactly how severely it might affect you — it varies even within families."

Many common diseases have genetic risk components but don't follow Mendelian inheritance:

Type 2 diabetes: 2-6x increased risk if first-degree relative affected. Polygenic risk + lifestyle factors. MODY should be considered in young, slim, non-insulin-dependent diabetics with strong family history.
Coronary artery disease: Family history of premature CVD (<60 years) increases risk. Use QRISK3 calculator.
Hypertension: Familial clustering common. Lifestyle modification + pharmacotherapy regardless of genetic risk.
Obesity: Heritability 40-70% but modifiable through lifestyle. Rare monogenic causes (e.g. MC4R mutations, leptin deficiency) exist — consider in severe early-onset obesity.

💬 Consultation Approach: "Your family history does increase your risk, but lifestyle factors are equally important. The good news is that healthy eating, regular exercise, and not smoking can significantly reduce your risk, even with a family history."

4️⃣ Common Conditions GPs Should Manage Confidently

The conditions you will see in every practice — know these cold

Autosomal Dominant Conditions

50% risk to offspring; vertical transmission; both sexes equally affected

Prevalence: 1 in 250 (underdiagnosed — only ~10% currently identified in UK)
Gene: Autosomal dominant — LDLR gene (most common), APOB, PCSK9
Clinical features: Total cholesterol >7.5 mmol/L, LDL-C >4.9 mmol/L (adults), tendon xanthomata, corneal arcus <45 years
Simon Broome criteria — Definite FH: TC >7.5 + tendon xanthomata, OR DNA-confirmed mutation
Simon Broome criteria — Possible FH: TC >7.5 + family history of premature CVD or high cholesterol
Genetic testing: Available via lipid clinic (LDL receptor, APOB, PCSK9 genes)

First-line statin (high-intensity) — NICE CG71:
- Atorvastatin 20mg once daily — titrate to 40–80mg once daily as tolerated. Lifelong. (Source: NICE CG71, 2017 update)
- Alternative: Rosuvastatin 10mg once daily — titrate to 20–40mg once daily. Lifelong.
LDL-C target: >50% reduction from baseline LDL-C (NICE CG71)
If statin-intolerant or LDL target not met: Add ezetimibe 10mg once daily — or refer to lipid clinic for PCSK9 inhibitors (specialist-led)
Lifestyle: Low saturated fat diet, regular exercise, smoking cessation, maintain healthy weight
Refer to lipid clinic: For genetic testing, if LDL-C target not met on maximum tolerated statin + ezetimibe
Children: Start statin from age 10 years (specialist-led, doses per BNFc)

⚠️ Pregnancy: Stop all statins at least 3 months before attempting to conceive and during pregnancy and breastfeeding. (NICE CG71)

✓ Cascade Testing Success: One FH diagnosis can save an entire family. Cascade testing prevents 76% of premature deaths. Test all first-degree relatives.

Who to test: All first-degree relatives (parents, siblings, children) of confirmed FH case
Test: Fasting lipid profile. If genetic mutation known in proband, offer DNA testing to relatives.
When to test children: From age 10 (earlier if strong FH of premature CVD)
GP role: Coordinate family testing, ensure all relatives contacted, start treatment if diagnosed

💬 Script: "Your cholesterol is very high despite your healthy lifestyle — this suggests it might be inherited (familial hypercholesterolaemia). The good news is it's very treatable, and we should also test your close relatives as they may have it without knowing."

Prevalence: 1 in 1000 (most common inherited kidney disease)
Presentation: Often asymptomatic until 30s–40s. May present with hypertension (often first sign), haematuria, loin pain, UTIs, renal stones
Diagnosis: Renal USS showing age-dependent cyst criteria. Genetic testing (PKD1, PKD2) available but not usually needed in primary care.
Complications: CKD (50% reach ESRF by age 60), hypertension, liver cysts (70%), berry aneurysms (5-10%), mitral valve prolapse
Management: BP control (target <130/80 — ACEi/ARB first-line), avoid NSAIDs, annual eGFR + urine ACR, nephrology follow-up, genetic counselling for family
Screening relatives: Renal USS for first-degree relatives from age 18–20 years

⚠️ Berry Aneurysms: Consider MRA if family history of subarachnoid haemorrhage or patient in high-risk occupation. Risk is 5-10% overall but higher with positive family history.

