IGxome is Insight Genomica’s whole exome sequencing (WES) assay. The IGxome assesses almost all genes from the human genome including coding regions and adjacent introns. The IGxome Health Screen is intended for clients who are basically healthy, but who would like to learn their carrier status for recessive disease and / or their susceptibility to adult onset disorders.
Although nearly all human genes are sequenced, our laboratory analyses and reports sequence variants only in genes that have been proven with high confidence to be involved in Mendelian (also called single gene) disorders (MacArthur et al., 2014). The list of “clinically-relevant” genes currently includes about 4000 genes and is updated every few months. Variations in genes that cannot be accurately sequenced due to technical reasons (for example, pseudogenes) will not be reported.
In addition, although our laboratory identifies and interprets all sequence variants (differences between the person’s sequence and the reference sequence), only variations that are disease causing or very likely disease causing (Pathogenic and Likely Pathogenic variants) will be included in the report.
For this test, clients also have the option of receiving results of Pathogenic and Likely Pathogenic variants in genes that predispose to or confirm a diagnosis of adult onset disorders such heart disease and cancer.
Because new Mendelian disease genes are being continuously identified and because the ability to interpret sequence variants is steadily improving, it is important to consider reanalysis and reinterpretation of exome data in future. For this purpose, our laboratory retains raw sequence data indefinitely from Insight Genomica’s exome tests.
Reports will consist of up to four different sections:
1. Variants that are causative for recessive disease
2. Medically actionable variants (if requested) *[American College of Medical Genetics (ACMG)] recommended list of genes (Richards et al., 2015; Kalia et al., 2016)
3. Variants in other genes that result in a dominant Mendelian disorder (if requested)
4. Pharmacogenetic variations that may influence the response to medications (if requested) (Kalman et al., 2015; Caudle et al., 2016)
All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories (Pathogenic, Likely Pathogenic, Variant of Uncertain Significance, Likely Benign and Benign) as per ACMG Guidelines. All sequence variants in appropriate gene regions will be detected and interpreted, but only Pathogenic and Likely Pathogenic variants will be included in the test report.
LIMITATIONS AND OTHER TESTS NOTES
Interpretation of the test results is limited by the information that is currently available. Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.
When sequencing does not reveal any heterozygous differences from the reference sequence, the laboratory cannot be certain that they were able to detect both client alleles. Occasionally, a client may carry an allele which does not capture or amplify, due to a large deletion or insertion. In these cases, the report will contain no information about the second allele.
Due to technical reasons, the IGxome test is not 100% sensitive. Some exons cannot be efficiently captured, and some genes cannot be accurately sequenced because of the presence of multiple copies in the genome. Therefore, a small fraction of causative sequence variants will not be detected. For those planning reproduction, the laboratory nor Insight Genomics cannot guarantee a child free of genetic disorders.
Caudle, K. E., Dunnenberger, H. M., Freimuth, R. R., Peterson, J. F., Burlison, J. D., Whirl-Carrillo, M., … & Relling, M. V. (2016). STANDARDIZING TERMS FOR CLINICAL PHARMACOGENETIC TEST RESULTS: CONSENUS TERMS FROM THE CLINICAL PHARMACOGENETICS IMPLEMENTATION CONSORTIUM (CPIC). Genetics in medicine: official journal of the American College of Medical Genetics.
Kalia, S. S., Adelman, K., Bale, S. J., Chung, W. K., Eng, C., Evans, J. P., … & McKelvey, K. D. (2016). Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2. 0): a policy statement of the American College of Medical Genetics and Genomics. Genetics in Medicine, 19(2), 249-255.
Kalman, L. V., Agúndez, J. A., Appell, M. L., Black, J. L., Bell, G. C., Boukouvala, S., … & Daly, A. K. (2016). Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting. Clinical Pharmacology & Therapeutics, 99(2), 172-185.
MacArthur, D. G., Manolio, T. A., Dimmock, D. P., Rehm, H. L., Shendure, J., Abecasis, G. R., … & Barrett, J. C. (2014). Guidelines for investigating causality of sequence variants in human disease. Nature, 508(7497), 469.
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., … & Voelkerding, K. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine, 17(5), 405-423.