Genomic variants traced forward to genetic disorders: A new approach?

Genomic variants traced forward to genetic disorders: A new approach?

Last Updated on January 12, 2023 by Joseph Gut – thasso

January 08, 2023 – In precision and/or targeted medicine of today, physicians typically start out with the determination of the patients phenotypic expression of a disease (i.e., establish a clinical finding) and then go on into finding out the patients genetic background (i.e., genetic variations therein) which may be responsible (at the base) of the identified patient/disease phenotype. This would be the current “phenotype to genotype” pathway of research. It is, however, imaginable to inverse this pathway and come up with a “genotype to phenotype” pathway instead. Thus, in such an approach, one would successfully trace genomic variants forward to genetic-based disorders in patients. This concept would possibly change reactive medicine to proactive/preventive medicine.

In fact, along these lines, researchers at the US National Institutes of Health (NIH)  have just published an assessment of 13 studies that took a so-called  “genotype-first” approach to patient care, which in itself would constitute a revolution in everyday’s medicine. In these studies, patients with specific genomic variants were selected and then studied for their traits and symptoms. The findings uncovered new relationships between patients genes and clinical conditions, broadened the traits and symptoms associated with known disorders, and offered insights into newly described disorders.

The present study in the American Journal of Human Genetics demonstrated that “genotype-first” research is useful, especially for identifying people with rare disorders who otherwise might not have been brought to clinical attention, according to Dr. Wilczewski of the National Human Genome Research Institute’s (NHGRI) Reverse Phenotyping Core and first author. The published study documents three types of discoveries from a “genotype-first” approach. First, the researchers this approach helped to discover new relationships between genomic variants and specific clinical traits. For example, having more than two copies of the TPSAB1 gene was associated with symptoms related to the gastrointestinal tract, connective tissues, and the nervous system. Second, this approach helped researchers find novel symptoms related to a disorder that clinicians previously missed because the patient did not have the typical symptoms. NHGRI researchers identified a person with a genomic variant associated with a known metabolic disorder. Further testing found that the individual had high levels of certain chemicals in their body associated with the disorder, despite having only minor symptoms. Third, this approach allowed researchers to determine the function of specific genomic variants, which has the potential to help clinicians understand newly described disorders. For example, in one study, NHGRI researchers and their collaborators found that a genomic variant was associated with immune dysfunction at the molecular level in blood cells.

These results indicate that in a “genotype-first” concept, it might be possible to exploit and get to know the full spectrum of symptoms and diseases (overt and rare)  for which genomic variants may be responsible. Given the fact that genes (or their allelic variants) and their coded for proteins are typically involved in unlimited numbers of biological pathways, a wide spectrum 0f resulting symptoms or clinical phenotypes even originating from a single genetic variation should not be too surprising and should even be expected.


In order to become an accepted standard in applied predictive medicine, the study also illustrates the limitations that would have to be overcome, however. Thus, the 13 studies that implemented a genotype-first approach used genomic data from NHGRI’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 (NIAID) Centralized Sequencing Protocol, which together allowed analyses to be performed on more than 16,000 research participants who have undergone genome or exome sequencing. All these patients / study participants consented to broad genomic data sharing and being recontacted for future research. In order to make “genotype-first” an truly accepted and productive means of predictive medicine (meaning for patients and physicians alike), there would have to be some conditions fulfilled.

First, data frameworks and core centres would have to be opened up to the medical and patient communities and provide broad genomic and phenotypic data sharing with the ability to recontact participants explicitly stated during the informed consent process. These centers and their processes would have to be validated, approved, and under control of national health authorities.

Second,  the personal consenting processes and sharing of personal genomic and phenotypic data would equally have to be under approval by health authorities. This in combination with extremely strict implementation of privacy controls. The recontacting and backtracking of individuals/patients would be a most sensitive issue in this context and need very strict regulation.

Third, more and more individuals/patients obtain DNA-sequencing or whole genome (direct-to consumer-genetic-testing) analysis data for a variety of reasons. These individual data may contain invaluable information of potentially disease initiating genetic variants the particular individual is a carrier of, but can not recognize it predictively, because there are not yet any phenotypic symptoms. Data frameworks and core centres will have to be capable to integrate such individual patients genetic data into their frameworks (again under highest privacy standards) in order to find in largest scale comparative analysis hidden or rare genetic risk alleles, which may or may not affect the carrier actually or in the future in overt  or rare disease (i.e., produce a clinical phenotype).

Lastly, 0n a legal and health/or life insurance level, regulations have to be developed, in order to handle prospective genome-based risks in health and/or disease, which may be recognised on a large population basis but which may or may never materialise on a single individual’s basis. Being a carrier does not make you guilty or an actual disease victim.


So, in conclusion, the new approach of tracing genomic variants forward to genetic disorders (i.e., genotype-first approach) has certainly great potential. At the moment perhaps more in the clinical research area then in practical and applied medicine and patients care. To become the true standard in genotype-first predictive/preventive medicine applied everyday and serving clinicians, treating physicians and “to be patients” alike, some big efforts are still needed.  It may easy be that a genetic variant is innocent until proven guilty.

See here the original article and also a short sequence out of the real world on genotype-first associated possible pitfalls:

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Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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