Prevalence: 1 in 10,000
Presentation: Progressive chorea, cognitive decline, psychiatric symptoms (depression, irritability, psychosis). Onset usually 30–50 years.
Genetics: CAG trinucleotide repeat expansion in HTT gene. Anticipation — earlier onset in successive generations, especially with paternal inheritance
Diagnosis: Clinical + genetic testing — NEVER test in primary care
Management: Supportive — neurology, psychiatry, social services. Tetrabenazine for chorea (specialist-prescribed). No disease-modifying treatment currently available.
Predictive testing: At-risk relatives can request testing but need specialist genetics input and psychological support

⚠️ NEVER test for Huntington's in primary care. Requires extensive pre-test counselling, psychological assessment, and post-test support. Testing children for adult-onset conditions is not done until they can consent as adults.

Factor V Leiden: Most common (5% population). 3-7x VTE risk increase. Test if unprovoked VTE <50 years or strong family history.
Prothrombin G20210A: 2% prevalence. 2-3x VTE risk increase.
Protein C/S deficiency: Rare but higher VTE risk. Consider if recurrent VTE or neonatal purpura fulminans.
Antithrombin deficiency: Rare, highest VTE risk. Often presents with recurrent VTE despite anticoagulation.
Anticoagulation for acute VTE — first-line (NICE NG158):
- Apixaban 10mg twice daily for 7 days, then 5mg twice daily. Minimum 3 months. (Source: NICE NG158, updated August 2023)
- Alternative: Rivaroxaban 15mg twice daily with food for 21 days, then 20mg once daily with food. Minimum 3 months. (Source: NICE NG158)
Duration: At least 3 months for provoked VTE; decisions beyond 3 months involve haematology assessment of bleeding vs recurrence risk

⚠️ Testing Timing: Don't test during acute VTE or on anticoagulation (false results). Test at least 6 weeks after stopping anticoagulation. Protein C/S levels are affected by warfarin.

Autosomal Recessive Conditions

25% risk if both parents carriers; horizontal transmission; consanguinity increases risk

Prevalence: 1 in 2500 births (UK). Carrier frequency 1 in 25 Caucasians.
Genetics: CFTR gene (>2000 mutations). ΔF508 most common (70% UK cases).
Presentation: Newborn: meconium ileus, failure to thrive. Child: recurrent chest infections, malabsorption, steatorrhoea. Adult: bronchiectasis, CF-related diabetes, infertility (males — absent vas deferens).
Diagnosis: Newborn bloodspot screening, sweat test (chloride >60 mmol/L), genetic testing
Management: Specialist CF centre. Physiotherapy, pancreatic enzyme replacement, fat-soluble vitamins, antibiotics for exacerbations, CFTR modulators (elexacaftor/tezacaftor/ivacaftor — Kaftrio — specialist-prescribed, eligibility by genotype)
GP role: Coordinate care, annual flu + pneumococcal vaccination, screen for CF-related diabetes annually from age 10, fertility counselling

🖋 CFTR Modulators: Kaftrio (elexacaftor/tezacaftor/ivacaftor) has transformed CF prognosis for eligible patients — now >50% of UK CF patients qualify. Specialist-prescribed. Median survival now >50 years.

Prevalence: 1 in 200 Northern Europeans are C282Y homozygotes (but only ~10% develop clinical disease)
Genetics: HFE gene. C282Y homozygosity most common. H63D compound heterozygosity less severe.
Presentation: Often asymptomatic. Fatigue, arthralgia (especially MCPJs), abnormal LFTs, diabetes, skin bronzing ("bronze diabetes"), impotence
Screening tests: Fasting transferrin saturation >45% + ferritin >300 μg/L (men) or >200 μg/L (women)
Diagnosis: HFE genetic testing (C282Y, H63D). Liver biopsy rarely needed now — only if ferritin >1000 μg/L or raised liver enzymes.
Treatment: Venesection (200-400mL weekly initially, then 3-4 monthly maintenance) — specialist/haematology-supervised. Target ferritin 50-100 μg/L.
Family screening: Test first-degree relatives with ferritin + transferrin saturation + HFE genotyping
Avoid: Iron / vitamin C supplements, excess alcohol

⚠️ Don't Miss: Think haemochromatosis in any patient with unexplained fatigue + abnormal LFTs, especially in men of Celtic ancestry. Early treatment prevents cirrhosis, hepatocellular carcinoma, diabetes, and cardiomyopathy.

