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PLAB 1 (Professional and Linguistic Assessments Board Part 1)

17.4 Genetics, Genomics & Pharmacogenomics

Q: A man with haemophilia A and a woman with no family history of bleeding disorders plan a family. What is the risk for their children?

No sons will be affected and all daughters will be carriers. Haemophilia A is X-linked recessive. An affected father passes his Y chromosome to his sons, so none of his sons inherit the condition (there is no male-to-male transmission). He passes his single X chromosome, which carries the variant, to every daughter, so all daughters are obligate carriers. Half of sons being affected applies to the children of a carrier mother.

Q: A 32-year-old woman of Han Chinese ancestry is diagnosed with focal epilepsy and carbamazepine is being considered. Which test should be done before starting it?

HLA-B1502. People of Han Chinese or Thai ancestry who carry HLA-B1502 have a markedly increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis with carbamazepine, so testing before treatment is recommended. TPMT testing is done before thiopurines such as azathioprine, HLA-B*5701 before abacavir, and DPYD before fluoropyrimidine chemotherapy. In practice lamotrigine or levetiracetam is also usually preferred first-line for focal epilepsy.

Q: A 45-year-old woman's colorectal cancer shows loss of mismatch repair protein expression. Her mother had endometrial cancer at 48. What is the most likely underlying diagnosis?

Lynch syndrome. Mismatch repair deficiency in a colorectal cancer, with a family history of early endometrial cancer, suggests Lynch syndrome (hereditary non-polyposis colorectal cancer), an autosomal dominant mismatch repair gene condition. NICE recommends testing all colorectal and endometrial cancers for mismatch repair deficiency to identify Lynch syndrome, leading to germline testing, surveillance and cascade testing of relatives. Familial adenomatous polyposis causes hundreds of polyps, BRCA2 mainly affects breast, ovarian, prostate and pancreatic cancer risk, and Peutz-Jeghers syndrome causes hamartomatous polyps with mucocutaneous pigmentation.

Key Takeaways

Autosomal dominant conditions give each child of an affected parent a 50% risk; autosomal recessive conditions give a 25% risk to each child of two carriers.
In X-linked recessive conditions such as haemophilia and Duchenne muscular dystrophy, there is no male-to-male transmission and all daughters of an affected man are carriers.
Lynch syndrome is a mismatch repair gene condition that greatly increases the risk of colorectal and endometrial cancer; NICE recommends testing all such tumours for it.
HLA-B5801 predicts severe skin reactions to allopurinol, HLA-B1502 to carbamazepine and HLA-B*5701 to abacavir, while DPYD variants predict fluoropyrimidine toxicity.
CYP2D6 ultra-rapid metabolisers convert codeine to morphine quickly, causing toxicity; codeine is contraindicated in breastfeeding and in children under 12.

Last updated: October 2026

Genetics, Genomics & Pharmacogenomics

Patterns of Inheritance

Pattern	Key Features	Examples
Autosomal dominant	Affected people in every generation; males and females equally affected; 50% risk to each child of an affected parent; variable expressivity and incomplete penetrance	Huntington's disease, familial hypercholesterolaemia, adult polycystic kidney disease, Marfan syndrome, neurofibromatosis type 1, hypertrophic cardiomyopathy, BRCA1/2, Lynch syndrome, myotonic dystrophy
Autosomal recessive	Parents usually unaffected carriers; 25% risk of an affected child when both parents carry the variant (50% carriers); more common with consanguinity	Cystic fibrosis, sickle cell disease, thalassaemia, haemochromatosis, phenylketonuria, Wilson's disease, spinal muscular atrophy
X-linked recessive	Mainly males affected; no male-to-male transmission; sons of carrier women have a 50% risk; all daughters of an affected man are carriers	Haemophilia A and B, Duchenne and Becker muscular dystrophy, G6PD deficiency, red-green colour blindness
X-linked dominant	Affected fathers pass it to all daughters and no sons	X-linked hypophosphataemic rickets
Mitochondrial	Maternal inheritance only; variable severity (heteroplasmy)	MELAS, Leber's hereditary optic neuropathy

Trinucleotide Repeat Disorders & Anticipation

Expanding repeats cause anticipation (earlier onset or greater severity in successive generations): Huntington's disease (CAG; worse with paternal transmission), myotonic dystrophy (CTG; congenital form via the mother), fragile X syndrome (CGG; the commonest inherited cause of learning disability) and Friedreich's ataxia (GAA).

