Genetics in disease
Genetics in disease: inheritance patterns, risk sums, chromosomal syndromes and imaging
Medical genetics for FCPS Part 1: inheritance patterns, carrier risk sums, imprinting, chromosomal syndromes and DNA repair disorders. It also lists the 'most common' facts CPSP repeats and the mechanisms behind genetic imaging findings.
Single-gene inheritance
| Pattern | Key features | Examples |
|---|---|---|
| Autosomal dominant | Every generation, both sexes, 50% to each child | Von Willebrand disease (commonest inherited bleeding disorder), familial hypercholesterolaemia, achondroplasia, ADPKD, NF1, Marfan, Huntington, familial adenomatous polyposis, Lynch, Ehlers–Danlos (most types), Noonan, Crouzon and Apert |
| Autosomal recessive | Healthy carrier parents, 1 in 4 risk; consanguinity raises it | Cystic fibrosis, β-thalassaemia, haemochromatosis (HFE), SMA, most DNA repair disorders (Fanconi anaemia, xeroderma pigmentosum, ataxia telangiectasia, Bloom) |
| X-linked recessive | Males affected through carrier mothers; no male-to-male spread | Haemophilia A and B, G6PD deficiency, Duchenne, colour blindness, fragile X (X-linked with expansion) |
| X-linked dominant | Affected father: all daughters, no sons | Hypophosphataemic rickets, most Alport syndrome |
| Mitochondrial | Mother's mitochondrial DNA to all children; severity varies with heteroplasmy | MELAS, Leber optic neuropathy |
- Cancer syndromes from a germline tumour suppressor mutation (FAP with APC, Li–Fraumeni, retinoblastoma, BRCA) are inherited as autosomal dominant, although each cell needs a second hit. Lynch syndrome (mismatch repair genes) causes colorectal and endometrial cancer (the commonest extracolonic cancer in women with Lynch).
- Telomerase restores telomere ends, so cancer cells keep dividing.
The "most common" facts
| Question | Answer |
|---|---|
| Commonest pattern of genetic disease overall | Multifactorial |
| Commonest chromosomal abnormality in live births | Down syndrome |
| Commonest sex chromosome abnormality | Klinefelter (47,XXY) |
| Commonest inherited cause of intellectual disability | Fragile X syndrome |
| Commonest autosomal recessive in Northern Europeans | Haemochromatosis (cystic fibrosis is the commonest lethal one) |
| Commonest trisomy in miscarriage | Trisomy 16 |
| Best prenatal test for karyotype | Amniocentesis (15 weeks on) or CVS (11–14 weeks) |
Risk sums
- Two carrier parents: each child 1 in 4 affected, 1 in 2 carriers; an unaffected sibling has a 2/3 chance of being a carrier.
- Carrier frequency from incidence (Hardy–Weinberg): 1 in 10,000 affected gives q = 1/100, so carriers (2pq) are about 1 in 50. A healthy sister of an affected man marrying an unrelated man: 2/3 × 1/50 × 1/4 = 1 in 300.
- X-linked recessive: a carrier mother's sons have a 1 in 2 risk, daughters 1 in 2 carriers. An affected man's daughters are all carriers.
- Dominant disorder with 80% penetrance: 1/2 × 0.8 = 40%.
- First cousins share 1/8 of genes.
Concepts that explain odd pedigrees
| Term | Meaning and example |
|---|---|
| Incomplete penetrance | Carrier without disease (skipped generation) |
| Variable expressivity | Same mutation, different severity (NF1) |
| Pleiotropy | One gene, many organs (Marfan: lens, aorta, skeleton) |
| Anticipation | Worse, earlier disease in later generations: Huntington CAG expansion via the father; fragile X CGG expansion in maternal meiosis |
| Germline mosaicism | Normal parents, two children with a "new" dominant mutation |
| Locus heterogeneity | Two deaf recessive parents with hearing children |
| Genomic imprinting | 15q11–13: paternal loss gives Prader–Willi; maternal loss gives Angelman |
| Heterozygote advantage | Sickle and thalassaemia carriers resist falciparum malaria |
- Lyonisation: one X in each female cell is inactivated as a Barr body; the drumstick appendage on neutrophils is the inactive X. Barr bodies = number of X chromosomes minus one: present in Klinefelter men, absent in 45,X Turner. A girl with Turner features and a Barr body has a mosaic (45,X/46,XX) or a structural X such as isochromosome Xq.