Sickle Cell Disease

Prevalence: 1 in 2000 UK births. African-Caribbean, Middle Eastern, Mediterranean populations.
Genetics: HbSS (most severe), HbSC, HbS/β-thalassaemia. Carriers (HbAS) usually asymptomatic.
Presentation: Painful vaso-occlusive crises, acute chest syndrome, stroke, splenic sequestration, infections (functional asplenia)
GP-initiated management:
- Penicillin V prophylaxis: Phenoxymethylpenicillin 62.5mg twice daily (<1 year), 125mg twice daily (1–4 years), 250mg twice daily (≥5 years). Lifelong continuation recommended for all ages in UK practice. If penicillin allergic: erythromycin. (UK Sickle Cell Society Standards 2018; NICE CG143)
- Folic acid supplementation: Folic acid 5mg once daily, continuous lifelong. (BNF; UK Sickle Cell Society Standards 2018)
Specialist-managed: Hydroxycarbamide, blood transfusion programmes, gene therapy (Casgevy) — all specialist-led
Vaccinations: Pneumococcal, meningococcal ACWY + B, Hib, annual flu — essential due to functional asplenia
GP role: Low threshold for hospital admission; manage minor crises at home with oral analgesia + hydration if appropriate

Thalassaemia

Beta-thalassaemia major: Severe anaemia from infancy, requires lifelong transfusions. Specialist haematology. Iron chelation essential.
Thalassaemia trait: Mild microcytic anaemia, usually asymptomatic. No treatment needed. Genetic counselling important.
Screening: Antenatal screening offered to all pregnant women. FBC + haemoglobin electrophoresis if MCV <80 fL.

💡 Thalassaemia Trait Trap: Never give iron supplements for microcytic anaemia without checking ferritin first. Thalassaemia trait causes low MCV but normal/high ferritin. Iron supplementation is unnecessary and potentially harmful.

X-Linked & Chromosomal Disorders

Duchenne MD: 1 in 3500 male births. X-linked recessive. Onset 2–5 years. Gowers' sign, calf pseudohypertrophy. Wheelchair by age 12. Cardiomyopathy and respiratory failure lead to death in 20s–30s if untreated.
Becker MD: Milder, later onset (teens–20s). Same gene (dystrophin), partially functional protein.
Diagnosis: CK 10–100x normal → confirm with genetic testing (dystrophin gene)
Management: Specialist neuromuscular clinic. Corticosteroids (deflazacort or prednisolone — specialist-prescribed), cardiac monitoring, respiratory support.

⚠️ Don't Miss: Any boy with delayed walking, frequent falls, or difficulty climbing stairs → check CK. Early diagnosis enables access to corticosteroids and emerging exon-skipping therapies.

Haemophilia A: Factor VIII deficiency. 1 in 5000 males. X-linked recessive.
Haemophilia B: Factor IX deficiency (Christmas disease). 1 in 30,000 males.
Severity: Severe (<1% factor activity) = spontaneous bleeds; Moderate (1–5%) = bleeds with minor trauma; Mild (5–40%) = bleeds with surgery only
Diagnosis: Prolonged APTT, normal PT, reduced factor VIII or IX
Management: Specialist haemophilia centre. Factor replacement or emicizumab (specialist). Avoid NSAIDs/aspirin/IM injections in primary care.

🚨 Emergency: Any head injury in haemophilia patient = immediate factor replacement + CT head. Contact haemophilia centre urgently. Do NOT wait for symptoms.

Prevalence: 1 in 700 births. Risk increases with maternal age (1 in 100 at age 40)
Genetics: 95% non-disjunction (extra chromosome 21), 4% translocation, 1% mosaic
Associated conditions: CHD (40–50%), hypothyroidism, hearing/vision problems, atlantoaxial instability, early-onset Alzheimer's
GP role: Annual thyroid function, regular hearing/vision checks, cardiac follow-up, transition to adult services, health promotion
Life expectancy: Now >60 years (was <10 years in 1960s)

Prevalence: 1 in 2500 live-born females. Only affects females.
Presentation: Short stature, delayed/absent puberty, primary amenorrhoea, infertility, webbed neck, low hairline, lymphoedema of hands/feet (newborn)
Associated: Coarctation of aorta (15%), bicuspid aortic valve, hypothyroidism, hearing loss
Diagnosis: Karyotype. Consider in any girl with short stature or delayed puberty.
Management: Growth hormone therapy, oestrogen replacement — specialist-led. Lifelong cardiac follow-up. Increased risk of aortic dissection in pregnancy.

