September is Newborn Screening Awareness Month. Newborn screening (NBS) is a public health program offered to all infants born in the United States and many countries internationally. The aim of this program is to identify babies potentially at risk for genetic disorders, where early diagnosis, monitoring, and treatment could greatly improve the prognosis of the child.
When a baby receives a positive NBS result, confirmatory biochemical or molecular testing is needed to determine next steps. Invitae offers molecular testing, which is performed by next-generation sequencing (NGS). NGS is a powerful method that has enabled laboratories to sequence more genes rapidly and obtain more detailed sequencing information. However, a patient can receive an uncertain result, also known as a variant of uncertain significance (VUS), in cases when there is not enough information to support a more definitive classification of the sequence change.
Recently, Invitae conducted a study1—presented at the 2018 ACMG Annual Meeting—in which we reviewed cases that were referred for a positive NBS result. We focused on the cases that were classified as VUS but had the potential to be reinterpreted as a positive molecular diagnosis with additional information, such as biochemical results, clinical information on the patient, or parental testing. Our aim was to demonstrate how the laboratory and clinician working together can contribute to increasing the number of positive diagnoses.
Our study included 464 patients, the majority of whom were under 1 year of age. Relevant genes were sequenced by NGS depending on the patient’s NBS result. Twenty-seven percent received a positive diagnosis, 17% were determined to be carriers of a genetic condition, 27% had uncertain results, and 29% had negative results.
Of the uncertain cases, 34% had VUS with the potential to reclassify, leading to a positive diagnosis, which would increase the number of cases with positive diagnoses to 32%. More evidence in the form of additional labs and/or clinical information, phasing/segregation by testing parents, and development of specific evidence criteria within the lab for individual genes* can help to confirm a significant number of additional positive molecular diagnoses. With minor effort from the ordering clinician, the data can make a substantial difference in variant interpretation and a potential positive diagnosis for the patient. Although an increase of 7% (25 cases) may seem small, the impact of making additional diagnoses of rare and potentially treatable disorders is significant.
Aiming at enhancing NBS confirmation, we recommend these additional steps for the clinician and laboratory as collaborators:
1. The clinician can submit comprehensive clinical information (clinic notes, pedigree, medical records, biochemical lab results) at the time of the initial test order.
2. The clinician’s team can discuss the expectation for possible parental testing with the family during the at-risk individual’s genetic counseling sessions, both before and after the proband’s testing. We recognize this can be overwhelming for a family facing a positive NBS result, but it will introduce the option and expectation to the parents.
3. The diagnostic laboratory can develop additional evidence criteria for more genetic conditions.
4. The diagnostic laboratory can provide outreach and education to the clinical community about the process of variant interpretation and classification and types of evidence used.