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|Clinical Genetics Revision Guide
🧬 Clinical genetics is the branch of medicine concerned with inherited disease, genomic variation, family history, genetic testing and counselling.
For medical students, the key skill is not memorising every syndrome, but recognising patterns of inheritance, knowing when to suspect a genetic condition, and understanding how results affect the patient and their relatives.
🧠 Core Concepts
- Gene: A DNA sequence that codes for a functional product, usually a protein.
- Allele: A version of a gene.
- Genotype: The genetic make-up of an individual.
- Phenotype: The observable clinical features produced by genotype plus environment.
- Variant: A difference in DNA sequence. This may be benign, pathogenic, or of uncertain significance.
- Mutation: Traditionally used for a disease-causing DNA change, though “pathogenic variant” is now preferred.
📚 Patterns of Inheritance
| Pattern |
Key Features |
Examples |
| Autosomal dominant |
One abnormal copy is enough to cause disease. Often seen in every generation. Each child has a 50% risk if one parent is affected. |
Marfan syndrome, Huntington disease, familial hypercholesterolaemia, adult polycystic kidney disease |
| Autosomal recessive |
Two abnormal copies required. Parents are usually unaffected carriers. Siblings may be affected. Higher risk with consanguinity. |
Cystic fibrosis, sickle cell disease, thalassaemia, phenylketonuria |
| X-linked recessive |
Usually affects males. Female carriers may be asymptomatic or mildly affected. No male-to-male transmission. |
Duchenne muscular dystrophy, haemophilia A/B, G6PD deficiency |
| X-linked dominant |
Affected males pass the condition to all daughters but no sons. Females may be affected variably. |
Rett syndrome, fragile X syndrome is often discussed separately due to repeat expansion |
| Mitochondrial |
Inherited from the mother only. Affects tissues with high energy demand such as brain, muscle and heart. |
MELAS, MERRF, Leber hereditary optic neuropathy |
👨👩👧 Family History Clues
- Multiple affected relatives with the same or related condition.
- Early-onset disease, for example breast cancer under 40 or bowel cancer under 50.
- Multiple primary cancers in one person.
- Congenital anomalies, dysmorphic features or developmental delay.
- Recurrent miscarriage, stillbirth or unexplained neonatal death.
- Consanguinity, especially with rare autosomal recessive disease.
- Ethnic background associated with higher carrier risk, for example sickle cell disease, thalassaemia or Tay-Sachs disease.
🧠 Exam pearl: A three-generation family history is often the most important “genetic test” in the first consultation. Ask about ages, diagnoses, age at diagnosis, cause of death, miscarriages, stillbirths and consanguinity.
🧬 Important Genetic Terms
| Term |
Meaning |
| Penetrance |
The proportion of people with a pathogenic variant who show clinical features. Reduced penetrance means some people carry the variant but appear unaffected. |
| Variable expressivity |
The same genetic condition can cause different severity or features in different people. |
| Anticipation |
Disease appears earlier or more severely in successive generations, often due to repeat expansion. |
| Mosaicism |
Two or more genetically different cell lines in one individual, arising after fertilisation. |
| De novo variant |
A new variant in the child that is not present in either parent. |
| Carrier |
A person with one copy of a recessive pathogenic variant who is usually unaffected but may pass it on. |
| Copy number variant |
A deletion or duplication of a section of DNA. |
| Variant of uncertain significance |
A genetic variant where there is not enough evidence to classify it as benign or pathogenic. |
🔬 Types of Genetic Testing
- Karyotype: Looks at whole chromosomes. Useful for large chromosomal abnormalities such as trisomy 21 or Turner syndrome.
- Microarray: Detects smaller deletions and duplications. Often used in developmental delay, congenital anomalies or autism with additional features.
- Single-gene testing: Used when one specific condition is strongly suspected.
- Gene panel: Tests multiple genes linked to a clinical presentation, for example cardiomyopathy or inherited cancer.
- Whole exome sequencing: Analyses protein-coding regions of the genome.
- Whole genome sequencing: Analyses coding and non-coding regions more broadly.
- Carrier testing: Identifies whether a person carries a recessive condition.
- Predictive testing: Tests an unaffected person for a later-onset condition, such as Huntington disease.
- Diagnostic testing: Used in someone with symptoms to confirm a suspected condition.
