Boosting Genetic Diagnosis with Functional Evidence

Genetic diagnosis plays a key role in identifying the causes of inherited conditions. It allows for better treatment and support for those affected by genetic diseases. However, classifying the importance of genetic variations can be tricky. Many individuals who might have inherited conditions do not get a clear molecular diagnosis. This problem needs our attention, as more evidence needs to be included in the classification process to improve outcomes.

#The Guidelines for Classification

To help with this classification challenge, experts have created guidelines. The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have come up with rules that are being used all over the world. One of these rules says that researchers can use data from established functional studies to support their classification of genetic variants.

Additional recommendations from a group called ClinGen offer more guidance. They suggest that when looking at functional assay results, it’s essential to check if the Assays are suitable and to determine how strong the evidence is. If the evidence is strong enough, it can actually change how a genetic variant is classified.

#The Value of Functional Evidence

Functional evidence is crucial because it doesn’t depend on having information from individuals who are affected. In fact, it can be gathered before anyone even sees a variant in a clinical setting. This means it has the potential to help a lot of people.

ClinGen has specialized panels called Variant Curation Expert Panels (VCEPs) that develop specific guidelines based on genes. These VCEP guidelines have been shown to be more effective than the baseline guidelines. All the approved specifications are available for anyone to see. However, research has shown that there can be differences in how functional evidence is applied among these expert panels.

In Australia and New Zealand, a platform called Shariant lets laboratories share information about genetic variants. This platform found that functional evidence was only used in ten percent of the genetic variant classifications. Thankfully, new methods and tools are making it easier to obtain functional data, which can help in diagnosing diseases.

#The Study

To better understand how professionals in the field feel about evaluating functional evidence, an interesting study was conducted. This study looked at how well genomic diagnostic experts in Australasia understand and use functional evidence. They wanted to find out what kind of training and support these professionals need to improve their use of functional evidence.

A survey was created and shared among various genetics organizations. It aimed to gather information on demographics, experience with curating variants, education needs, and overall attitudes of the participants. The research was approved by a relevant ethics committee.

#Gathering Functional Evidence

In a review of VCEP guidelines as of July 2024, researchers looked closely at the types of functional assays mentioned. They collated specific assays and the recommendations for their use. The study found a large number of assays mentioned, covering thousands of variants. Most of these assays were not very high throughput, meaning they were more traditional in terms of data collection.

#Analyzing the Survey Results

The survey received responses from thirty-three genomic diagnostic professionals. This group included scientists and genetics clinicians, all of whom had experience with variant curation. On average, participants had twelve years of experience in this field.

However, when it came to confidence in interpreting functional assays, results varied widely. For instance, half of the participants felt comfortable with animal models, but fewer felt the same about other types of assays. Many participants were unaware of the existing recommendations and resources available to them.

When asked about barriers to using functional evidence, respondents identified a lack of familiarity with specific assays and difficulty finding functional data. In contrast, they identified education and additional guidelines as potential ways to improve their ability to use functional evidence. Most participants expressed a desire for further training and suggested expert guidance materials as a helpful resource.

#What Participants Think

The survey aimed to gather feedback on barriers, enablers, and preferred training resources. Participants were quite vocal about what they believed might prevent them from using functional evidence effectively. Most agreed that lack of familiarity with certain assays was a key barrier, while many also wanted more education and clearer methods to improve their use of functional evidence.

#Findings from the VCEP Specifications

The review of the VCEP specifications showed that many guidelines highlighted the need for specific assays. Of the 34 specified, nineteen mentioned specific publications covering thirty-three genes, leading to a total of 226 assays being cited. It's quite an assortment, but it highlights the need for shared knowledge among practitioners.

#The Importance of Increasing Functional Evidence Use

Improving how functional evidence is included in genetic diagnosis is vital for making the most of genetic testing. The survey results suggest that many professionals lack the confidence to evaluate functional data. They expressed clear preferences for expert guidance and tools that could aid in their practice.

Many professionals either didn’t use the existing recommendations or were simply unaware of them. This reveals a significant gap that needs to be addressed. The desire for expert guidance and better tools indicates that more effective communication and sharing of resources is critical.

#Conclusion

The survey findings underscore the need for making functional evidence more accessible and enhancing awareness among all levels of expertise in the field. Most participants indicated that expert guidance documents would be beneficial.

Given that participants showed less comfort with high throughput assays, it’s essential to promote cooperation among international experts. Sharing not only functional data but also resources and training will go a long way in improving clinical practice.

Overall, this study highlights the importance of guidance, tools, and education for professionals in the genetics field to maximize the use of functional evidence. After all, the more we know, the better we can help those in need. And that kind of knowledge can lead to some pretty hopeful results—kind of like finding the missing sock in a laundry load that has left you puzzled!