No Findings Related to Patient Symptoms: “Negative” Genomic Test Reports

Key Points:

  • A negative (normal) result reduces but does not eliminate the possibility that there is a genetic cause for the patient’s condition.
  • Whole genome sequencing may identify genetic causes missed by whole exome sequencing.
  • With time, more variants will be recognized as disease causing and reanalysis of whole exome or whole genome data may be helpful in the  future.

With whole exome or whole genome sequencing, when a genetic cause is not identified that is believed to account for the patient’s symptoms (phenotype), the result is described as “normal” or “negative” or “none detected” for mutations in disease genes related to phenotype. In other words, there is no answer and there is no identifiable genetic cause for the patient. A normal result reduces but does not eliminate the possibility that there is a genetic cause for the patient’s condition. Rather, it indicates that a genetic cause could not be identified.

The limitations of the test should be reviewed with the patient. There are important reasons why a genetic cause may not be identified by whole exome or whole genome sequencing. Whole exome sequencing only captures and sequences 1-2% of the genome, and the disease causing variants could be in non-coding DNA regions that are not targeted for capture or in coding regions that are not well captured by the test.

On average, more than 95% of most genes are captured with current technology, but coverage varies by the lab, capture kit, and by gene. The disease causing variant may have been captured and sequenced, but it may be part of a gene that is not yet associated with disease. The disease causing variant may have been sequenced and may be present in a known disease causing gene but may be a novel variant that was not understood to be disease causing. While laboratories can sequence whole exomes and genomes, there are limitations in the technology and the interpretation of the data that may allow for a disease-causing genetic change to be missed. Additional limitations include certain kinds of genetic changes that are not easily detected through sequence based methods, including repeat expansions and structural chromosome rearrangements. It is important to make sure any genes of particular interest were adequately interrogated by the chosen test. A negative genomic test does not rule out a genetic cause for disease.

Sequencing a trio, meaning a patient and both of his or her biological parents, can increase the diagnostic yield as it allows the laboratory to identify variants that are de novo (not inherited). If only the affected individual was sequenced, such variants are less likely to be interpreted correctly and less likely to be reported.

Sequencing an individual as well as both biological parents can increase diagnosticyield as it allows for the identification of de novo (not inherited) variation.

Sequencing an individual as well as both biological parents can increase diagnosticyield as it allows for the identification of de novo (not inherited) variation.

Next Steps to Consider

  • Referral to genetic services (medical geneticist and/or genetic counselor) for medical evaluation and/or additional testing that may supplement the genomic test
  • Consider other types of diagnostic testing for the patient as the cause of symptoms or reason for testing has not yet been explained
  • Consider periodic reanalysis of genomic test data as knowledge and databases used in analysis improves over time

 

Resources

  • National Society of Genetic Counselors (http://nsgc.org/): the professional organization for genetic counselors, with patient and provider resources and a searchable tool to “find a genetic counselor” near you.