Genotype-first approach

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 have 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.

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.

Initially the idea of identifying the genotype of individuals and subsequently their associated phenotype(s) was first used in early cytogenetic studies. Around 1960 the discovery of Trisomy 21 led to the realization that genetics could be used to predict phenotype(s). From the 1960s to 1990s cytogenetic techniques such as chromosome banding and fluorescence in situ hybridization (FISH) were used to identify and phenotypically characterize patients with chromosomal abnormalities.

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