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Investigators Propose New Tool for Establishing Gene-Disease Relationships in Rare Diseases


Advances in whole genome sequencing are helpful in linking genetic variants with diseases, but the process is more challenging in cases of rare and ultra-rare diseases.

Genetic factors are known to play a role in the pathogenesis of many diseases, but it is not always known just how much, especially regarding rare diseases for which little genetic investigation has been conducted.

In a new paper in Human Mutation: Variations, Informatics, and Disease, investigators offer a checklist to help determine the strength of potential gene-disease relationships (GDRs) in cases where very little genetic information is available.

They explain that when attempting to determine whether a DNA variant is causally associated with a condition, 2 factors must be considered. The first is to determine whether the genetic mutations are actually associated with well-described phenotypic features, something that can be difficult in rare or heterogeneous conditions. The second consideration is to determine whether the variant is pathogenic.

“The second part of this decision process is thoroughly covered by the DNA variant interpretation criteria designed by the American College of Medical Genetics and Genomics, which provide an excellent framework for DNA variant interpretation in clinical practice and are widely used,” the investigators wrote.

When it comes to the first consideration—determining whether GDRs exist in the first place—the investigators have successfully evaluated a number of GDRs. The ClinGen GDR Framework is an important resource in this effort, they noted. However, the framework’s efficacy is limited in cases of rare or ultra-rare diseases.

“Identifying a DNA variant in a single patient, or even a few patients, in a gene in which germline DNA variants are very rare does not prove that a variant in a ‘new’ gene is truly causally related rather than just coincidentally identified in a patient with a particular disorder or clinical features,” the authors said.

Clinicians and clinical scientists do have better tools, however, including the broader availability of whole genome/exome sequencing. Yet, this has also led to something of an inversion of the process of GDR establishment. Whereas clinicians might previously have begun by grouping patients based on phenotypic features and then performing sequencing, it is now possible to begin the process of establishing GDRs after genotyping has taken place—but that can be problematic, the authors said.

“Assessing a phenotype with knowledge of the genotype may easily lead to logical fallacies,” they wrote. “In mathematical terms, the phenotypic features assessed are not independently ascertained from the genotype and can therefore not be multiplied to achieve statistical significance.”

Thus, the authors said, it is important to have a cautious approach that recognizes the complexity and limits of the tools and data. To aid in the process, they propose a checklist for establishing GDRs in rare diseases and provide clinical examples to show how the checklist could be used to evaluate potential GDRs.

They said the checklist is not meant to supplant the ClinGen framework, but rather to offer structure when insufficient genetic data are available.

“This checklist is to provide clinicians and clinical scientists with a quick estimate for a DNA variant’s pathogenicity for a gene where very few putatively pathogenic variants have been reported,” they wrote.

When sufficient data are available, the authors said, they “strongly advise” using the ClinGen framework to formally establish GDRs, “and we expect that this will become more and more feasible as ever-larger sequencing studies are being rolled out worldwide.”


Santen GWE, Leitch HG, Cobben J. Gene-disease relationship evidence: a clinical perspective focusing on ultra-rare diseases. Hum Mutat. Published online March 9, 2022. doi:10.1002/humu.24367

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