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PH-FD30

Autosomal dominant and recessive disorders

How a change in one gene causes disease: why one altered copy is enough in dominant disorders and two are needed in recessive ones, the family patterns and chances that follow, and sickle cell disease as a worked example.

By the end, you can

  • Explain how a pathogenic variant leads to loss or gain of protein function.
  • Explain why some disorders need one altered copy (dominant) and others two (recessive).
  • Predict the chance of inheritance for each child in dominant and carrier-by-carrier families.
  • Relate penetrance, expressivity and new variants to irregular dominant pedigrees.
  • Trace sickle cell disease from a single base change to anaemia and painful crises.
  • Recognise the classic features of Marfan syndrome, cystic fibrosis, phenylketonuria and storage diseases, X-linked patterns and the genetic and newborn tests, and explain how diet, enzyme replacement and CFTR modulators act on the mechanism.

What it is

Single-gene (Mendelian) disorders are caused by a pathogenic variant in one gene and pass through families in predictable patterns. In autosomal dominant disorders one altered copy of a gene on an autosome (a non-sex chromosome) is enough to cause disease; in autosomal recessive disorders both copies must be altered, and people with one altered copy are healthy carriers. X-linked and mitochondrial patterns follow other rules.

2 types to tell apart
Autosomal dominant
One altered allele causes disease, through haploinsufficiency, a dominant-negative effect or gain of function. Affected people usually have an affected parent; each child has a 1 in 2 chance.
Autosomal recessive
Both alleles must be altered, usually causing loss of an enzyme or transporter. Affected people usually have two unaffected carrier parents; each child of two carriers has a 1 in 4 chance.

Normal function

Two copies of every autosomal gene

The inside the holds 46 chromosomes: 22 pairs of autosomes and one pair of sex chromosomes. One chromosome of each pair comes from each parent, so every autosomal gene is present in two copies, its two alleles, which may be identical or differ slightly.

A gene is copied into messenger RNA, which leaves the nucleus and is translated into protein on ribosomes, many of them on the . Usually both alleles are used, so the cell’s protein is a mixture of their products.

When eggs and sperm form by meiosis, each receives one allele of each pair, chosen at random. This is why single-gene disorders follow predictable chances.

Point to it on the model