Genetics and Inheritance Patterns
Knowledge of inheritance patterns is essential for understanding genetic diseases, genetic counselling, and risk assessment for conditions including cystic fibrosis, Huntington's, and haemophilia.
Key Facts
Autosomal dominant: 50% offspring affected, variable penetrance; e.g., Huntington's disease, Marfan syndrome, ADPKD Autosomal recessive: 25% offspring affected if both parents carriers; e.g., cystic fibrosis, sickle cell disease, PKU X-linked recessive: Males affected, females carriers; e.g., haemophilia A/B, Duchenne muscular dystrophy, G6PD deficiency X-linked dominant: Affects both sexes, often lethal in males; e.g., Rett syndrome, Alport syndrome (some forms) Mitochondrial inheritance: Maternal transmission only; e.g., MELAS, Leber hereditary optic neuropathy Trinucleotide repeat disorders show anticipation (earlier onset in successive generations); e.g., Huntington's (CAG), myotonic dystrophy (CTG) Carrier frequency of CF in UK Caucasians is approximately 1 in 25 (autosomal recessive, CFTR gene, chromosome 7) Hardy-Weinberg equation: p² + 2pq + q² = 1; used to calculate carrier frequencies in populations
Overview
Key Facts
Mendelian inheritance patterns describe how single-gene disorders are transmitted through families. Understanding these patterns is crucial for genetic counselling, prenatal diagnosis, and risk stratification.
Epidemiology
- Approximately 1 in 25 individuals carry a pathogenic variant — most are autosomal recessive carriers
- Genetic conditions account for approximately 30% of paediatric hospital admissions
- Newborn screening in the UK tests for 9 conditions including CF, sickle cell, PKU, and congenital hypothyroidism
- Approximately 6,000 recognised single-gene disorders
Aetiology
Genetic variation types:
- Point mutations: Missense, nonsense, silent
- Frameshift mutations: Insertions, deletions
- Trinucleotide repeat expansions: Dynamic mutations causing anticipation
- Large deletions/duplications: Detected by MLPA or array CGH
- Chromosomal abnormalities: Aneuploidies, translocations, inversions
Pathophysiology
Disease mechanisms:
- Loss of function (most recessive): Both alleles must be non-functional (e.g., CF — absent CFTR chloride channel)
- Gain of function (most dominant): One mutant allele confers new/enhanced activity (e.g., achondroplasia — constitutive FGFR3 activation)
- Dominant negative: Mutant protein interferes with wild-type (e.g., osteogenesis imperfecta — abnormal collagen)
- Haploinsufficiency: One functional copy insufficient (e.g., Williams syndrome — elastin deletion)
Clinical Presentation
Autosomal Dominant Conditions
- Huntington's disease: Chorea, psychiatric symptoms, dementia — onset 30-50 years
- Marfan syndrome: Tall stature, arachnodactyly, lens subluxation, aortic root dilatation
- ADPKD: Bilateral renal cysts, hypertension, berry aneurysms
- Familial hypercholesterolaemia: Tendon xanthomata, premature CVD
Autosomal Recessive Conditions
- Cystic fibrosis: Recurrent chest infections, malabsorption, male infertility
- Sickle cell disease: Vaso-occlusive crises, splenic sequestration, stroke
- Phenylketonuria: Intellectual disability if untreated, musty odour
X-linked Conditions
- Duchenne muscular dystrophy: Progressive proximal weakness, Gower's sign, calf pseudohypertrophy
- Haemophilia A: Spontaneous haemarthroses, prolonged bleeding
Red Flags for Genetic Referral
- Family history of multiple affected individuals
- Consanguinity
- Multiple congenital anomalies
- Unexplained intellectual disability
- Recurrent pregnancy loss
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Autosomal dominant condition | Vertical transmission, 50% risk, variable expressivity | Family pedigree, genetic testing |
| Autosomal recessive condition | Horizontal transmission, consanguinity, 25% risk | Carrier testing, sweat test (CF), Hb electrophoresis |
| X-linked recessive | Male-predominant, carrier females, no male-to-male transmission | Factor levels, CK, genetic testing |