🧪 Common Chromosomal Disorders
| Condition |
Genetics |
Clinical Features |
| Down syndrome |
Trisomy 21 |
Learning disability, hypotonia, characteristic facial features, congenital heart disease, increased risk of leukaemia and Alzheimer disease |
| Edwards syndrome |
Trisomy 18 |
Severe developmental problems, clenched fists, rocker-bottom feet, congenital heart disease, high infant mortality |
| Patau syndrome |
Trisomy 13 |
Cleft lip/palate, holoprosencephaly, polydactyly, severe congenital abnormalities |
| Turner syndrome |
45,X |
Female phenotype, short stature, webbed neck, coarctation of the aorta, ovarian insufficiency |
| Klinefelter syndrome |
47,XXY |
Male phenotype, tall stature, small testes, infertility, gynaecomastia, low testosterone |
🧠 Trinucleotide Repeat Disorders
- Huntington disease: Autosomal dominant CAG repeat expansion. Causes chorea, psychiatric symptoms and dementia.
- Fragile X syndrome: CGG repeat expansion in FMR1. Causes learning disability, autism traits, long face, large ears and macro-orchidism.
- Myotonic dystrophy: CTG repeat expansion. Causes myotonia, muscle weakness, cataracts, diabetes, cardiac conduction disease and frontal balding.
- Friedreich ataxia: GAA repeat expansion. Causes progressive ataxia, neuropathy, cardiomyopathy and diabetes.
⚠️ Anticipation is classically seen in repeat expansion disorders. The unstable repeat can expand between generations, causing earlier onset or more severe disease.
🫀 Genetic Conditions by Specialty
| Specialty |
Examples |
Clinical Relevance |
| Cardiology |
Hypertrophic cardiomyopathy, long QT syndrome, Marfan syndrome |
Syncope, sudden cardiac death, family screening, ECG/echo surveillance |
| Respiratory |
Cystic fibrosis, alpha-1 antitrypsin deficiency |
Recurrent infections, bronchiectasis, liver disease, infertility |
| Gastroenterology |
Familial adenomatous polyposis, Lynch syndrome, haemochromatosis |
Bowel cancer risk, surveillance colonoscopy, cascade testing |
| Renal |
Autosomal dominant polycystic kidney disease, Alport syndrome |
CKD, haematuria, hearing loss, intracranial aneurysm risk in ADPKD |
| Neurology |
Huntington disease, Duchenne muscular dystrophy, spinal muscular atrophy |
Progressive weakness, movement disorders, predictive testing |
| Endocrine |
MEN syndromes, congenital adrenal hyperplasia |
Endocrine tumours, adrenal crisis risk, family screening |
| Haematology |
Sickle cell disease, thalassaemia, haemophilia |
Carrier screening, antenatal testing, anaemia, bleeding disorders |
| Oncology |
BRCA1/2, Lynch syndrome, Li-Fraumeni syndrome |
Cancer surveillance, risk-reducing surgery, cascade testing |
🎗️ Cancer Genetics
- BRCA1 and BRCA2: Increased risk of breast, ovarian, prostate and pancreatic cancer.
- Lynch syndrome: Increased risk of colorectal, endometrial, ovarian, gastric and urinary tract cancers.
- Familial adenomatous polyposis: Hundreds to thousands of colonic polyps with very high colorectal cancer risk if untreated.
- Li-Fraumeni syndrome: TP53-related; associated with sarcoma, breast cancer, brain tumours, adrenal cortical carcinoma and leukaemia.
- MEN1: Parathyroid, pancreatic neuroendocrine and pituitary tumours.
- MEN2: Medullary thyroid carcinoma, phaeochromocytoma and hyperparathyroidism.
🧠 Clinical reasoning: Cancer genetics is about recognising when the pattern is unlikely to be sporadic. Red flags include young age, bilateral disease, multiple primary cancers, rare tumours, and several relatives with related cancers.
🤰 Prenatal and Reproductive Genetics
- Antenatal screening: Estimates risk of chromosomal conditions such as Down syndrome, Edwards syndrome and Patau syndrome.
- Non-invasive prenatal testing: Uses cell-free fetal DNA from maternal blood to screen for common trisomies.
- Chorionic villus sampling: Diagnostic test usually performed earlier in pregnancy than amniocentesis.