- SHOX lies in the pseudoautosomal region and escapes X-inactivation, so normal females need two active copies. Turner girls have one functional copy, giving short stature, short 4th metacarpals and Madelung deformity (bowed distal radius).
Chromosomal disorders
- Aneuploidy: an extra (trisomy) or missing (monosomy) chromosome from non-disjunction.
| Disorder | Mechanism and features |
|---|---|
| Down syndrome (trisomy 21) | Usually maternal meiosis I non-disjunction; risk rises with maternal age. Flat face, upslanting eyes, protruding tongue, single palmar crease. Atrioventricular septal defect (endocardial cushion: check first on fetal echo), duodenal atresia (double bubble, polyhydramnios), thick nuchal fold, hypothyroidism, leukaemia, early Alzheimer disease (extra APP) |
| Translocation Down | Phenotypically normal parent with a balanced Robertsonian translocation (14;21); 100% recurrence with a 21;21 translocation |
| Edwards (trisomy 18) | Clenched overlapping fingers, rocker-bottom feet |
| Patau (trisomy 13) | Holoprosencephaly, cleft lip, polydactyly |
| Turner (45,X) | Short stature, webbed neck, cystic hygroma, streak ovaries with high FSH (primary amenorrhoea), horseshoe kidney, coarctation and bicuspid valve |
| Klinefelter (47,XXY) | Tall, small firm testes, gynaecomastia, azoospermia, high FSH and LH |
| Williams | 7q11 deletion including elastin: supravalvular aortic stenosis, hypercalcaemia |
- Noonan syndrome (RAS pathway, autosomal dominant) looks like Turner (webbed neck, short stature, low hairline, pectus) but occurs in both sexes with a normal karyotype, and has pulmonary valve stenosis rather than coarctation.
- Antenatal quadruple test in Down syndrome: low AFP and oestriol, high hCG and inhibin A.
Connective tissue and skeletal syndromes
| Syndrome | Gene | Clue |
|---|---|---|
| Ehlers–Danlos | Collagen (type V in classic; type III in vascular) | Hypermobile joints, stretchy skin, poor scarring; vascular type risks arterial and bowel rupture |
| Marfan | Fibrillin-1 | Tall, lens upward dislocation, aortic root dilatation |
| Osteogenesis imperfecta | Type I collagen | Fractures, blue sclerae, deafness |
| Achondroplasia | FGFR3 activation | Short limbs, narrowing interpedicular distance |
| Crouzon | FGFR2 | Craniosynostosis, midface hypoplasia, proptosis, normal hands and feet |
| Apert | FGFR2 | Craniosynostosis with syndactyly of hands and feet |
Inherited marrow failure
- Fanconi anaemia (autosomal recessive, consanguinity): defective repair of DNA cross-links; short stature, café-au-lait spots, absent thumb and radius, progressive pancytopenia with hypocellular marrow, AML risk. Very sensitive to radiation and alkylating drugs, so conditioning doses are reduced.
- Diamond–Blackfan anaemia: ribosomal protein gene mutation (RPS19) causing failed erythropoiesis in infancy: macrocytic anaemia, almost no reticulocytes, marrow lacking red cell precursors, triphalangeal thumb; red cell adenosine deaminase is raised.
Mechanisms behind imaging findings
| Condition | Mechanism | Imaging |
|---|---|---|
| Cystic fibrosis | ΔF508 CFTR misfolds and is destroyed in the endoplasmic reticulum before reaching the membrane; less chloride and water secretion | Meconium ileus (bubbly right lower quadrant, few fluid levels, microcolon), bronchiectasis, fatty pancreas |
| Duchenne | Dystrophin loss (X-linked; affected maternal uncle) | Pseudohypertrophic calves: muscle replaced by fat and fibrous tissue, bright on T1 |
| VHL | Failure to degrade hypoxia-inducible factor | Haemangioblastoma, renal and pancreatic lesions |
| Haemochromatosis | Iron in parenchymal cells | Liver and pancreas dark on T2; spleen spared |
| ADPKD | PKD1/2 | Cystic kidneys, liver cysts, berry aneurysm |
| NF1 | Neurofibromin loss | Plexiform neurofibroma; painful rapid growth means malignant change |
Remember Father-to-son transmission rules out X-linked inheritance; transmission only through mothers suggests mitochondrial or X-linked disease.
