Genetics and Immunology for MRCOG Part 1
Part 1 — Genetics
Inheritance Patterns
| Pattern | Recognition | Obstetric examples | |---|---|---| | Autosomal dominant | Every generation affected; male-to-male transmission possible; 50% recurrence | Marfan, Huntington, familial breast cancer (BRCA), myotonic dystrophy | | Autosomal recessive | Skips generations; consanguinity; 25% recurrence for carrier parents | Cystic fibrosis, sickle cell, thalassaemia, CAH | | X-linked recessive | Males affected, females carriers; no male-to-male transmission; carrier mother has 50% affected sons | Haemophilia A and B, Duchenne, red-green colour blindness | | X-linked dominant | Affected males often lethal in utero; affected father transmits to all daughters, no sons | Rett syndrome, incontinentia pigmenti, X-linked hypophosphataemia | | Mitochondrial | Exclusively maternal transmission; variable expression from heteroplasmy | MELAS, Leber hereditary optic neuropathy |
The two facts most often tested: no male-to-male transmission in X-linked conditions, and mitochondrial disease is never transmitted by a father.
Chromosomal Abnormalities
| Condition | Karyotype | Points | |---|---|---| | Down syndrome | Trisomy 21 | ~95% non-disjunction (maternal age related), ~4% Robertsonian translocation, ~1% mosaic. A translocation carrier parent has a substantially higher recurrence than the age-related risk, so karyotype the parents when a translocation is found. | | Edwards | Trisomy 18 | Most die in the first year | | Patau | Trisomy 13 | Most die within weeks | | Turner | 45,X | Short stature, streak gonads, coarctation, horseshoe kidney; ~99% of 45,X conceptions miscarry | | Klinefelter | 47,XXY | Commonest cause of primary male hypogonadism and non-obstructive azoospermia | | Triple X | 47,XXX | Usually a normal phenotype |
Non-disjunction is failure of separation in meiosis and is the mechanism underlying the maternal age association. Robertsonian translocation involves the acrocentric chromosomes (13, 14, 15, 21, 22); a balanced carrier is phenotypically normal but has recurrent miscarriage and an increased risk of an unbalanced conceptus.
Genomic Imprinting and Mosaicism
Imprinting means expression depends on parental origin:
- Prader-Willi — loss of the paternal 15q11-13 contribution
- Angelman — loss of the maternal 15q11-13 contribution
- Complete hydatidiform mole — entirely paternal genome (46,XX, usually androgenetic diploidy from a single sperm duplicating), no fetal tissue
- Partial mole — triploid (69,XXY), two paternal sets and one maternal, with fetal tissue present
Confined placental mosaicism matters practically: CVS samples trophoblast, so an abnormal CVS result may not reflect the fetus, and amniocentesis is used to resolve it.
Prenatal Testing
| Test | Timing | Nature | Loss rate | |---|---|---|---| | cfDNA / NIPT | From 10 weeks | Screening, not diagnostic — a positive needs confirmation | None | | CVS | 11–14 weeks | Diagnostic; placental tissue | ~0.2% above background | | Amniocentesis | From 15 weeks | Diagnostic; fetal cells | ~0.1–0.2% above background |
cfDNA analyses placental DNA, which is why confined placental mosaicism, vanishing twin and maternal malignancy produce discordant results. Its positive predictive value is far higher for trisomy 21 than for the rarer trisomies or microdeletions, because PPV depends on prevalence.
Genetic Terminology
Penetrance — proportion of genotype carriers showing any phenotype. Expressivity — how severely it manifests among those affected. Anticipation — earlier onset and greater severity in successive generations, seen in trinucleotide repeat disorders such as myotonic dystrophy and Huntington. Heteroplasmy — mixed populations of mitochondrial DNA within a cell, explaining variable severity.
Part 1 — Immunology
Innate versus Adaptive
Innate: immediate, no memory. Physical barriers, complement, neutrophils, macrophages, natural killer cells, pattern-recognition receptors. Adaptive: slower, antigen-specific, with memory. T and B lymphocytes.
Immunoglobulins
| Class | Points | |---|---| | IgG | Most abundant; the only class that crosses the placenta, actively, via FcRn, mainly after 32 weeks — hence preterm infants' relative hypogammaglobulinaemia. Basis of haemolytic disease of the newborn and of maternal vaccination. | | IgM | First in a primary response; pentameric; too large to cross the placenta — fetal IgM implies fetal infection | | IgA | Mucosal secretions and breast milk, where secretory IgA gives passive mucosal protection | | IgE | Mast cells and basophils; type I hypersensitivity and parasites | | IgD | Naive B cell surface receptor |
Hypersensitivity
| Type | Mechanism | Example | |---|---|---| | I | IgE, mast cell degranulation | Anaphylaxis, latex allergy | | II | Antibody against cell-surface antigen | Rhesus disease, ITP, Graves | | III | Immune complex deposition | SLE, post-streptococcal glomerulonephritis | | IV | T-cell mediated, delayed | Contact dermatitis, TB skin test, graft rejection |
Rhesus disease is the obstetric archetype of type II. Anti-D works by clearing fetal red cells from the maternal circulation before they provoke a primary response — which is why timing matters and why it is useless once sensitisation has occurred.
Maternal Immune Tolerance
The fetus is a semi-allograft and is not rejected. Contributing mechanisms:
- Trophoblast does not express classical HLA-A or HLA-B; it expresses HLA-G, which inhibits NK-cell killing
- A shift toward a Th2 cytokine profile in pregnancy
- Regulatory T cells expand
- The placenta acts as a physical and immunological interface
The clinical corollary is examinable: Th1-mediated conditions such as rheumatoid arthritis often improve in pregnancy, while Th2-mediated conditions such as SLE may flare, and both frequently rebound postpartum.
Complement
Three activation routes converge on C3: classical (antibody–antigen), alternative (pathogen surfaces), lectin (mannose-binding). Downstream: C3a and C5a are anaphylatoxins and chemotactic; C5–C9 form the membrane attack complex. Terminal complement deficiency predisposes to Neisseria infection — relevant to eculizumab, which requires meningococcal vaccination.
High-Yield Exam Points
- IgG alone crosses the placenta; detecting IgM in fetal or neonatal blood means the fetus made it, so the fetus was infected.
- No male-to-male transmission in X-linked inheritance; mitochondrial inheritance is maternal only.
- A complete mole is androgenetic with no fetal tissue; a partial mole is triploid with fetal tissue.
- cfDNA is placental DNA and is a screening test whatever the reported "99% accuracy" implies.
- Rhesus disease is type II hypersensitivity; anti-D prevents sensitisation and does nothing once it has happened.
- RA improves and SLE flares in pregnancy, on the Th1/Th2 shift.
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