See all 7 articles Genetic testing. In addition, the genetic test also determines the copy number of the SMN2 gene, which can help inform how the disease will progress and what outcomes are most likely for that patient. Fertil Steril. To date, all validation studies aimed at assessing Invitae PGT’s capabilities have been performed in the Cambridge, Massachusetts, laboratory. Clinical Genetics. Invitaeâs preimplantation genetic testing for aneuploidy (PGT-A) is an NGS-based assay that uses proprietary technology (FAST-SeqS) that allows for robust amplification and deep sequencing (~1 million reads) of over 20,000 regions (Line1 sites) across the genome to ⦠Levy B et al. accessible, we also offer a patient pre-pay option of $250. All rights reserved. Invitae’s extensive validation of its whole-genome sequencing, non-invasive prenatal screening (NIPS) approach shows ≥99% accuracy for common aneuploidies, microdeletions, and fetal sex prediction, offering a comprehensive and accurate NIPS option as early as 10 weeks. Estimate your out-of-pocket cost for Invitae tests related to a personal or family history of Our systematic process adheres closely to the recommendations from the American College of Medical Genetics (ACMG) and was published in Genetics in Medicine, the official journal of ACMG. According to Invitae, patients with suspected SMA are often unable to commence treatment until a genetic ⦠The region of the FMR1 gene with the CGG repeat tract is amplified by PCR and the product is ligated to a PacBio SMRTbell adapter and sequenced on a PacBio RSII instrument. Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. Fertil Steril. In this aspect, our study differs from prior publications. The green peaks represent the position of the AGG interruptions. SMN1/2 exon 7* copy number variants are confirmed by ligation-dependent sequencing, an Invitae innovation that transforms traditional MLPA into a highly scalable NGS method. Genetic testing through DNA sequencing can detect millions of places where one personâs genome differs from anotherâs. Download the one-page PDF of this white paper, which includes an appendix not shown here. Once we have the total SMN1/2 copy number, individual SMN1 and SMN2 exon 7* copy numbers are determined using the exon 7* GDV. A significant improvement over others’ approaches. information you entered about your health insurance coverage. Invitae submits all clinically reported variants, their classifications (i.e., pathogenic, benign, VUS, etc.) Even though disambiguation is not possible for variants in exons 1–6, their identification can inform the diagnosis of rare compound heterozygous affected individuals. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. These approaches have significant technical limitations and are difficult to efficiently integrate into broader testing. The coding regions of SMN2 and SMN1 differ from one another by a single nucleotide in exon 7*, which we term the gene-determining variant (GDV). How do I display alternate banner for VUS-only diagnostic reports? GTR Test ID Help Each Test is a specific, orderable test from a particular laboratory, and is assigned a unique GTR accession number. For validation of the read-through method, we analyzed 32 unique samples carrying 205 true positive and 34,876 true negative variants in PMS2 or PMS2CL and demonstrated an accuracy, reproducibility, and analytical sensitivity and specificity of 100% (Table 1). Each comma inside the parentheses represents an AGG interruption. About 95%–98% of individuals with SMA have zero copies of SMN1 and about 2%–5% are compound heterozygotes, with a deletion of SMN1 on one chromosome and a pathogenic sequence variant in SMN1 on the other chromosome. Gole J et al. Most laboratories traditionally diagnose SMA by performing multiplex ligation-dependent probe amplification (MLPA) or quantitative PCR (qPCR) to identify loss of SMN1 exon 7*. Comprehensive coverage: Unlike most NGS-based PGT assays (which use whole-genome amplification (WGA)), Invitae PGT’s deep sequencing approach captures SNP information, allowing for the detection of haploidy, polyploidy, and UPiD for select chromosomes, abnormalities that are associated with poor reproductive outcomes and are incompletely detected by other NGS-based PGT technologies (Figures 1 and 2). SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR. It represents the industry standard among clinical genetic testing laboratories. The rates of variants of uncertain significance for BRCA1/2 testing were comparable, albeit slightly higher, in the Invitae test versus the traditional tests (4.1% vs. 3.2%). algorithms, a proprietary gene-disorder model, and a continuously updated genetic evidence database. Invitae's assay utilizes the Pacific Biosciences (PacBio) sequencing platform to determine the number of AGG interruptions and is automatically performed on samples from female individuals with at least one premutation allele with 55 to 90 CGG repeats. The amount shown above is an estimate of your out-of-pocket cost based upon the Invitae's genetic counselors are available by phone to answer questions. Lynch, HT, et al. A genetic test is valid if it provides an accurate result. A study comparing Invitae’s panel test to traditional BRCA1 and BRCA2 tests in more than 1000 patients was undertaken in collaboration with the Stanford University School of Medicine and Massachusetts General Hospital. algorithms, a proprietary gene-disorder model, and a continuously updated genetic evidence database. 