Exam trap An unaffected sibling of a recessive patient has a 2/3, not 1/2, chance of being a carrier.
Exam trap Turner and Noonan look alike; Noonan has a normal karyotype, affects boys and has pulmonary stenosis.
How FCPS asks about this
- Carrier frequency when 1 in 10,000 is affected: about 1 in 50.
- Drumstick on neutrophils: the inactivated X chromosome (Barr body).
- Short 4th metacarpals in 45,X: one functional copy of SHOX.
- Webbed neck, pulmonary stenosis, 46,XY: Noonan syndrome.
- Absent thumb, pancytopenia, consanguinity: Fanconi anaemia, defective DNA cross-link repair.
- Cardiac lesion to seek in trisomy 21: atrioventricular septal defect.
- Craniosynostosis with normal hands: Crouzon syndrome (FGFR2).
Test yourself on this topic
5 of the 127 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 7-year-old boy has a waddling gait, rises from the floor by climbing up his legs and has large firm calves. His mother's brother died of the same disease at 19. What has caused the calf enlargement?
Answer: Fat and fibrous tissue replacing muscle
Duchenne muscular dystrophy is X-linked recessive and is passed through carrier women, as in this family. Absent dystrophin leaves the sarcolemma fragile, so fibres tear, necrose and are slowly replaced by fat and connective tissue. The calves get bigger while getting weaker, which is pseudohypertrophy. Creatine kinase is very high from early childhood.
Pseudohypertrophy
- X-linked recessive, absent dystrophin
- Fibres tear and necrose
- Replaced by fat and fibrosis
- Gowers sign, very high CK
Remember Big but weak calves = fat, not muscle.
Exam trap Pseudohypertrophy means the muscle is enlarged by fat and fibrous tissue, so the bigger calf is the weaker one.
Why the other options are wrong
- Hypertrophy of the remaining muscle fibres True hypertrophy would make the muscles stronger, not weaker.
- Oedema from active inflammation Inflammatory myositis causes pain and weakness, not big calves.
- Glycogen stored in muscle fibres Glycogen storage is seen in metabolic myopathies such as Pompe disease.
- Calcification of necrotic fibres Calcification is not the cause of the enlargement.
A tall 22-year-old man with long fingers and a FBN1 mutation has annual imaging of his aorta. Where is dilatation most likely to be seen first?
Answer: Aortic root at the sinuses of Valsalva
Fibrillin-1 forms microfibrils that support elastic fibres and also holds TGF-beta in an inactive form. When it is defective, the elastic media weakens and TGF-beta signalling rises, causing cystic medial degeneration. The aortic root, under the greatest stress, dilates first at the sinuses of Valsalva, giving a flask-shaped root (annuloaortic ectasia). This leads to aortic regurgitation and type A dissection, so the root diameter is monitored on echo or MRI.
Marfan aorta
- FBN1: fibrillin-1
- Cystic medial degeneration
- Root dilates at sinuses of Valsalva
- Risk: type A dissection, AR
Remember Marfan: watch the aortic root.
Exam trap Atherosclerotic aneurysms are infrarenal; Marfan aneurysms start at the root.
Why the other options are wrong
- Distal aortic arch beyond the subclavian The site of coarctation and traumatic tears, not Marfan dilatation.
- Descending thoracic aorta at T8 Not the first site affected in Marfan syndrome.
- Infrarenal abdominal aorta Typical site of atherosclerotic aneurysm in older men.
- Aortic bifurcation Not a Marfan site.
A 22-year-old man has a slowly enlarging firm mass in the soft tissues behind the knee, close to but not within the joint. Biopsy shows a biphasic tumour of spindle cells and epithelial glands. Which genetic change confirms the diagnosis?
