NIH Study Highlights Success of Genotype-First Approach in Unveiling Links to Genetic Disorders

Researchers from the National Institutes of Health (NIH) have successfully examined 13 studies that applied a genotype-first approach to patient care, revealing novel relationships between genes and diseases. The new approach deviates from the traditional phenotype-first methodology in medical research that typically starts with clinical findings.

In the genotype-first approach, patients with particular genomic variants are chosen, and their traits and symptoms are then studied. The results of this novel methodology have broadened the understanding of symptoms linked to known disorders, uncovered new associations between genes and diseases, and given insights into newly identified disorders. The findings have been published in the American Journal of Human Genetics.

The lead author of the study, Dr. Caralynn Wilczewski, a genetic counselor at the National Human Genome Research Institute’s (NHGRI) Reverse Phenotyping Core, explains that this research demonstrates that the genotype-first method is particularly useful in identifying individuals with rare disorders who otherwise may have been overlooked in clinical settings.

Typically, when dealing with genetic conditions, patients exhibiting symptoms are first identified, and their genomes are then studied to determine potential explanatory variants. This traditional approach can introduce bias as it relies heavily on the researchers’ preconceived understanding of the disorders. Moreover, it can restrict researchers from comprehending the full spectrum of symptoms and the associated genomic variants.

The genotype-first approach holds potential for transforming reactive medicine into a preventative form of care, says Leslie Biesecker, M.D., a distinguished NIH investigator and director of NHGRI’s Center for Precision Health Research. This methodology could be a stepping stone towards predictive and precision medicine.

The study classified three primary discoveries from the genotype-first approach. Firstly, it assisted in establishing new relationships between genomic variants and specific clinical traits. For instance, one NIH study discovered that more than two copies of the TPSAB1 gene were linked with symptoms related to the gastrointestinal tract, connective tissues, and the nervous system.

Secondly, the approach helped uncover novel symptoms of a disorder that had previously gone undetected due to the patient not displaying typical symptoms. This was exemplified when NHGRI researchers identified an individual with a genomic variant linked to a known metabolic disorder. Further investigation revealed that this person had high levels of certain chemicals, despite exhibiting only minor symptoms.

Finally, the genotype-first approach allowed for a better understanding of the function of specific genomic variants, potentially assisting clinicians in understanding newly described disorders.

The 13 studies employed genomic data from over 16,000 research participants, collected through programs like ClinSeq(R) and the National Institute of Allergy and Infectious Disease (NIAID) Centralized Sequencing Protocol.

NIH intramural researchers now have access to the exome and genome sequencing data from participants who consented to broad genomic data sharing and future research contact through the Reverse Phenotyping Core Genomic Data Browser.

The researchers propose a framework for other institutions looking to conduct genotype-first studies. The framework emphasizes broad genomic data sharing, informed consent with recontact provisions, strategic planning for deciding on genomic findings to be returned, and communication with study participants.

Dr. Clesson Turner, director of NHGRI’s Reverse Phenotyping Core, commented on the framework: “With more programs adopting this approach, we can improve our understanding of the predictive potential of genomic medicine.”

Dr. Wilczewski adds that the adoption of this approach by more researchers could potentially help more individuals who may benefit from having their genome sequenced, especially as genome-sequencing studies diversify in terms of participant population.

Funding for this research was provided by the NIH and the National Human Genome Research Institute.

Reference: “Genotype first: Clinical genomics research through a reverse phenotyping approach” by Caralynn M. Wilczewski, et al. American Journal of Human Genetics, 5 January 2023, DOI: 10.1016/j.ajhg.2022.12.004.

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More about Genotype-first approach

• National Institutes of Health
• National Human Genome Research Institute
• American Journal of Human Genetics
• The Genotype-first approach study
• NHGRI’s Center for Precision Health Research
• ClinSeq
• National Institute of Allergy and Infectious Disease (NIAID)