NextStepDx PLUS is a whole exome sequencing (WES) test, one of the most comprehensive genetic tests available to identify disease-causing variants and end the diagnostic odyssey. With WES, all protein-coding regions of the human genome (known as the exome) are sequenced and analyzed. NextStepDx PLUS also includes copy number variant analysis for all samples that started the analysis process starting December 6, 2023. Although the exome only makes up 1–2% of the genome, approximately 85% of all known disease-causing variants are found there.
WES is appropriate for someone:
WES is available as a trio or duo, meaning that family members can submit samples along with the patient for segregation analysis.
Bionano Laboratories offers clinical support to patients and providers through access to our genetic counselors who can discuss testing capabilities, strategy, informed consent, and results.
Providers can call our genetic counselors at
As required, genomic DNA is extracted from patient specimens. Patient DNA corresponding to these regions is captured using hybridization probes. Captured DNA is sequenced on the NovaSeq 6000 using 2×150 bp paired-end reads (Illumina, San Diego, CA, USA). The following quality control metrics are generally achieved: >97% of target bases are covered at >20x and mean coverage of target bases >100x.
Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. CNVs that pass our interval quality metrics are not confirmed using another technology.
The exome refers to the portion of our genome which codes for specific proteins. The exome comprises only about 1–2% of the entire genome. However, approximately 85% of known genetic diseases are found within the exome.
This test can be performed for a single individual or samples can be submitted for one or two relatives (preferably biological parents). When both parental samples are available to analyze alongside the primary individual, we call this “trio testing.” Trio testing has several advantages, including a slightly increased diagnostic rate for the patient and automatic inheritance information to assist with clinical interpretation and the family’s recurrence risk estimations. Importantly, only the patient receives a report as the primary purpose of the parental samples is to assist in the interpretation of their child’s results.
Secondary findings are genetic variants with an associated risk for specific genetic conditions. Notably, these conditions do not typically cause disorders of childhood development. Instead, they may present in adulthood with increased risk for cancers, serious heart problems, or other significant health issues. Importantly, the genetic conditions associated with secondary findings are considered highly medically actionable. This means early intervention, like screening for tumors or heart problems, is likely to reduce or prevent serious morbidity or early mortality. Knowing about genetic variants in these genes can give individuals the opportunity to closely monitor their health and take precautions.
As part of our NextStepDx PLUS service, families can speak with a genetic counselor to discuss the implications of secondary findings in detail. Families may then choose to pursue evaluation and interpretation of the secondary gene list. If families do not opt-out of this assessment, we will automatically analyze any genetic variants identified in the secondary gene list. The secondary gene list follows the guidance set forth by The American College of Medical Genetics and Genomics (ACMG), which can be viewed here.
There are many different types of genetic tests, and NextStepDx PLUS is just one. Each genetic test is able to look at the genome in its own way, and no single genetic test can diagnose any/all currently known genetic conditions. For this reason, a non-diagnostic NextStepDx PLUS test alone is not sufficient to eliminate a genetic condition as the cause of a patient’s symptoms.
Other types of tests, such as chromosomal microarray analysis or targeted panels, may also be considered. Additionally, an evaluation or consultation by a medical geneticist (physician who specializes in genetic conditions) or genetic counselor could be useful to help determine a follow-up testing strategy.
The underlying genetic cause for an individual’s clinical features can be due to many different types of genetic variants. While FirstStepDx PLUS can identify chromosomal deletions (missing genetic material) and duplications (extra genetic material), NextStepDx PLUS looks for single nucleotide variants that are much smaller and can’t be detected by FirstStepDx PLUS.
If we consider our genetic material to be like an instructional manual, FirstStepDx PLUS looks for missing or duplicated chapters or pages while NextStepDx PLUS looks for misspellings within a single word. Neither test can do the other’s job. Instead, they complement each other. If FirstStepDx PLUS does not find an underlying genetic cause for your patient’s clinical features, performing NextStepDx PLUS is a way to look at your patient’s genetic information in a totally different way.
If there is a change in the clinical course for the tested individual within 9 months of the issue date of the report, re-analysis may be requested and is provided at no additional charge. After 9 months, fees may apply for re-analysis.