Master Genetics
for PLAB 1

What the PLAB 1 Tests in Genetics

PLAB 1 tests applied clinical genetics: recognising patterns of inheritance (autosomal dominant, recessive, X-linked, mitochondrial) from family histories and pedigrees. Candidates must identify common genetic syndromes (e.g., Down, Turner, Klinefelter, Marfan, Noonan, neurofibromatosis type 1) from dysmorphic features, congenital anomalies, and cardiac or neurological presentations. You must know diagnostic criteria (e.g., Ghent criteria for Marfan, NIH criteria for NF1), first-line investigations (e.g., karyotype, FISH, microarray, specific gene panels), and management principles (e.g., screening for aortic root dilation in Marfan, growth hormone therapy in Turner). Ethical and legal aspects include consent for genetic testing, implications for relatives, and the UK's NHS Genomic Medicine Service. Questions often present a clinical scenario with a pedigree or list of features; you must select the most likely diagnosis, inheritance pattern, or appropriate next step.

High-Yield Concepts

• Down Syndrome (Trisomy 21): Most common chromosomal abnormality; risk increases with maternal age. Features: hypotonia, flat facial profile, upslanting palpebral fissures, single palmar crease, duodenal atresia, AVSD. Associated with increased risk of leukaemia, Alzheimer's disease, and atlantoaxial instability. Diagnosis: combined test (nuchal translucency, β-hCG, PAPP-A) at 11–14 weeks; confirm with karyotype or QF-PCR.
• Turner Syndrome (45,X): Presents with short stature, webbed neck, low hairline, cubitus valgus, coarctation of the aorta, and primary amenorrhoea. Management: growth hormone therapy, oestrogen replacement at puberty, regular echocardiogram, and monitoring for autoimmune thyroiditis and hypertension.
• Marfan Syndrome (FBN1 mutation): Autosomal dominant; Ghent criteria require major involvement in two systems (e.g., aortic root dilation, ectopia lentis, dural ectasia) plus family history. Features: tall stature, arachnodactyly, pectus deformity, mitral valve prolapse. Key management: annual echocardiogram, beta-blockers (e.g., atenolol) to reduce aortic root growth, avoid contact sports.
• Neurofibromatosis Type 1 (NF1): Autosomal dominant; NIH diagnostic criteria: ≥2 of café-au-lait spots (≥6, >5mm prepubertal/>15mm postpubertal), neurofibromas, optic glioma, Lisch nodules, freckling in axilla/groin, distinctive osseous lesion, first-degree relative with NF1. Monitor for hypertension (renal artery stenosis), scoliosis, and malignant peripheral nerve sheath tumours.
• Cystic Fibrosis (CFTR mutation): Autosomal recessive; presents with meconium ileus, recurrent chest infections, pancreatic insufficiency, and male infertility (CBAVD). Diagnosis: sweat chloride >60 mmol/L (two tests) or two CFTR mutations. Management: chest physiotherapy, DNase, ivacaftor for specific mutations, pancreatic enzyme replacement, fat-soluble vitamins.
• Huntington Disease (CAG repeat): Autosomal dominant; onset typically 30–50 years with chorea, cognitive decline, psychiatric symptoms. Anticipation occurs with paternal transmission. Predictive testing requires genetic counselling and informed consent; UK guidelines recommend multidisciplinary support. No disease-modifying treatment; manage chorea with tetrabenazine.
• Fragile X Syndrome (FMR1 CGG repeat): Most common inherited cause of intellectual disability; X-linked dominant with anticipation. Features: long face, large ears, macroorchidism, autistic traits. Premutation carriers (55–200 repeats) at risk for FXTAS (tremor/ataxia) and POI. Diagnosis: PCR and Southern blot. Management: supportive therapies, behavioural interventions.
• Duchenne Muscular Dystrophy (DMD): X-linked recessive; presents by age 5 with proximal weakness, Gowers' sign, calf pseudohypertrophy, raised CK (50–100x normal). Diagnosis: genetic testing (deletion/duplication in DMD gene). Management: corticosteroids (prednisolone or deflazacort) to prolong ambulation, physiotherapy, cardiac monitoring (dilated cardiomyopathy), respiratory support.

Common Traps in Genetics Questions

• Confusing autosomal dominant (e.g., Marfan, NF1) with autosomal recessive (e.g., CF) — look for affected individuals in every generation vs. only siblings.
• Assuming all cases of Down syndrome are due to nondisjunction — remember Robertsonian translocation (especially 14;21) carries recurrence risk and requires parental karyotyping.
• Missing that Turner syndrome often has normal intelligence but specific learning difficulties (e.g., visuospatial, maths) — not intellectual disability.
• Forgetting that in X-linked recessive conditions (e.g., Duchenne), affected males are hemizygous; carrier females are usually asymptomatic but may have mild CK elevation.
• Overlooking that genetic testing for Huntington requires pre- and post-test counselling and the patient must give informed consent — never test without counselling.
• Mistaking achondroplasia (autosomal dominant, FGFR3 mutation, rhizomelic shortening) for other skeletal dysplasias — always check for normal trunk length and frontal bossing.

How to Revise Genetics for the PLAB 1

Prioritise memorising key diagnostic criteria (Ghent, NIH, Amsterdam for Lynch syndrome) and classic triad presentations (e.g., Down: hypotonia + flat face + AVSD; Turner: short stature + webbed neck + coarctation). Questions often give a pedigree; practise determining inheritance by pattern (vertical = AD, horizontal = AR, affected males linked through females = XLR). Know which conditions require urgent referral (e.g., Marfan with acute aortic pain) and which screening is lifelong (e.g., echocardiogram in Marfan, colonoscopy in Lynch). Focus on UK guidelines: NICE for CF and Down syndrome screening, NHS genomic test directory. Do not over-study rare syndromes; stick to the 20 most common conditions tested.

Practise it: MedLumen has 50 Genetics questions for the PLAB 1, each with a full explanation and references.