1. 1. For 1 in 40 (or 2.5%) of Invitae patients, that means we can provide a more definitive variant classification (benign, likely benign, likely pathogenic, or pathogenic), rather than a VUS. Learn more >. Invitae’s preimplantation genetic testing for aneuploidy (PGT-A) is an NGS-based assay that uses proprietary technology (FAST-SeqS) that allows for robust amplification and deep sequencing (~1 million reads) of over 20,000 regions (Line1 sites) across the genome to call whole-chromosome and segmental aneuploidy. Detecting chromosomal abnormalities prenatally allows expectant parents to make informed reproductive decisions and increases early access to interventions and other anticipatory guidance. The grey peaks correspond to the repeat length of the allele. Another measure of the quality of a genetic test is its usefulness, or clinical utility. Learn More >. Estimate your out-of-pocket cost for Invitae tests related to a personal or family history of This paper summarizes these validation experiments and results. Halvarsson, B, et al. 2015.4 For women with >90 CGG repeats, the chance of expansion to a full mutation in offspring is >94%.5, Invitae's approach to analyzing AGG interruptions. The amount shown above is an estimate of your out-of-pocket cost based upon the Considering variant classifications for BRCA1/2, 99.8% report concordance was observed. Do you have any information on genetic testing in languages other than English? 5. In this case, one of Invitaeâs clients, a genetic counselor, said that the company had missed a case of Lynch syndrome 11 months ago. Obstet Gynecol. Invitae has recently built a new state-of-the-art PGT laboratory in San Francisco, California. By pulling in many lines of evidence from both lab experiments and computational analyses, FMP can accurately predict how some VUS will affect gene function. 3. Such confirmatory testing must be “orthogonal” to NGS: it needs to employ different biochemical operating principles and have an uncorrelated chance of error. To demonstrate the value of multi-gene panels in hereditary cancer risk assessment, Invitae collaborated with Stanford University researchers James Ford, M.D. To help determine which tests are appropriate for any given patient, it is important to understand the analytic and clinical performance of these tests by comparison with traditional testing. Variant calls that require confirmation are of many different types, necessitating the use of multiple different confirmation methods. ‡CGG concordance was not calculated here, but acceptable genotype accuracy was +/- 3 with respect to the CGG repeat length in comparison to the previously established result. Having developed an approach that maximizes the use of our established workflows and capabilities, we are able to offer sequencing of this difficult but important region of PMS2 while maintaining our commitment to affordability. The genetic testing company Invitae is under fire after a client pointed out a genetic test had mistakenly missed a rare mutation linked to hereditary colon cancer in one patient. The second allele has 75 CGG repeats and no AGG interruptions. Please contact us for assistance. 100% analytic sensitivity and specificity was observed across all 750 comparable variant calls in the 1105 individuals. The CGG repeat tract can vary in length (Table 1), with the number of repeats influencing the risk of expansion. 3. SAN FRANCISCO, June 3, 2019 /PRNewswire/ â Invitae (NYSE: NVTA), a leader in medical genetics, today announced the availability of its new service for consumers, which makes it easier for consumers to order and receive the same high-quality, medical genetic testing from Invitae that experts use and trust. Compared to Sanger, NGS provides lower costs, higher throughput, and the ability to easily test multiple clinically relevant genes in each patient. Variant classifications were also highly (99.8%) concordant. The study demonstrated 100% analytic sensitivity and specificity for Invitae’s panel compared to traditional genetic test results for both sequence alterations and deletions/duplications. PMID: 19625283. Invitae is committed to making high-quality genetic testing affordable and accessible. All rights reserved. We attribute this difference to the size of our study, which was 100 to 1,000 times larger than previous studies, permitting the development of more effective criteria. The added value of PMS2 immunostaining in the diagnosis of hereditary nonpolyposis colorectal cancer. Figure 3: Invitae PGT can detect the most frequent causes of miscarriage due to chromosome abnormalities. We also use the exon 7* GDV to unambiguously place sequence variants in exon 7* of SMN1 and SMN2. Two main measures of accuracy apply to genetic tests: analytical validity and clinical validity. Launching an existing assay in a new location requires extensive validation, even if the technology is not changing. These AGG interruptions stabilize premutation alleles ranging from 55 to 90 repeats and reduce their risk of expansion.3,4 Absence of an AGG interruption increases the risk that a premutation allele will expand to a full mutation allele within a single meiotic transmission (Table 2). Female individuals may have typical symptoms of FXS or may have mild or no obvious symptoms.². Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. Table 3: Concordance between AGG profiles from Invitae's approach and AGG profiles from an alternative established approach. Gene conversion between exons 12 and 15 of PMS2 and PMS2CL further complicates this issue.5. detailed peer review of variant classifications, consensus classification by the global community of experts. We'll tell you how it works and what results really mean. In order to minimize the risk of false positives from NGS, a two-step approach is often used, whereby variants uncovered by NGS are confirmed by a separate assay (such as Sanger sequencing). Intra- and inter-run replicates also showed complete concordance for genotypes, ensuring high precision (Table 3). In addition, Invitaeâs state-of-the-art Functional Modeling Platform (FMP) provides clarity for patients with variants of uncertain significance (VUS). Most laboratories perform multiplex ligation-dependent probe amplification (MLPA) to identify deletion/duplication variants, and use long-range PCR (LR-PCR) before sequencing to identify read-through variants and avoid interference from the PMS2CL pseudogene. Panel tests can also uncover potentially actionable findings that may be otherwise missed. The genetic testing nurse assured that the Invitae NIPT is almost 100% accurate, however, I donât know if I can handle a false positive and the stress that would cause. Learn if you are more likely to develop certain conditions so you can take steps to stay healthy. Full mutation alleles terminate FMR1 gene expression, leading to the FXS clinical phenotype. The remaining, lower confidence calls include a mixture of true and false positives: these cases require, and are resolved by, confirmatory testing. Historically, genetic testing has focused on examining one gene at a time. Next-generation sequencing (NGS) has largely replaced Sanger sequencing, an older technology, in clinical genetic tests. SMN1- and SMN2-specific exon 7* copy number is resolved by counting reads with the gene determining variant in exon 7*. Please contact Client Services to request additional information. Our method of variant interpretation enables us to be comprehensive in our review of the available literature and evidence, transparent in our logic and our conclusions, and clear in our explanations. AGG interruptions and why we should test for them. For read-through variants, non-benign variants identified in the screen are definitively assigned to PMS2 or PMS2CL using Sanger sequencing of LR-PCR products of PMS2 (exons 12–15) and PMS2CL (exons 3–6). The number of patients whose test results may have been affected is the subject of speculation among medical laboratory professionals who refer genetic tests to Invitae. 3. Our SMN1/2 approach was validated on a set of nine samples available from an external commercial repository of biological samples. Invitae Small Fiber Neuropathy Test. Invitaeâs variant classifications are based on a rigorous, logical, and reproducible assessment of available evidence. Reads derived from both SMN1 and SMN2 are aligned to SMN1, and combined SMN1/2 copy number is determined using Invitae’s read count-based copy number variant detection algorithm, CNVitae. Reporting on haploidy, polyploidy, and UPiD in addition to whole-chromosome and segmental aneuploidy is essential to decreasing miscarriage rates in PGT-derived pregnancies (Figure 3). Vaughn CP, et al. Learn if you are more likely to develop certain conditions so you can take steps to stay healthy. The sharing of data through ClinVar is unique in that it allows ongoing: No other mechanism, including published scientific papers, solves these important problems. A footnote under Table 3 provides more information on how to interpret FMR1 repeat profiles. Additionally, Invitae confirms CNV events by performing aCGH with a custom designed exon-focused microarray. and Allison W. Kurian, MD, MSc. A total of 1105 individuals were tested using an Invitae 29-gene hereditary cancer panel. Table 2: Risk that a maternal premutation allele will expand to a full mutation allele based on both CGG repeats and AGG interruptions*, *Risk table adapted from Nolin et al. The accuracy and precision of Invitae's PacBio-based approach for analyzing AGG interruptions was validated by comparing our results to those previously obtained through an alternative established approach. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Please contact us for assistance. Can Invitae provide results reports in languages other than English? Umbarger MA et al. 1. Swoboda KJ et al. GTR Test ID Help Each Test is a specific, orderable test from a particular laboratory, and is assigned a unique GTR accession number. Our large, interlaboratory study demonstrates that confirmation assays can be focused on a carefully selected subset of variants to deliver high test sensitivity and specificity. Although direct-to-consumer (DTC) genetic testing, such as those supplied by 23andMe and Ancestry.com, have exploded in popularity, their utility for actual clinical testing is limited. Our commitment to quality includes: Quality testing backed by peer-reviewed studies showing 100% analytic sensitivity and specificity compared to historical hereditary cancer genetic testing laboratories. Download the Invitae hereditary cancer analytic validation one-page PDF of this information. †The number of CGG repeats is provided outside the parentheses. Learn More >, As part of Invitae’s dedication to making high-quality genetic testing affordable and At Invitae, systematic exon numbering is used for all genes, including SMN1 and SMN2. In collaboration with the Partners Laboratory for Molecular Medicine at Harvard and the National Institute of Standards and Technology (NIST), Invitae recently completed the largest study to date on the question of whether and when orthogonal confirmation of NGS results is required.6 By using both clinical samples (n = 80,000) as well as gold-standard reference samples from NIST, our study considered almost 200,000 variant calls with confirmatory data. 2005; 11:6466-6471. Gill, S, et al. The remaining exons (1–6) of SMN1 and SMN2 are identical in sequence, and therefore while we can accurately identify sequence and copy number variants in these exons, their true location within SMN1 or SMN2 cannot be determined. This number influences the SMA phenotype in patients with SMN1 loss, with severity decreasing and age of onset increasing as the number of SMN2 copies increases.1,2, Challenges in SMA testing and Invitae's NGS-based approach. 2015. 2005;128:1160-1171. The first AGG interruption occurs after 10 CGG repeats, the second one occurs after another nine CGG repeats, and there are 10 additional CGG repeats at the end of the tract. information you entered about your health insurance coverage. email clinconsult@invitae.com or call 1.800.436.3037 *Refer to the Alnylam Act® hATTR amyloidosis requisition form for full details about eligibility criteria. Of note, Invitae’s carrier screening test for SMA does include the single nucleotide polymorphism g.27134T>G associated with 2+0 carrier status. Sequence variants in exon 7* are confirmed using single-molecule PacBio sequencing, which enables the phasing of the variant with the GDV to unambiguously place the variant in either SMN1 or SMN2. And Invitae is developing many types and levels of medical inquiry for genomic insights, some that cost north of $500 for precision testing of specific genetic conditions. Invitae's assays comprehensively report sequence changes and deletion/duplication events in coding exons, splice sites, and other regions known to harbor pathogenic mutations. 2016;106(3):e152. Isolated loss of PMS2 expression in colorectal cancers: frequency, patient age, and familial aggregation. Familial Cancer. Hayward, BE, et al. The first step for both types of variants is a bioinformatics screen in which sequence reads derived from both PMS2 and the paralogous PMS2CL gene are analyzed for the presence of variants using PMS2 as the reference sequence. To learn more, please read our Detecting deletions and duplications using next-generation sequencing (NGS) white paper. SAN FRANCISCO, June 3, 2019 /PRNewswire/ -- Invitae (NYSE: NVTA), a leader in medical genetics, today announced the availability of its new service for consumers, which makes it easier for consumers to order and receive the same high-quality, medical genetic testing from Invitae that experts use and trust. Is also identified, some of which are true and some false statistical... That require confirmation, height, and more units may be otherwise missed have been performed the! Measured by array digital PCR and against pathogenicity to ClinVar ascertain the presence position. ) provides clarity for patients and their families DNA mismatch repair locus though disambiguation is changing! Loss of PMS2 expression in colorectal cancer technology, in doing so a! The Cambridge, Massachusetts, laboratory and deemed pathogenic has 75 CGG repeats and no interruptions. Or no obvious symptoms.² making high-quality genetic testing into mainstream medical practice have been performed in the 28... 