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Missing Information Could Help Reclassify VUS Uncovered in Newborn Screening

NEW YORK (GenomeWeb) – Researchers from Emory University have found that certain types of missing information could help classify variants of uncertain significance as pathogenic or benign.

Not all variants uncovered through clinical exome and whole-genome sequencing can be definitely classified, so they wind up being reported by labs as variants of uncertain significance (VUS). But certain added information — such as biochemical testing results, parental testing results, or enzyme studies — could help clarify VUS, according to Emory's Patricia Hall and her colleagues.

Hall and her team examined how variants in genes linked to three monogenic metabolic disorders in newborns were categorized at their institute and what information was needed to reclassify those they had called VUS as either pathogenic or benign. As the researchers reported recently in Genetics in Medicine, that needed information fell three overarching categories: additional information from the referring clinician, further clinical testing, or research testing.

"VUS are being reported either because of incomplete communication between the laboratory and the ordering provider or because of missing test results, such as copy-number variant or parental testing," the researchers wrote in their paper. This, they added, suggests that certain steps such as incorporating copy-number analysis and confirmation of inheritance testing could help clarify some VUS and provide patients with more definitive diagnoses.

To examine how variants are currently classified, Hall and her colleagues focused on variants uncovered during clinical sequencing analysis of newborns for three common Mendelian metabolic disorders — classic galactosemia, phenylketonuria, and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency — at Emory between 2005 and 2015.

In that timeframe, the lab identified 46 unique VUS in GALT, the gene linked to classic galactosemia; 32 unique VUS in ACADM, the MCAD deficiency-linked gene; and 17 unique VUS in PAH, the phenylketonuria-linked gene.

Missing data, the researchers reported, impeded classification of some VUS. For example, they noted that for one individual in their sample who was homozygous for a VUS in GALT, the researchers lacked biochemical testing results, which are diagnostic for these diseases. This affected their ability to make a judgment regarding the variant.

Each VUS was then reviewed by experienced personnel to update its classification, if warranted. After review, the researchers reclassified nine of the VUS found in GALT. For example, the c.414G>T/p.T138T variant was reclassified as benign based on data from the Exome Aggregation Consortium study, while the c.820 + 13A>G variant was reclassified as pathogenic based on published cases and functional data. Similarly, the team reclassified seven ACADM VUS and one PAH VUS. There was no new information for most of the VUS that couldn't be reclassified, the researchers noted.

Hall and her colleagues also classified the types of information needed to further clarify the importance of certain VUS. Level-one information, which they said could be obtained fairly easily, includes testing and clinical information that's typically available before molecular testing is ordered, including why the patient has been referred for testing, biochemical testing results, pedigree, and familial testing results.

Level-two information includes clinically available testing like copy-number analysis of the proband and confirmation of inheritance by testing other family members, and would require additional effort and cost. They noted that while parental testing in the case of a newborn screening result "seems frustratingly easy" to do, there could be practical barriers like cost, death, and adoption to consider.

Lastly, level-three information is the most difficult to obtain as it includes research testing such as splicing, RNA, and enzyme studies and would require further cost, expertise, and resources, the researchers said.

Based on this, Hall and her colleagues argued that certain changes might improve the classification of current VUS. If clinicians and payors could be persuaded, the researchers said that adopting a panel approach to testing that includes copy-number analysis and confirmation of inheritance "may allow laboratories to obtain crucial information with a minimal amount of additional effort."

At the same time, they said that clinical laboratories should share their findings with research groups so that researchers could seek to show through functional studies whether or not certain variants are pathogenic.

"Combined efforts of all parties involved are necessary to provide the best and most conclusive results for all patients in a timely manner," the authors wrote.