New approach successfully tracks genetic variants back to genetic disorders

New release

Thursday, January 5, 2023

The NIH study shows that the first genotype approach reveals new links to genetic conditions.

NIH researchers have published an evaluation of 13 studies that took a genotype-first approach to patient care. This approach contrasts with the phenotype-first approach to clinical research, which begins with clinical findings. The genotype approach to patient care involves first selecting patients with specific genetic variants and then studying their traits and symptoms; This finding revealed new relationships between genes and clinical conditions, expanded the features and symptoms associated with known disorders, and provided insights into newly described disorders. the study Posted in American Journal of Human Genome.

“We’ve shown that first-line genotype research can work, especially in identifying people with rare disorders who might otherwise not have been brought to clinical attention,” says Karalyn Wilczewski, PhD, a genetic counselor at the National Human Genome Research Institute. NHGRI) heart reversed phenotype and first author of the paper.

Typically, to treat genetic conditions, researchers first identify patients with symptoms, and then look for variants in the patients’ genomes that might explain these findings. However, this can lead to bias because researchers study clinical outcomes based on their understanding of the disorder. The phenotypic approach first limits researchers’ understanding of the full range of symptoms of disorders and associated genetic variants.

“Genomics has the potential to change reactive medicine into preventive medicine,” said Leslie Bisker, MD, NIH distinguished investigator, director of the NHGRI Center for Precision Health Research and lead author of the article. “Examining how a genotype-first approach to research can help us learn how to model predictive and accurate medicine in the future.”

The study documents three types of findings from the genotype-first approach.

First, the researchers found that this approach helped discover new relationships between genetic variants and specific clinical features. For example, one of the National Institutes of Health study Found that there are more than two copies of TPSAB1 The gene has been associated with symptoms related to the gastrointestinal tract, connective tissue, and nervous system.

Second, this approach helped the researchers find new symptoms related to a disorder that doctors had previously missed because the patient was not having the typical symptoms. NHGRI The researchers identified a person with a genetic variant associated with a known metabolic disorder. Additional testing found that the individual had high levels of certain body chemicals associated with the disorder, despite only having mild symptoms.

Third, this approach allowed the researchers to determine the function of specific genetic variants, which have the potential to help clinicians understand newly described disorders. For example, in one study, NHGRI researchers and collaborators have found That the genetic variant was associated with impaired immunity at the molecular level in blood cells.

The 13 studies that implemented the genotype approach first used genetic data from the NHGRI Invert the reverse phenotype At the Precision Health Research Center. The center collects genomic data from programs such as ClinSeq(s) and the National Institute of Allergy and Infectious Diseases (NIAID) Central Sequencing protocol, which together allowed analyzes to be performed on more than 16,000 research participants who underwent genome or exome sequencing.

Exome and genome sequencing data from participants who agreed to share genomic-wide data and reconnect for future research studies are currently available to researchers within the National Institutes of Health through Core genomic data browser for phenotyping To identify genetic variants of interest for their own research.

“Importantly, we provide a framework for other institutions to build research programs that allow genotype studies first. With more programs that adopt this approach, we can study the predictive potential of genomic medicine,” said Claesson Turner, director of NHGRI’s Reverse Phenotyping Center and lead author of the article. Better.

The framework includes broad sharing of genomic data with the ability to re-contact explicitly named participants during the informed consent process. The NHRI researchers recommend that institutions aiming to establish genotype centers first develop strategic plans, especially for determining which genetic results will be returned, which may include genetic counseling services. Most importantly, according to the study, researchers should actively communicate with study participants to build mindful, trusting, long-term relationships.

“In the future, as more researchers adopt this approach, we hope to identify more people who can be helped by the availability of their genome sequences, especially as more diverse populations join genome sequencing studies,” says Dr. Wilczewski.

National Human Genome Research Institute (NHGRI) It is one of 27 institutes and centers within the National Institutes of Health, an agency of the Department of Health and Human Services. NHGRI’s Department of Internal Research develops and implements technology to understand, diagnose, and treat genetic and hereditary diseases. Additional information about NHGRI can be found at:

About the National Institutes of Health (NIH):NIH, the nation’s medical research agency, includes 27 institutes and centers and is part of the US Department of Health and Human Services. The National Institutes of Health is the primary federal agency that conducts and supports basic, clinical, and multidisciplinary medical research, investigating the causes, treatments, and cures for both common and rare diseases. For more information about the National Institutes of Health and its programs, visit

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