Guide to identifying mode of inheritance from genetic pedigrees

Genetic pedigrees are diagrams that show the genetic relationships between family members over multiple generations. They can be used to help determine the mode of inheritance of a genetic disorder, which is important for diagnosing and managing patients with these conditions and for providing guidance and genetic counselling. Here is a guide to determining the mode of inheritance for genetic pedigrees, aimed at medical students:

Step 1 – Draw the pedigree

Collect and analyse the family history. This involves asking the patient and their family members about their medical history, including any known genetic disorders or conditions. The information should be organized into a family tree or pedigree, which shows the relationships between family members. Don’t forget that many disorders present with different outcomes depending on the genetic background, and the same condition might affect different tissues for example asthma and atopic dermatitis are connected by defective epithelial barrier function.

Step 2 – Look for broad patterns

Interpreting pedigrees is all about Occam’s razor – the most likely interpretation is usually right.

First, get a broad feel for what is going on:

Does the condition affect every generation or does it skip?

Does the condition affect disproportionately males or females?

What proportion of the pedigree are affected (5%, 25%, 50%, higher?)

Step 3 – Use the patterns to make a prediction

From these points you can start to narrow down the options, ruling some out entirely or getting an early feeling for what is unlikely.

Autosomal dominant (AD): In this pattern, the affected gene is located on one of the 22 pairs of autosomes and the condition only requires the presence of one copy of the mutant allele to be present. If one parent has the condition, there is a 50% chance of passing it on to each child. You can rule-out AD if there unaffected carriers, or if the condition skips a generation (grandparents and children affected, parents not). If there are not very many affected people in the pedigree then you can begin to lean away from AD but don’t rule it out entirely!

X-linked dominant (XD): In this pattern, the affected gene is located on the X chromosome and is expressed in the presence of only one copy of the mutant allele. If the mother has the condition, there is a 50% chance of each son or daughter inheriting it. If the father has the condition, all daughters will inherit it, but none of the sons will. You can rule-out XD if there are generational skipping or unaffected carriers. After you consider those points, you might start to lean toward X-linked dominant rather than AD if all the male offspring have the disorder but not all the female. Of course, in a small pedigree AD and X-linked dominant could both be possible. At that point, you then consider the likelihoods of each occurring by chance.

Autosomal recessive (AR): In this pattern, the affected gene is located on one of the 22 pairs of autosomes and is only expressed in the presence of two copies of the mutant allele. If both parents are carriers, there is a 25% chance of each child inheriting the condition. If there is any generational skipping, start thinking recessive. However, you can’t immediately rule out AR if there is no skipping. Instead, you need to look at incidence. Two affected parents will give 100% affected offspring in AR, whereas one affected parent with an unaffected partner will give roughly 50%. Overall recessive conditions will have lower total numbers than affected. If you see consanguineous mating (cousin or close relative marriage, shown with double line joining parents), AR will be more likely!

X-linked recessive (XR): In this pattern, the affected gene is located on the X chromosome and is only expressed in the presence of two copies of the mutant allele. If the mother is a carrier, there is a 50% chance of each son inheriting the condition, and a 50% chance of each daughter being a carrier. If the father has the condition, all daughters will be carriers, but none of the sons will inherit it. Again, you are looking for generational skipping, but now it is all about which sex has the incidence. The tell-tale sign between XR and XD is that all the male offspring from an affected mother will be affected, whereas only half will be in XD.

Mitochondrial inheritance (MI): Here the mutation is carried on the mitochondrial genome. As mitochondria come down the maternal lineage only, these conditions are dominant and will be present in every offspring from an affected mother. An affected father can not pass this on. Look for whole families being affected down the maternal side.

Incomplete penetrance / semi-dominant: These disorders are characterised by people with one affected allele presenting with a milder or incomplete phenotype compared with the individuals with two affected alleles. Usually these will be quite obvious but you might confuse with AD or XD. This is more likely to happen if there people dying from the disorder. The alive patients might be heterozygous while the dead might be homozygous. It might not be easy to distinguish, so take into account things like age and reason for death.

Non-Mendellian inheritance: genetic mutations can happen spontaneously. If they don’t affect the germ line, then they won’t necessarily be passed on. Look for very low numbers of affected individuals. The other time these come up is when multiple genes contribute to the phenotype. Usually I consider non-Mendellian when I have very few affected individuals and all other options are exhausted.

Step – 4 Confirm your prediction

Usually when I have a feel for what is going on, I break down the pedigree into family groups and confirm that my prediction holds true for each sub-family. The more your hypothesis stands up to testing, the more likely it is to be true.

When dealing with patients, it is important to then confirm the diagnosis through genetic testing or clinical evaluation. Although the prediction you make is likely to be correct, you should acknowledge that the options that are unlikely may still be possible. When dealing with large populations (the 7+ billion people on earth), low probability things happen very frequently!

Test your skills

Some MCQs (with answers) to test your skills.