Answer: t(X;18) SS18–SSX fusion
Synovial sarcoma usually affects adolescents and young adults, most often near the knee, and despite its name it does not arise from synovium. It may be biphasic (spindle and epithelial cells) or monophasic, and calcifies in about a third of cases. Almost all cases carry the t(X;18) translocation that fuses SS18 with an SSX gene, and finding this fusion confirms the diagnosis. The other translocations mark Ewing sarcoma, alveolar rhabdomyosarcoma and myxoid liposarcoma.
Sarcoma translocations
- Synovial sarcoma: t(X;18)
- Ewing: t(11;22)
- Alveolar rhabdo: t(2;13)
- Myxoid liposarcoma: t(12;16)
Remember Biphasic soft-tissue tumour near a young knee: think t(X;18).
Exam trap Slow growth does not exclude synovial sarcoma; it often behaves like a benign lump for years.
Why the other options are wrong
- t(11;22) EWSR1–FLI1 fusion Marks Ewing sarcoma, usually of bone in children.
- t(2;13) PAX3–FOXO1 fusion Marks alveolar rhabdomyosarcoma.
- MDM2 amplification Seen in well-differentiated and dedifferentiated liposarcoma.
- t(12;16) FUS–DDIT3 fusion Marks myxoid liposarcoma.
A 34-year-old man with achondroplasia has pain and numbness in both legs on walking that ease when he sits and bends forward. His foot pulses are normal. What is the most likely cause of his symptoms?
Answer: Lumbar spinal canal stenosis
In achondroplasia an activating FGFR3 mutation slows endochondral bone growth. The pedicles are short and the interpedicular distance narrows down the lumbar spine instead of widening, so the canal is congenitally narrow. Small extra changes such as a minor disc bulge then compress the cauda equina, causing neurogenic claudication relieved by flexion. Vascular claudication eases on standing still, is not position dependent and comes with weak pulses.
Achondroplasia spine
- Activating FGFR3
- Short pedicles
- Interpedicular distance narrows caudally
- Spinal stenosis in adults
Remember Achondroplasia adult with claudication: think spinal stenosis.
Exam trap Infants with achondroplasia are at risk of foramen magnum stenosis, adults of lumbar stenosis.
Why the other options are wrong
- Lumbar disc prolapse at L5–S1 Possible, but does not explain the congenital canal narrowing and flexion relief.
- Peripheral arterial disease Vascular claudication eases on standing, not on bending forward.
- Spondylolysis of L5 A pars defect does not narrow the interpedicular distance.
- Tethered spinal cord Usually presents in childhood with bladder signs.
A 35-year-old man has hypertension, haematuria and bilateral ballotable flank masses. His mother had cystic kidneys and died of a sudden severe headache at 45. Which intracranial lesion is he at increased risk of?
Answer: Intracranial berry aneurysm
Autosomal dominant polycystic kidney disease is caused by mutations in PKD1 or PKD2, which encode polycystins found in renal tubules and vessel walls. About 8–10% of patients have saccular (berry) aneurysms of the circle of Willis, and the risk is higher when a relative has had subarachnoid haemorrhage. A sudden severe headache followed by death suggests his mother had a ruptured aneurysm. Liver cysts and mitral valve prolapse are other extrarenal features.
ADPKD beyond the kidney
- PKD1 or PKD2, autosomal dominant
- Liver cysts common
- Berry aneurysm risk
- Screening if a relative had SAH
Remember Cystic kidneys plus family SAH: think berry aneurysm.
Exam trap Liver cysts in ADPKD rarely affect liver function, unlike the kidneys.
Why the other options are wrong
- Cerebellar haemangioblastoma Seen in von Hippel-Lindau disease.
- Cavernous malformation Not a feature of polycystic kidney disease.
- Dural arteriovenous fistula Acquired lesion, not linked to ADPKD.
- Moyamoya vessels Not associated with ADPKD.
Where this sits in the CPSP syllabus
- Diagnostic Radiology, Paper 2: General pathology and genetics, Genetics and genomics in disease
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