Challenges in variant interpretation for pedigrees

A childhood onset, highly penetrant severe disease probably offers an oversimplified setting for variant interpretation. This is particularly true if the variant effect size is large. However, we are often challenged with complicated situations in real life.

A genetic variant can result in a range of phenotypic expressions (variable expression). Conditions like tuberous sclerosis show different degrees of severity of the disease in the affected members of a pedigree. A mildly affected individual, whose phenotype escapes clinical recognition might be incorrectly labelled ‘healthy’ or unaffected. Such variable expression of the condition is common in autosomal dominant pedigrees, but recessive conditions are less variable. These differences are attributed to the different genetic backgrounds of the individuals and to variable external environmental influences.

In addition, not all individuals with a disease-causing variant demonstrate a phenotype. In other words, the chance of developing the disease may not be 100% (reduced penetrance) in individuals with the disease-causing variant. Each dominant condition has a different degree of penetrance. Prior knowledge about the disease and the penetrance of the variant is essential to understand why not all individuals who have the variant are affected by the disease.

Age is also an important consideration for variant interpretation, and having a good understanding of the usual age of onset for the condition or disease is needed when interpreting family histories. For example, a young individual may be considered unaffected, but they have not yet reached the age where you would expect to see the disease present. Many autosomal dominant conditions show age-dependent penetrance including hereditary breast and ovarian cancer and Huntington’s disease.

Another example is while childhood lethal conditions often occur due to sporadic (de novo) variants, gonadal mosaicism can mislead the interpretation of inheritance patterns. Likewise, Skewed X-inactivation, male lethality in X-linked pedigrees and consanguineous relationships can interfere with the interpretation of inheritance of X-linked conditions.

Furthermore, clinical and laboratory information, when collected after a careful evaluation is likely to aid variant interpretation by providing better information on the penetrance and expression.