| Chromosomal disorder | Dysmorphism, multiple anomalies, intellectual disability | Karyotype, microarray |
| Multifactorial inheritance | Family clustering, no clear Mendelian pattern | Clinical diagnosis, risk assessment |
| Mitochondrial disorder | Maternal inheritance, variable severity, neuromuscular features | Muscle biopsy, mitochondrial DNA sequencing |
Diagnosis / Investigation
Bedside
- Three-generation family pedigree: Essential for identifying inheritance pattern
- Dysmorphology examination: Systematic assessment of facial features, hands, feet
Bloods
- Newborn blood spot screening: PKU, CF, SCD, congenital hypothyroidism, and others
- Haemoglobin electrophoresis: Sickle cell disease, thalassaemia
- Enzyme assays: Gaucher, Fabry, Tay-Sachs
Imaging
- Echocardiography: Marfan syndrome (aortic root), hypertrophic cardiomyopathy
- Renal USS: ADPKD screening
- MRI brain: Huntington's (caudate atrophy), metabolic disorders
Special Tests
- Karyotype: Chromosomal analysis (Down's, Turner's, Klinefelter's)
- Microarray (array CGH): Copy number variants, microdeletions/duplications
- Single gene testing: Sanger sequencing for known mutations
- Gene panels / whole exome/genome sequencing: Via NHS Genomic Medicine Service
- Prenatal diagnosis: CVS (10-13 weeks), amniocentesis (15-20 weeks), NIPT (from 10 weeks)
Management
Non-pharmacological
- Genetic counselling: Non-directive, informed decision-making
- Cascade testing: Screen at-risk family members
- Preimplantation genetic testing (PGT): For known pathogenic variants
- Prenatal testing: CVS, amniocentesis, NIPT for high-risk pregnancies
- Newborn screening: UK blood spot programme
Pharmacological
- Disease-specific treatments:
- CF: CFTR modulators (ivacaftor/lumacaftor, elexacaftor/tezacaftor/ivacaftor [Kaftrio])
- Sickle cell: Hydroxycarbamide 15-30mg/kg/day, crizanlizumab
- FH: High-intensity statin, ezetimibe, PCSK9 inhibitors
- Huntington's: Tetrabenazine for chorea (symptomatic only)
- Gaucher disease: Enzyme replacement therapy (imiglucerase)
Referral Criteria
- Suspected genetic condition → clinical genetics service
- Positive newborn screening → specialist paediatric service
- Family history of genetic condition and planning pregnancy → genetic counselling
- Consider genomic testing via NHS Genomic Medicine Service for rare diseases
Prognosis
- CF: Median survival now >50 years with modern treatments including CFTR modulators
- Huntington's disease: Progressive, fatal within 15-20 years of symptom onset; no disease-modifying therapy
- Duchenne MD: Most wheelchair-dependent by age 12; median survival to late 20s with optimal care
- Sickle cell disease: Median survival in UK ~60 years with comprehensive care
- FH: Untreated homozygous FH — CVD in childhood; heterozygous — 50% risk of CHD by age 50 without treatment
- PKU: Normal life expectancy and intelligence if dietary restriction maintained from birth
Other Relevant Information
Inheritance Pattern Summary
| Pattern | Risk to Offspring | Key Features | Examples |
|---|---|---|---|
| Autosomal dominant | 50% | Vertical transmission, variable penetrance | Huntington's, Marfan, NF1, ADPKD |
| Autosomal recessive | 25% (both parents carriers) | Horizontal, consanguinity risk | CF, SCD, PKU, Wilson's |
| X-linked recessive | 50% sons affected, 50% daughters carriers | No male-to-male transmission | Haemophilia, DMD, G6PD |
| X-linked dominant | 50% (often male lethal) | All daughters of affected male affected | Rett syndrome, incontinentia pigmenti |
| Mitochondrial | All children of affected mother at risk | Variable severity, maternal | MELAS, LHON |
Hardy-Weinberg Equation
p² + 2pq + q² = 1 (where p + q = 1)
- p² = frequency of homozygous dominant
- 2pq = frequency of carriers (heterozygotes)
- q² = frequency of affected individuals (homozygous recessive)
- Example: CF q² = 1/2500, so q = 1/50, carrier frequency (2pq) ≈ 1/25