Cautions

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

To discuss the availability of additional testing options or for assistance in the interpretation of these results, contact Mayo Clinic Laboratories genetic counselors at 800-533-1710.

Whole genome sequencing may not detect all types of genomic variants; therefore, false-negative results are possible. There may be regions of genes that cannot be effectively evaluated by whole genome sequencing as a result of technical limitations of the assay, including variable depth of coverage, regions of homology, and repetitive sequences. Given these limitations, negative results do not rule out the diagnosis of a genetic disorder. If a specific clinical disorder is suspected, evaluation by alternative methods can be considered. In addition, in rare cases false-positive results may occur; however, false-positive events should be exceedingly rare as confirmation of reportable variants will be performed by alternate methodologies based on internal laboratory criteria.

Single Nucleotide Variants:

Genome-wide sensitivity for single nucleotide variants (SNV) is greater than 98% and in noncomplex regions sensitivity is greater than 99.9%.

Deletions and Insertions (less than 1000 base pairs):

This test is validated to detect greater than 99% of deletions and insertions (delins) up to 50 base pairs (bp) for noncomplex regions. Performance in complex regions is slightly reduced with sensitivities of 92% to 99% depending on the size of the delins event. Although detected by this assay, performance for larger delins (51-999 bp) is not comprehensively established.

Copy Number Variants (greater than or equal to 1000 base pairs):

Genome-wide sensitivity for copy number variants (CNV) detectable by chromosomal microarray is >99.9% as established by a comprehensive comparison with clinically validated nonmosaic CNV detected by chromosomal microarray.

Additional Variant Classes:

A variety of additional variant classes can be detected by this test, including mitochondrial variants, repeat expansions, select spinal muscular atrophy (SMA)-associated variants, balanced structural rearrangements, and mosaic variants of all classes. A limited validation of each of these additional variant classes was conducted before inclusion in this assay; however, comprehensive assessment of sensitivity and false-negative rate has not been established. These variants will be evaluated per laboratory protocol, and findings of clinical relevance will be reported following confirmation with validated laboratory methods. Importantly, the sensitivity and performance for these variant classes is not expected to meet that of current gold-standard testing methodologies; therefore, additional testing may be indicated if there is clinical suspicion for a disorder involving these variant classes. Specific technical limitations for each class are described below.

Mitochondrial Genome Variants:

This assay can detect mitochondrial genome SNV and small delins with heteroplasmy levels above 5%; however, comprehensive sensitivity/false-negative rate is not established. Detection of large deletion and duplication events involving the mitochondrial genome is not available with the current analysis. Any clinically relevant and reportable mitochondrial variants detected will be confirmed with standard validated methods prior to reporting.

Repeat Expansion Variants:

Select short tandem repeats (STR; also known as repeat expansions) in pathogenic ranges can be detected with this assay; however, comprehensive sensitivity/false negative rate is not established. STR loci included in this assay are: C9orf72, CSTB, ATN1, FXN, FMR1, HTT, AR, ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7. Only loci overlapping the patient's (proband's) clinical features will be evaluated and reported. All repeat expansions meeting laboratory reporting criteria will be confirmed and further characterized by standard validated methods prior to reporting.

SMA Variants:

Absence of the definitive C nucleotide in exon 7 of SMN1 (NM_000344.3:c.840C) indicating the homozygous loss of SMN1 exon 7 is detectable by this assay; however, comprehensive sensitivity/false-negative rate is not established. This assay does not identify SMN1 or SMN2 variants outside of this specific single nucleotide change. This assay does not detect SMN1 carrier status or phase of SMN1/SMN2 alleles. All variants will be confirmed by validated laboratory methods before reporting.

Balanced Structural Rearrangements:

This assay does not involve comprehensive evaluation of balanced structural rearrangements (eg, translocations and inversions). However, select genomic regions may be evaluated and balanced events reported when there is a directed clinical focus (eg, known family history or specific locus of high clinical suspicion communicated to the laboratory). Comprehensive sensitivity/false-negative rate is not established. All reported rearrangements will be confirmed by validated laboratory methods before reporting (additional specimen may be required for further characterization).

Mosaicism:

This assay is not designed to detect mosaicism or to differentiate between somatic and germline variants. Mosaic variants may be detected; however, comprehensive limits of detection for mosaic events are not established. All mosaic variants meeting laboratory reporting criteria will be confirmed by validated laboratory methods before reporting.

If the patient has had an allogeneic hematopoietic stem cell transplant or a recent blood transfusion, results may be inaccurate due to the presence of donor DNA. Call Mayo Clinic Laboratories for instructions for testing patients who have received a bone marrow transplant.

Reclassification of Variants:

At this time, it is not standard practice for the laboratory to systematically review previously classified variants on a regular basis. The laboratory encourages healthcare providers to contact the laboratory at any time to learn how the classification of a particular variant may have changed over time. Due to broadening genetic knowledge, it is possible that the laboratory may discover new information of relevance to the patient. Should that occur, the laboratory may issue an amended report.

Variant Evaluation:

Evaluation and categorization of variants are performed using published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline.(9,10) Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Variants classified as benign or likely benign are not reported.

Rarely, incidental or secondary findings outside of the genes recommended by the ACMG may implicate another predisposition or presence of active disease. These findings will be carefully reviewed to determine whether they will be reported.

Data Sharing:

Deidentified variant information may be shared in public genetic databases, such ClinVar and Matchmaker Exchange.

A genetic consultation is recommended for patients undergoing this test, both prior to testing and after results are available.