The genotype-first approach is a type of strategy used in genetic epidemiological studies to associate specific genotypes to apparent clinical phenotypes of a complex disease or trait. As opposed to “phenotype-first”, the traditional strategy that has been guiding genome-wide association studies (GWAS) so far, this approach characterizes individuals first by a statistically common genotype based on molecular tests prior to clinical phenotypic classification. This method of grouping leads to patient evaluations based on a shared genetic etiology for the observed phenotypes, regardless of their suspected diagnosis. Thus, this approach can prevent initial phenotypic bias and allow for identification of genes that pose a significant contribution to the disease etiology.[1][2]
This approach is unaffected by phenotypic heterogeneity, incomplete penetrance and levels of expressivity. Therefore, it is useful in complex diseases that also overlap, such as autism spectrum disorder and intellectual disability, enabling the diseases to be distinguished, and specific subtypes of the disease based on the genomic content to be determined.
Currently, the genotype-first approach is used primarily for research objectives. However, the implications from these studies can have valuable clinical applications, including improved diagnosis, counselling, and support groups for individuals with the same genetic etiology.[1]
- ^ a b Stessman, H. A., Bernier, R. & Eichler, E. E. A genotype-first approach to defining the subtypes of a complex disease. Cell 156, 872–877 (2014).
- ^ Mefford, H. C. Genotype to phenotype-discovery and characterization of novel genomic disorders in a “genotype-first” era. Genet. Med. 11, 836–842 (2009).