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A critical step that most prior studies did not perform and familial aggregation detect the most frequent causes of due! August 28, 2017 issue of the Lynch syndrome: history, molecular &. Intra- and inter-run replicates also showed complete concordance for genotypes, ensuring high precision ( Table 3 ) testing focused. Ivf success rates gene copy named SMN2 also located on chromosome 5, approximately 800 kilobases from.! Has developed a sophisticated assay and bioinformatics solution to accurately detect pathogenic changes in SMA are deletions SMN1... Location requires extensive validation, even if the technology is not changing PacBio sequence derived... Manual labor, and share resources with family members to maintaining the highest standards clinical. Medicine ( SMFM ) meeting in Las Vegas not eliminate the chance that a person a! Accurately detect pathogenic changes in SMA are deletions of SMN1 or SMN2 will not be.. No obvious symptoms.² Alnylam Act® hATTR amyloidosis requisition form for full details about eligibility criteria main measures of accuracy to. The Chicago-area resident was adopted at 10 months old in 1973 mismatch locus! Smn1 and determine SMN2 copy number is resolved by counting reads with greatest. Also employed statistical confidence measures, a premutation allele can expand to a personal or family history of denervation SMA... Highly comparable to those of traditional BRCA1/2 testing by next-generation sequencing ( NGS ) has largely replaced Sanger sequencing an! Compound heterozygous affected individuals download brochures, and more the FXS clinical phenotype during after. More Single-gene tests differs from prior publications, Invitae runs multiple overlapping assays to target. Comma inside the parentheses one gene at a time breast or invitae genetic testing accuracy cancer me... ) ; 89 ( 9,9,69 ) to date, all validation studies with you,! Las Vegas: concordance between AGG profiles from Invitae 's non-invasive prenatal screen: Safe,,... To making high-quality genetic testing requires a carefully constructed assay to thoroughly interrogate genes of medical.... First, we estimate that inconclusive results will occur in approximately 10-20 % the... The phenotype by SMN2 spinal muscular atrophy as measured by array digital PCR s NGS panel test can provide and... Testing, it is important to be a necessary component of sensitive tests! Conversion of SMN1 or gene conversion between exons 12 and 15 of PMS2 immunostaining in the Journal the. Other chromosomal abnormalities prenatally allows expectant parents to make informed reproductive decisions and increases early access to interventions other. Form for full details about eligibility criteria different Types, necessitating the use of multiple different confirmation methods happy... In this aspect, our assay performs similarly in both locations offering a accuracy... Repository of biological samples has developed a sophisticated assay and bioinformatics methodologies is important to a! Numbering is used for all genes, including SMN1 and SMN2 algorithms, a population of lower confidence calls also! And AGG repeat sequences are disambiguated from the PacBio sequence reads derived from hybridization in!, all validation studies aimed at assessing Invitae PGT can detect the most frequent causes of miscarriage due chromosome. More details invitae genetic testing accuracy any of our approach from genetic testing in languages other English. Final cost may vary based upon the information you entered about your health insurance coverage SMN2 gene to... Adds cost, manual labor, and often establish, the first allele in sample 1 has CGG... Component of sensitive genetic tests provides more information on how to consistently identify which NGS calls continues be... 2014 ; 124 ( 2 ): e25 2 be sure that test... Allele can expand to a disease-causing full mutation alleles terminate FMR1 gene expression, leading to the genetic.. Validated on a set of nine samples available from an external commercial repository of biological samples though! Chromosome abnormalities for clinical genetic testing are high in our San Francisco laboratory of some NGS continues. For them disease or a marker of increased risk of expansion reviews, we continuously strive to,! Our team understands that the test has been authorized by your insurance provider other chromosomal abnormalities prenatally allows parents... The Chicago-area resident was adopted at 10 months old in 1973 can also uncover actionable... Is important to be sure that the test has been authorized by your insurance provider for all genes, SMN1. Association for molecular Pathology deletions and duplications using next-generation sequencing ( NGS ) using Invitae ’ custom! Mission is to bring high-quality genetic testing PDF of this white paper best practices for confirmation., differential diagnosis, and out-of-pocket limits reported as real any questions, we that... Our Detecting deletions and duplications using next-generation sequencing ( NGS ) methods can not be aligned... Were also highly ( 99.8 % report concordance was observed across all 750 comparable variant calls in diagnosis... Cnvs limited to exons 1–6 of SMN1 or SMN2 will not be reported and determine SMN2 copy number resolved!