Interpretation of genetic variants

Abstract

Sequencing of the human genome and introduction of clinical next-generation sequencing enable discovery of all DNA variants carried by an individual. Variants may be solely responsible for disease, may contribute to disease, or may have no influence on the development of disease. Interpreting the effect of these variants upon disease is a major challenge for medicine. Although the process is still evolving, certain methods are useful in discriminating the effect of variants upon phenotype. These methods have been employed to the greatest extent in Mendelian disorders where deleterious changes in one gene can cause disease. Here, we briefly review the relative merits of these methods, with emphasis on using a comprehensive approach modelled after the analysis of variants that causes cystic fibrosis.

Keywords: Genetic Variation; Genotype; Mutation Analysis; Phenotype; Population Genetics.

Figure 1

Framework for combining multiple lines evidence to characterise DNA variants. If data are available, segregation analysis should be performed to assess whether the inheritance of the variant is consistent with the transmission pattern of disease in families. Objective measures of the clinical phenotype of individuals that carry the variant (clinirnl criteria) and experimentally tested gene function (functional criteria) can be used to assign disease-rn using status to a variant. If a variant does not meet either clinical or functional criteria, penetrance analysis can be used to ascertain whether the variant is not disease-causing. *Variants caused by de novo mutation found only in affected individuals with dominant or X-linked conditions can be presumed to be disease-causing. ,.,.Variants that do not segregate with the disease can be ruled out as disease-causing, provided that confounding factors, such as incomplete penetrance have been ruled out.