Genetics and Immunology for MRCOG 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.

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.

Clinically reviewed by NHS obstetricians and gynaecologists

MRCOG AI is an independent educational tool. It is not affiliated with, endorsed by, or connected to the Royal College of Obstetricians and Gynaecologists (RCOG).