Credit: Julia Fekecs, National Human Genome Research Institute

U.S. research has provided new insights into how genetic variants cause disease by turning conventional research methods upside down.

Genomic studies have traditionally involved identifying individuals affected by an inherited disease and then working backwards towards a genetic explanation for the findings.

Now, researchers have shown greater discoveries are possible by grouping individuals according to specific genetic variants and then working from here to determine how these manifest as disease.

The “genotype-first” approach revealed new relationships between genetic variants and specific clinical traits, the team reports in the American Journal of Human Genetics.

The novel approach also highlighted unusual symptoms for a disorder that had previously been missed by clinicians due to their atypical nature.

It further helped identify the function of specific genomic variants, which could aid in the understanding of newly described disorders.

“We demonstrated that genotype-first research can work, especially for identifying people with rare disorders who otherwise might not have been brought to clinical attention,” said first author Caralynn Wilczewski, PhD, a genetic counselor at the National Human Genome Research Institute’s (NHGRI) Reverse Phenotyping Core.

Senior author Leslie Biesecker, director of NHGRI’s Center for Precision Health Research, added: “Genomics has the potential to change reactive medicine into preventative medicine.

“Studying how taking a genotype-first approach to research can help us learn how to model predictive and precision medicine in the future.”

The researchers assessed 13 studies completed at the U.S National Institutes of Health that deployed their genotype-first approach by identifying patients with specific genomic variants and then studying their traits and symptoms.

These facilitated novel genotype-disease associations, expanded the phenotypic spectra, and demonstrated hitherto unknown functional mechanisms of disease.

The team highlighted several studies in which the reverse phenotyping approach was crucial to the conclusions reached.

One showed that having duplications in the TPSAB1 gene was associated with symptoms relating to the gastrointestinal tract, connective tissues, and the nervous system. Individuals with duplications had elevated serum tryptase levels compared with others and were significantly more likely to display symptoms associated with the hereditary condition alpha-tryptasemia.

Another study revealed novel symptoms relating to the serious and typically severe metabolic disorder of combined malonic and methylmalonic aciduria.

This is associated with an elevated ratio of methylmalonic acid (MMA) to malonic acid (MA) in urine and has traditionally been linked with clinical symptoms such as metabolic acidosis, failure to thrive, seizures, and immunodeficiency.

A 66-year-old woman homozygous for a pathogenic genetic variant had an unremarkable medical history and would likely have gone unnoticed.

However further investigations triggered by her genetics revealed she had one of the highest MMA:MA ratios in the study group, atypical incontinence and medical problems and multiple abnormalities on magnetic resonance imaging.

A third study identified a genomic variant associated with immune dysfunction at a molecular level in peripheral blood mononuclear cells, the researchers report.

“Using genomic ascertainment research to understand the implications of genomic variants in phenotypically unselected populations will be critical as we prepare to implement genomic screening for an increasing number of health conditions,” they predict.

“In this regard, targeted reverse phenotyping is an essential tool to increase our ability to predict phenotype from genotype, understand the molecular taxonomy of disease, and eventually provide precision medicine.”

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