New approach puts genotype first

By Elissa Wolfson, The Science Advisory Board assistant editor

January 6, 2023 -- NIH researchers have published an assessment of 13 studies that took a genotype-first approach to patient care, in contrast to the more typical phenotype-first approach, which begins with clinical findings. The study, published January 5 in the journal American Journal of Human Genetics, demonstrated that a genotype-first approach can help identify people with uncommon disorders who might otherwise escape clinical attention.

Typically, in treating genetic conditions, researchers identify patients experiencing symptoms, then look for variants in the patients' genomes that might explain those findings -- a phenotype-first approach. However, as clinical findings are based on researchers' understanding of the disorder, inaccuracies may result.

By contrast, a genotype-first approach -- or reverse phenotyping -- involves selecting patients with specific genomic variants, then studying their traits and symptoms. This can uncover new relationships between genes and clinical conditions, broaden the symptoms associated with known disorders, and offer insights into newly described disorders.

The study documented these three types of discoveries. First, the genotype-first approach revealed new relationships between genomic variants and specific clinical traits. One study, for example, found that having more than two copies of the TPSAB1 gene was associated with gastrointestinal tract, connective tissue, and nervous system-related symptoms.

Second, this approach helped find novel symptoms related to a disorder that were initially missed because the patient lacked typical symptoms. One person had a genomic variant associated with a known metabolic disorder; further testing revealed high levels of chemicals associated with the disorder, despite only minor symptoms.

Finally, this approach allowed researchers to determine the function of specific genomic variants, furthering their understanding of new disorders. For example, one study found a genomic variant associated with molecular level immune dysfunction in blood cells.

The 13 studies that implemented the genotype-first approach utilized genomic data from the National Human Genome Research Institute's Reverse Phenotyping Core in the Center for Precision Health Research. The core aggregates genomic data from programs such as ClinSeq(R) and the National Institute of Allergy and Infectious Disease's Centralized Sequencing Protocol, which together allowed analyses to be performed on more than 16,000 participants who underwent genome or exome sequencing.

Data from participants who consented to genomic data sharing and recontact for future research are currently available to NIH researchers through the Reverse Phenotyping Core Genomic Data Browser. The study provides a framework for other institutions to build genotype-first research programs.

As this approach becomes more widely adopted, the researchers seek to identify more people who may be helped by genome sequence availability, especially as more diverse populations join genome-sequencing studies. They hope to see the predictive potential of genomic medicine better realized.

"Taking a genotype-first approach to research can help us learn how to model predictive and precision medicine in the future," noted NIH investigator and senior author Dr. Leslie Biesecker in a statement. "Genomics has the potential to change reactive medicine into preventative medicine."

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