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