Prevalence: 1 in 500–1000 males. Only 25% diagnosed during lifetime — massively underdiagnosed.
Presentation: Tall stature, small testes, gynaecomastia, reduced fertility (azoospermia), learning difficulties (language)
Management: Testosterone replacement (specialist-initiated), fertility referral early, psychological support
GP tip: Consider in any male presenting with infertility, small testes, or unexplained gynaecomastia

💡 Fertility: Most Klinefelter males are infertile but some have sperm in testes. Testicular sperm extraction + ICSI can achieve pregnancy. Refer to fertility clinic early if considering fatherhood.

🎙️ Familial Cancer Syndromes — GP Recognition Guide

Syndrome	Cancers	GP Recognition Clue	Action
BRCA1/2	Breast, ovarian, prostate, pancreatic	Young female with breast CA; male breast CA; ovarian at any age; Ashkenazi Jewish	Refer genetics (NICE CG164/NG151)
Lynch Syndrome (HNPCC)	Colorectal, endometrial, ovarian, urinary tract, brain	CRC <50, endometrial cancer, >1 Lynch-associated tumour in family, Amsterdam criteria met	Refer genetics; 2-yearly colonoscopy from age 25; prophylactic hysterectomy discussed
FAP	Colorectal (100% if untreated), duodenal	100s of colonic polyps on colonoscopy; CRC before age 40; desmoid tumours	Urgent genetics + gastroenterology; prophylactic colectomy
MEN1	Parathyroid, pituitary, pancreatic	Hypercalcaemia + pituitary tumour + insulinoma; raised PTH + prolactin	Refer endocrinology + genetics; calcium + PTH + pituitary MRI
MEN2	Medullary thyroid CA, phaeochromocytoma, parathyroid	Young patient with medullary thyroid CA; raised calcitonin; phaeochromocytoma	RET gene testing; refer endocrinology + genetics; prophylactic thyroidectomy
VHL Syndrome	Renal cell CA, CNS haemangioblastomas, phaeochromocytoma	Young patient with renal cell CA; cerebellar haemangioblastoma; bilateral renal cysts + tumours	Refer genetics; regular MRI surveillance of CNS + abdomen

Key Cancer Syndromes in Detail

BRCA1 breast cancer: 50–70% lifetime risk (vs 12% population)
BRCA1 ovarian cancer: 40–50% lifetime risk (vs 1–2% population)
BRCA2 breast cancer: 40–70% lifetime risk
BRCA2 ovarian cancer: 10–20% lifetime risk
Male breast cancer: BRCA2 carriers: 5–10% lifetime risk (vs 0.1% population)
Prostate cancer: Increased risk with both (especially BRCA2)
Pancreatic cancer: 2–5% lifetime risk, especially BRCA2

🧬 Ashkenazi Jewish Population: 1 in 40 carry BRCA mutation (vs 1 in 400 general population). Three founder mutations account for most cases. Lower referral threshold for this population.

NICE Referral Criteria for BRCA Testing

Personal history: Breast cancer <40, ovarian cancer any age, male breast cancer, triple-negative breast cancer <60, bilateral breast cancer
Family history (same side): ≥2 relatives with breast cancer (at least one <50), ≥2 relatives with ovarian cancer, ≥1 breast + ≥1 ovarian cancer
Ashkenazi Jewish ancestry: Breast cancer <50, or ovarian cancer any age
Known family mutation: Any first-degree relative with confirmed BRCA mutation

Mnemonic: YOUNG OVARY

YYoung breast cancer — <40 years
OOvarian cancer — any age
UUnusual — male breast, triple-negative <60
NNot one side — bilateral breast cancer
GGenetic background — Ashkenazi Jewish ancestry

Breast surveillance: Annual MRI from age 30–50, then annual mammography + MRI 50–70
Risk-reducing mastectomy: Reduces breast cancer risk by ~90%. Patient choice after counselling.
Risk-reducing salpingo-oophorectomy: Recommended from age 35–40 (after childbearing). Reduces ovarian cancer risk by 80–90% and breast cancer risk by 50%.
Chemoprevention: Tamoxifen or anastrozole — discuss with oncology (specialist-led)
Male carriers: Annual prostate screening from age 40 (PSA + DRE). Breast awareness.