- Amniocentesis: Diagnostic test using amniotic fluid, usually performed later than CVS.
- Pre-implantation genetic testing: May be considered for couples at high risk of passing on a serious inherited condition.
- Carrier screening: Useful for conditions such as cystic fibrosis, sickle cell disease and thalassaemia.
🗣️ Genetic Counselling
- Explain the suspected diagnosis and inheritance pattern clearly.
- Discuss benefits, limitations and possible outcomes of testing.
- Explore implications for relatives, reproduction, insurance and psychological wellbeing.
- Obtain informed consent before testing.
- Explain that a negative test does not always exclude a genetic condition.
- Discuss variants of uncertain significance carefully and avoid over-interpreting them.
- Offer referral to clinical genetics where appropriate.
⚖️ Ethical point: Genetic results are unusual because they may reveal important information about relatives as well as the patient. Confidentiality still applies, but clinicians should encourage patients to share relevant information with at-risk family members.
🚩 When to Refer to Clinical Genetics
- Suspected inherited cancer syndrome.
- Child with unexplained developmental delay, congenital anomalies or dysmorphic features.
- Family history suggesting autosomal dominant, X-linked or mitochondrial disease.
- Known pathogenic variant in a family.
- Recurrent miscarriages or suspected chromosomal rearrangement.
- Consanguinity with suspected autosomal recessive disease.
- Predictive testing for serious adult-onset conditions.
- Complex interpretation of genetic test results.
🧬 Examples of High-Yield Conditions
| Condition |
Inheritance |
Key Features |
| Cystic fibrosis |
Autosomal recessive |
Recurrent chest infections, bronchiectasis, pancreatic insufficiency, male infertility |
| Marfan syndrome |
Autosomal dominant |
Tall stature, long limbs, lens dislocation, aortic root dilatation |
| Huntington disease |
Autosomal dominant |
Chorea, psychiatric symptoms, dementia, anticipation |
| Duchenne muscular dystrophy |
X-linked recessive |
Progressive proximal weakness, Gower sign, calf pseudohypertrophy, cardiomyopathy |
| Haemophilia A |
X-linked recessive |
Factor VIII deficiency, haemarthroses, prolonged APTT |
| Familial hypercholesterolaemia |
Autosomal dominant |
High LDL cholesterol, tendon xanthomata, premature cardiovascular disease |
| ADPKD |
Autosomal dominant |
Renal cysts, hypertension, haematuria, CKD, berry aneurysms |
| Sickle cell disease |
Autosomal recessive |
Pain crises, anaemia, infection risk, acute chest syndrome |
🧠 Exam Approach to Inheritance Questions
- Every generation affected? Think autosomal dominant.
- Only siblings affected but parents unaffected? Think autosomal recessive.
- Mostly males affected with carrier females? Think X-linked recessive.
- No male-to-male transmission? Think X-linked inheritance.
- Only maternal transmission? Think mitochondrial inheritance.
- Disease gets earlier or worse each generation? Think anticipation.
⚠️ Common Pitfalls
- Assuming all genetic diseases present in childhood - many present in adulthood.
- Forgetting that autosomal dominant conditions can appear to “skip” generations because of reduced penetrance.
- Thinking a negative family history excludes genetic disease - de novo variants are possible.
- Over-interpreting a variant of uncertain significance.
- Forgetting that genetic results can affect relatives, not just the patient.
- Confusing diagnostic testing with screening.
📌 Quick Revision Summary
- Autosomal dominant = vertical pattern, 50% risk to children.
- Autosomal recessive = carrier parents, 25% risk to each child if both parents are carriers.
- X-linked recessive = mainly males, no male-to-male transmission.
- Mitochondrial = maternal inheritance only.
- Genetic counselling is essential before predictive testing.
- Family history should usually cover at least three generations.
- Variants may be benign, pathogenic or uncertain.
- Clinical genetics is increasingly relevant across cardiology, oncology, neurology, paediatrics, renal medicine and obstetrics.
✅ Take-home message: Clinical genetics is not just about rare diseases. It shapes everyday medicine through cancer risk, cardiac screening, antenatal care, developmental assessment, pharmacogenomics and family counselling. The safest approach is to recognise patterns, take a careful family history, explain uncertainty honestly and refer when results may affect relatives or future children.