Chromosomal Disorders

Condition	Karyotype	Key Features
Down's syndrome	Trisomy 21 (mostly non-disjunction, linked to maternal age; about 4% Robertsonian translocation, which can be inherited)	Learning disability, hypotonia, flat facial profile, single palmar crease; atrioventricular septal defect, duodenal atresia, hypothyroidism, coeliac disease, leukaemia, early-onset Alzheimer's disease
Edwards' syndrome	Trisomy 18	Rocker-bottom feet, clenched hands with overlapping fingers, cardiac defects; most die in infancy
Patau's syndrome	Trisomy 13	Midline defects (cleft lip and palate, holoprosencephaly), polydactyly; most die in infancy
Turner syndrome	45,X	Short stature, webbed neck, coarctation and bicuspid aortic valve, primary amenorrhoea (streak ovaries), lymphoedema in newborns
Klinefelter syndrome	47,XXY	Tall, small firm testes, infertility, gynaecomastia, hypogonadism
22q11.2 deletion (DiGeorge) syndrome	Microdeletion	Cardiac defects (tetralogy of Fallot), cleft palate, hypocalcaemia (absent parathyroids), immunodeficiency (thymic hypoplasia), learning and psychiatric difficulties

Hereditary Cancer & Other Common Genetic Conditions

BRCA1/BRCA2: high risks of breast and ovarian cancer (and prostate and pancreatic cancer with BRCA2). Carriers are offered enhanced breast surveillance, risk-reducing mastectomy or salpingo-oophorectomy, and cascade testing of relatives.
Lynch syndrome: an autosomal dominant mismatch repair gene variant causing early colorectal and endometrial cancers (and others). NICE recommends testing all colorectal and endometrial cancers for mismatch repair deficiency to find families with Lynch syndrome, who then have colonoscopic surveillance and aspirin may be considered.
Familial adenomatous polyposis (APC gene): hundreds of colonic polyps from adolescence and near-certain colorectal cancer without prophylactic colectomy.
Familial hypercholesterolaemia (NICE CG71): suspect with a total cholesterol above 7.5 mmol/L in adults or a personal or family history of premature coronary heart disease; use the Simon Broome or Dutch Lipid Clinic criteria, offer high-intensity statins, and arrange cascade testing of relatives (including children).
Hereditary haemochromatosis (HFE C282Y homozygosity): fatigue, arthralgia, raised transferrin saturation and ferritin, diabetes, liver disease and skin pigmentation; treated with venesection.

Genomic Medicine in the NHS

The NHS Genomic Medicine Service (from 2018) provides testing through regional laboratory hubs according to the National Genomic Test Directory, including whole genome sequencing for some rare diseases and cancers. Results may be diagnostic (explaining a condition), predictive (risk of future disease), carrier results, or incidental (secondary) findings.

Pharmacogenomics

Gene / Marker	Drug	Consequence
*HLA-B5801**	Allopurinol	Severe cutaneous adverse reactions (common in Han Chinese, Korean, Thai ancestry)
*HLA-B1502**	Carbamazepine	Stevens-Johnson syndrome or TEN (Han Chinese, Thai ancestry): test before starting
*HLA-B5701**	Abacavir	Hypersensitivity reaction: test before starting
TPMT / NUDT15	Azathioprine, mercaptopurine	Severe bone marrow suppression with low activity: check before starting
DPYD	Fluorouracil, capecitabine	Severe or fatal toxicity: test before chemotherapy
CYP2C19	Clopidogrel	Poor metabolisers gain less antiplatelet effect; NICE recommends genotype testing to guide treatment after ischaemic stroke or TIA
CYP2D6	Codeine, tramadol	Ultra-rapid metabolisers form morphine quickly (toxicity); codeine is contraindicated in breastfeeding and in children under 12
MT-RNR1	Aminoglycosides (gentamicin)	Permanent hearing loss after a single dose; rapid testing is used in some neonatal units

Ethics of Genetic Testing

Pre-test counselling and consent: discuss the purpose, possible results (including uncertain variants and incidental findings), and implications for relatives, insurance and mental health.
Predictive testing for adult-onset conditions (for example Huntington's disease) is usually deferred in children until they can decide for themselves, unless results change childhood care.
Confidentiality and relatives: genetic information is also relevant to family members. Encourage patients to share results; GMC guidance allows disclosure without consent in exceptional cases where the risk to a relative is serious and could be reduced, after weighing the patient's interests (the duty to consider this was confirmed in ABC v St George's Healthcare, 2020).
Insurance: the UK Code on Genetic Testing and Insurance means people are not required to disclose predictive genetic test results for most insurance (except Huntington's disease for large life insurance policies).

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Test Your Knowledge

A man with haemophilia A and a woman with no family history of bleeding disorders plan a family. What is the risk for their children?

Half of all children will be affected

No sons will be affected and all daughters will be carriers

Half of sons will be affected and half of daughters will be carriers

All sons will be affected and all daughters will be carriers

Test Your Knowledge

A 32-year-old woman of Han Chinese ancestry is diagnosed with focal epilepsy and carbamazepine is being considered. Which test should be done before starting it?

HLA-B*1502

DPYD genotype

HLA-B*5701

TPMT activity

Test Your Knowledge

A 45-year-old woman's colorectal cancer shows loss of mismatch repair protein expression. Her mother had endometrial cancer at 48. What is the most likely underlying diagnosis?

Peutz-Jeghers syndrome

BRCA2 variant

Lynch syndrome

Familial adenomatous polyposis

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