How clinical information impacts successful genetic diagnostics
Juulia Simonen · Aug 28, 2018

Sometimes, a few sentences about the clinical history of the patient can make or break the case for the geneticist. Professor Helena Kääriäinen, MD, PhD, and Blueprint Genetics Clinical Interpretation Team Leader Eveliina Salminen, MD, PhD, explain why.

A pathogenic mutation or harmless variation? The clinical information provided can make the difference in the interpretation

Whole exome sequencing based diagnostics have significantly increased the amount of data that the molecular geneticists wade through.

“We slice our panel data from whole exome sequencing data. At exome level, you can see about 20,000-35,000 variations in any patient and most of them are unlikely to be related to the phenotype in question,” says Blueprint Genetics Clinical Interpretation Team Leader Eveliina Salminen.

The more thoroughly symptoms are presented to the diagnostic laboratory, the faster focus can be turned to the relevant genes.

“Many of us may instinctively think that a whole exome investigation will detect all genetic issues. In reality, in diagnostic testing, the focus is, and should be, on finding an explanation for the patient’s symptoms,” says professor Helena Kääriäinen, Clinical Geneticist, former president of European Society of Human Genetics (ESHG).

With the immense amount of data, clinical information provides direction for the clinical interpretation team.

“Information about the patient’s phenotype, family history, previous medical tests, gives us an idea what types of genes are most relevant for the patient. Good clinical information means faster and more reliable results with an increased chance to make a diagnosis,” Salminen continues.

Too little clinical information may result in more VUS being reported

The task for a molecular geneticist is to recognize the 1 or 2 harmful variant(s) out of 20,000-35,000 that explain the patient’s phenotype. The ease of the task depends on panel composition and the quality of the technology, but also on the availability of clinical information.

“We talk about finding the right needle in the haystack. What we know about the patient and family history affects how well we are able to do the variant evaluation and matching against clinical and family information,” Salminen says.

Also, too little clinical information might lead to larger number of VUS findings or unreported variants if there is no apparent phenotype match. Professor Helena Kääriäinen describes genetic diagnostics as a collaborative process between the lab and the clinician.

“The importance of the provision of clinical information is a discussed topic in the industry. In a paper from ACMG Jan 2018,1 clinicians were urged to provide a more detailed phenotypic and family history data to clinical laboratories. In practice, this does not have to mean more than a few sentences and it can make all the difference,” Kääriäinen explains. In addition, sometimes it could be useful to include the latest summary of patient’s medical records.

Going the extra mile to confirm the result

Sometimes, when specific phenotype is provided, a genetic diagnosis can be identified using a custom analysis beyond what is standard. When such a likely, complex disease-causing variant is identified, the cases land on Clinical Development, a specialized team that works on customized solutions. The need for customization may arise when a low-quality variant is detected at a difficult-to-sequence or duplicated region, when strange SNP clusters are observed or when other quality control steps such as coverage analysis detects any events deviating from normal.

“Relevant clinical data combined with a closer look at raw data can lead to a finding that could otherwise be missed. We can only provide this kind of in-depth analysis for cases where clinical information is sufficient, and the phenotype is highly suggestive of a specific gene defect,” Salminen says.

A quick and easy roadmap to providing sufficient clinical information about your patient

1) A clear description of the phenotype – list your patient’s signs and symptom and also include what is normal about your patient.  Be thorough.  Sometimes it is the most unusual feature that is key.

2) Does the phenotype appear syndromic or nonsyndromic in your patient?

3) Describe when and how your patient’s symptoms began

4) List what kind of testing has already been done and describe the results including those that have been normal

5) Describe the relevant family medical history

List provided by Helena Kääriäinen and Eveliina Salminen.   


  1. Bush L., Beck A., Biesecker, L. Professional Responsibilities Regarding the Provision, Publication and Dissemination of Patient Phenotypes in the Context of Clinical Genetic and Genomic Testing. Points to Consider. A statement of the American College of Medical Genetics and Genomics (ACMG). Published online 2018 Jan 11. doi: 10.1038/gim.2017.242.


Last modified: October 30, 2020