🖋 2026 NHS Genomic Register: BRCA carriers automatically added to national register and receive screening invitations. Update family history regularly.

Prevalence: 1 in 300 (most common inherited cancer syndrome)
Genetics: Mismatch repair gene mutations (MLH1, MSH2, MSH6, PMS2). Autosomal dominant.
Associated cancers: Colorectal (50–80% lifetime risk), endometrial (40–60%), ovarian, gastric, small bowel, urinary tract, brain
Amsterdam Criteria: ≥3 relatives with Lynch-associated cancer, ≥2 successive generations, ≥1 diagnosed <50 years, one is first-degree of other two
Surveillance: Colonoscopy every 1–2 years from age 25. Endometrial sampling + TVUSS annually from age 35 (women).
Risk-reducing surgery: Hysterectomy + bilateral salpingo-oophorectomy after childbearing

💡 Diagnostic Pathway: Lynch is diagnosed via tumour testing (microsatellite instability, immunohistochemistry) then germline genetic testing. Flag to oncology if patient diagnosed with CRC <50 or endometrial cancer — request MSI/IHC testing on tumour.

Genetics: APC gene mutation. Autosomal dominant. 100% penetrance for colorectal cancer if untreated.
Presentation: Hundreds to thousands of colorectal polyps from teenage years. CRC by age 40 if untreated.
Management: Prophylactic colectomy usually by age 20–25. Annual flexible sigmoidoscopy from age 12–15. Lifelong upper GI endoscopy.
Family screening: Test at-risk relatives from age 10–12 years (genetic testing if family mutation known)

⚠️ Don't Miss: Any teenager or young adult with >10 colorectal polyps needs urgent genetics referral. FAP is preventable with prophylactic surgery but uniformly fatal if untreated.

5️⃣ Red Flags, Cancer Syndromes & Conditions Not to Miss

The diagnoses that will end careers if missed — and save lives if caught

Must-Not-Miss Genetic Red Flags

🚨Cancer in a first-degree relative under 50 — always ask about site, age, bilateral disease. Every. Single. Time.
🚨≥2 first-degree relatives with the same cancer — especially ovarian, breast, or colorectal
🚨Male breast cancer at any age — automatic BRCA2 referral
🚨Ovarian cancer at any age — all patients should be offered genetic testing (10-15% have BRCA mutation)
🚨Triple-negative breast cancer <60 years — associated with BRCA1 mutations
🚨Colorectal cancer <50 years — consider Lynch syndrome
🚨≥3 recurrent miscarriages — chromosomal cause in ~5%; refer to genetics/reproductive medicine
🚨Developmental delay + dysmorphic features — refer clinical genetics, not just community paeds
🚨Young patient with unexplained cardiomyopathy or arrhythmia — inherited cardiomyopathies, Long QT, Brugada syndrome
🚨Bilateral or multifocal tumours — bilateral breast, bilateral renal, multiple colon polyps

7️⃣ Pharmacogenomics — Genes & Drug Response

Why your patient's genes affect how they respond to medication — increasingly relevant to GPs

