Clinical overview
Genetics is not a niche academic subject in obstetrics and gynaecology — it sits at the centre of antenatal counselling, recurrent pregnancy loss, fetal medicine, sub-fertility, gynaecological oncology and paediatric gynaecology. Almost every working day a registrar fields a question that turns on a principle of inheritance: a couple who have had a baby with a neural tube defect and want to know their recurrence risk; a woman with a strong family history of breast and ovarian cancer asking whether her daughters are at risk; a pregnancy with a soft marker on the anomaly scan; a child with ambiguous genitalia (see Ambiguous genitalia); a primigravida whose brother has haemophilia. Answering these well requires you to reason from first principles rather than memorise condition lists, because the conditions are too many to memorise but the patterns of transmission are few.
In the South African context the burden and pattern of genetic disease has distinctive features. There is high consanguinity in some communities, founder mutations in others, a young population with high fertility, and — critically — limited and unevenly distributed access to clinical genetics services, karyotyping, chromosomal microarray and molecular testing. Most district and many regional hospitals have no on-site geneticist; the registrar is frequently the first and sometimes the only clinician to take a meaningful family history, recognise a pattern, and make a referral. Getting the basic principles right therefore has real consequences for which couples are offered prenatal diagnosis, carrier testing, or simply accurate reassurance.
Core knowledge
The molecular substrate
The human genome is carried on 46 chromosomes — 22 paired autosomes and two sex chromosomes (46,XX female; 46,XY male). Genes are segments of DNA that encode proteins; each gene occupies a fixed locus, and the alternative sequences at that locus are alleles. A person homozygous at a locus carries two identical alleles; a heterozygote carries two different ones. The observable trait is the phenotype; the underlying allelic make-up is the genotype. Reproductive cells (gametes) are haploid (23 chromosomes) and are produced by meiosis, in which homologous chromosomes pair, exchange material by recombination (crossing over), and segregate — the cellular basis of Mendel's laws and of genetic variability.
Figure K1.1 — From DNA to gametes: how chromosome structure, meiosis and fertilisation create genotype and phenotype.
Mendelian (single-gene) inheritance
Autosomal dominant — the phenotype is expressed in the heterozygote. An affected person typically has an affected parent (unless the variant is new), and each child of an affected person has, classically, a 1 in 2 (50%) chance of inheriting it, with males and females equally affected and male-to-male transmission possible. Dominant conditions often show variable expressivity (severity differs between carriers) and incomplete penetrance (some carriers never express the phenotype), which is why a pedigree may appear to "skip" a generation. Examples relevant to O&G include neurofibromatosis type 1, Marfan syndrome, myotonic dystrophy and the hereditary breast–ovarian cancer syndromes.
Autosomal recessive — the phenotype appears only in homozygotes (or compound heterozygotes). Affected children are usually born to unaffected carrier parents; if both parents are carriers, each pregnancy carries a 1 in 4 (25%) risk of an affected child, 1 in 2 of an unaffected carrier, and 1 in 4 of a homozygous-unaffected child. Consanguinity sharply increases the chance that both parents carry the same recessive allele and is therefore a key item of history. Cystic fibrosis, the haemoglobinopathies and many inborn errors of metabolism follow this pattern.
X-linked recessive — the variant lies on the X chromosome and is expressed in males (who are hemizygous — they have only one X) but usually not in heterozygous female carriers. A carrier mother transmits the variant to half her sons (who are affected) and half her daughters (who are carriers); an affected father transmits it to all his daughters (obligate carriers) but none of his sons, so there is no male-to-male transmission — a discriminating pedigree feature. Haemophilia A and B and Duchenne muscular dystrophy are the classic examples. X-linked dominant conditions (rarer) affect heterozygous females and may be lethal in males.