💊 Key Pharmacogenomic Interactions GPs Should Know

Gene	Drug(s) Affected	Effect	GP Action
TPMT	Azathioprine, mercaptopurine	Low TPMT → severe, potentially fatal myelosuppression at standard doses	⚠️ MANDATORY — CHECK TPMT BEFORE PRESCRIBING AZATHIOPRINE. Low/absent TPMT = avoid or dramatically reduce dose. Negligent to skip.
CYP2C19	Clopidogrel, PPIs, SSRIs	Poor metabolisers: clopidogrel less activated → reduced antiplatelet effect → increased cardiovascular events post-ACS/PCI	Consider genotyping before prescribing post-ACS. If poor metaboliser, use ticagrelor or prasugrel instead. RCGP 2025 statement advises considering genotype.
DPYD	Fluorouracil (5-FU), capecitabine	DPYD deficiency → severe, potentially fatal toxicity from 5-FU based chemotherapy	NICE 2023 mandates DPYD testing before all 5-FU chemotherapy in England. Oncology-led but GP may receive results — action promptly.
HLA-B*5701	Abacavir (HIV treatment)	HLA-B*5701 positive → severe hypersensitivity reaction, potentially fatal	NICE mandates testing before prescribing. HIV specialist-led but important to be aware. Never prescribe abacavir without confirmed HLA-B*5701 negative result.
G6PD	Primaquine, dapsone, nitrofurantoin, rasburicase	G6PD deficiency → haemolytic anaemia when exposed to oxidative drugs	Screen before prescribing in high-risk ethnicities (Mediterranean, African, Asian). Check BNF for full list of drugs to avoid.
CYP2D6	Many antidepressants (SSRIs, TCAs), codeine, tamoxifen	Poor metabolisers → increased side effects. Ultra-rapid → reduced efficacy. Codeine in ultra-rapid metabolisers → morphine toxicity risk.	Not routine testing yet in UK, but be aware. Codeine is now contraindicated in children — partly due to CYP2D6 variability. Note in discharge letters if mentioned.

⚠️ TPMT Before Azathioprine — No Exceptions: This is one of the few genuinely mandatory pharmacogenomic tests in GP practice. Failure to check TPMT before starting azathioprine (for IBD, rheumatological conditions, or transplant) is considered negligent. Always check TPMT activity or genotype before initiating. Result guides dosing — absent TPMT = avoid the drug entirely.

💡 Future of Pharmacogenomics: Expect pre-emptive panel testing to become routine — test once for multiple drug-gene interactions, results stored in the medical record for lifetime prescribing decisions. NHS Genomic Medicine Service is developing a national framework. GPs will need to know how to interpret and act on these results in everyday prescribing.

6️⃣ Ethics, Communication & Psychosocial Aspects

SCA-tested territory — where genomics meets real human beings

⚖️ Key Ethical Dilemmas — Frequently Tested

Mnemonic: "CARD" — for Genetic Consultation Ethics

CConfidentiality — maintain unless serious, unavoidable harm to identifiable others. Document carefully.
AAutonomy — patient's right to choose; non-directive counselling always; never push a particular path
RRight not to know — especially Huntington's, BRCA — never coerce testing
DDocumentation — document all discussions, decisions, and reasons clearly; GMC guidance applies

The Dilemma: Patient has genetic condition that affects relatives but refuses to inform family. Do you breach confidentiality?

GMC guidance: Confidentiality can be breached if: (1) serious harm to identifiable person; (2) patient refuses to inform relatives; (3) you've explored reasons for refusal; (4) you've offered to inform relatives yourself
When to consider breaching: High-penetrance, serious, preventable/treatable condition (BRCA, Lynch, FAP). NOT for low-risk or untreatable conditions.
How: Inform patient first. Contact relatives via GP or genetics service. Provide minimal information: "family history suggests you may be at increased risk — please see your GP"
Document everything: Record that the dilemma was recognised, what was discussed, what was decided, and why

⚖️ Legal Precedent: ABC v St George's Healthcare NHS Trust (2020) — Court ruled doctors have a duty to warn relatives of serious genetic risk, even if patient objects. Balance patient confidentiality against relatives' right to know. Always seek advice from your medical defence organisation in complex cases.

Competent adults have the right to choose NOT to know their genetic risk. This is particularly relevant in Huntington's disease — knowing carries huge psychological burden. Never pressure a patient to be tested. Support their autonomy absolutely.

Reasons for declining: Fear of discrimination (insurance), psychological burden, no treatment available, religious beliefs, prefer not to know
Offer alternatives: If declining predictive testing, they can still have surveillance (e.g. colonoscopy for Lynch syndrome risk without knowing mutation status)
Document: Record that information was offered and declined. Leave door open for future testing.

💬 Consultation Approach: "Some people want to know their genetic status so they can plan ahead. Others prefer not to know. Both choices are completely valid. What feels right for you?"

General Principle: Don't test children for adult-onset conditions unless testing will directly benefit the child now — not just the parents' peace of mind.

Test in childhood if: Condition manifests in childhood (FAP → colonoscopy from age 10–12; retinoblastoma); early intervention improves outcome
Defer until adulthood if: Adult-onset condition (Huntington's, BRCA); no childhood intervention possible; testing is for parents' reassurance
Rationale: Preserve child's future autonomy. Avoid psychological harm. Prevent discrimination (insurance, education).

⚠️ Never Test Children for Huntington's: No medical benefit to knowing in childhood. High risk of psychological harm. Defer until they can give informed consent as an adult (usually age 18+).

UK Moratorium: Voluntary agreement between government and insurance industry. Insurers will NOT ask for predictive genetic test results for most policies.
Exception: Life insurance >£500,000 — insurers CAN ask about Huntington's disease test results only. All other genetic tests protected.
Diagnostic tests: If you have symptoms and genetic test confirms diagnosis, this is a medical diagnosis and must be disclosed (like any other diagnosis).
Advice for patients: Take out insurance before having predictive genetic testing if concerned about future policy changes.

💡 Reassurance: Most patients worry unnecessarily about insurance. The moratorium protects predictive testing results. The only exception is Huntington's for very large life insurance policies. Family history (not genetic test results) is what insurers typically ask about.

💬 Communication Frameworks for Genomics Consultations

Explaining inheritance risk simply: "Think of genes like a recipe book — you get one copy from each parent. If this gene change causes problems, there's a 1-in-2 chance each of your children could inherit it."
Variant of uncertain significance (VUS): "We've found something in a gene that we don't fully understand yet — a 'variant of uncertain significance.' That means we're not sure if it causes problems. I'd like to refer you to the genetics team who are experts at interpreting this."
Direct-to-consumer test results: "These tests can be helpful, but they're not the same as clinical tests — they miss some important changes and sometimes flag things that aren't actually a risk. Let's look at this together and refer you to genetics if needed."
Cultural sensitivity: In some South Asian and Middle Eastern communities, disclosure of genetic carrier status can affect marriage prospects and carry stigma. Approach with empathy; offer privacy; ask "Are there any cultural or religious beliefs that might affect how you'd like to approach this?"
Non-directive counselling: Present options without pushing a particular choice. Say "some people choose..." rather than "you should..." Present information; let the patient lead.

⚠️ Cultural Sensitivity: Be aware that beliefs about inheritance, disability, and reproduction vary across cultures. Some communities may have concerns about genetic testing due to stigma, insurance implications, or religious beliefs. Always explore the patient's perspective before making assumptions.

You've Got This! 💪

Genomics might feel like uncharted territory, but you're already doing the hard part: listening to patients and taking thorough histories. That three-generation family tree you sketch? That's genomic medicine in action.

You don't need to be a clinical geneticist. You just need to know when to worry, when to treat, and when to refer. The regional genetics services are there to help — use them liberally.

Every time you identify a case of FH and start cascade testing, you're potentially saving an entire family from premature heart disease. Every BRCA referral you make could prevent a cancer. Your vigilance matters.

Key Takeaways for Your Exams (and Real Life):

✓ EARLY mnemonic — 1 flag = consider, 3+ flags = refer to genetics
✓ GASI for reading pedigrees: Generations, Affected ratio, Sex bias, Index case
✓ DAME X-M for the 6 inheritance patterns
✓ Male-to-male transmission rules OUT X-linked
✓ Mitochondrial = maternal only; Anticipation = worsening each generation
✓ FH: atorvastatin 20mg od, titrate to 80mg; cascade test all first-degree relatives (NICE CG71)
✓ Acute VTE: apixaban 10mg bd ×7 days then 5mg bd, min 3 months (NICE NG158)
✓ Sickle cell: phenoxymethylpenicillin + folic acid 5mg od lifelong — coordinate with specialist
✓ TPMT before azathioprine — mandatory, no exceptions
✓ NEVER test for Huntington's in primary care — refer always
✓ BRCA referral triggers: YOUNG OVARY mnemonic
✓ Ethics: CARD (Confidentiality, Autonomy, Right not to know, Documentation)
✓ Non-directive counselling: present options, never prescribe a choice

You're not just learning for exams — you're preparing to make a real difference in families' lives. Go forth and conquer genomics! 🧬