Massively Parallel Sequencing
See Related Tests
Mendelian diseases are inherited conditions linked to individual genes. This test entails rapid sequencing of ~4,900 genes of known function from a critically ill individual and both parents to quickly diagnose a Mendelian disease to improve medical management.
Test Overview
- Although humans have ~19,000 genes, the function of only ~4,900 genes is known.
- This test only sequences genes with known function
- See Rapid Mendelian Sequencing Gene List for genes included in this panel.
- Parental specimens are required to identify de novo variants and to determine phase and clinical significance of variants detected in proband.
Required for Testing
- Blood specimens from the proband and both parents
- Completed Informed Consent for Rapid Mendelian Genes Sequencing Panel, Trio form for proband
- Completed Patient History for Rapid Mendelian Genes Sequencing Panel, Trio form
- Clinical summary from genetic consultation (if available)
- Three-generation medical pedigree
- Copy of abnormal results, which may include:
- Genomic microarray
- Skeletal survey
- Magnetic resonance imaging (MRI)
Test Interpretation
Clinical Sensitivity
Reporting and Interpretation
- Accurate representation of biological relationships between family members is imperative for correct test interpretation.
- Only variants predicted to be related to the patient’s medical issues are reported.
- Interpretation is based on information available at the time of testing and may change in the future.
Secondary Findings
- American College of Medical Genetics and Genomics (ACMG) recommends that disease-causing variants in specific genes (see ACMG list in table below) be reported whether or not they are related to the patient’s medical issues.
- This information may enable disease monitoring or early treatment.
- Single pathogenic variants in autosomal recessive genes from this list are not reported.
- Additional medically actionable secondary findings may be reported at ARUP’s discretion.
- Pathogenic variants in genes recommended by ACMG, or other medically actionable secondary findings in non-ACMG genes, are reported if elected on the consent form.
- Parental inheritance is not reported for secondary variants detected in the proband.
- Parents are not issued reports of secondary findings.
- Familial Mutation, Targeted Sequencing (2001961) can be ordered on the parents to test for a medically actionable secondary finding reported in the proband.
Limitations
- A negative result does not exclude the possibility of a genetic condition.
- Diagnostic errors can occur due to rare sequence variations.
- Interpretation of this test result may be impacted if the individual or his/her parents have had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Genes with unknown function
- Variants outside coding regions and intron-exon boundaries of the targeted genes
- Regulatory region variants and deep intronic variants
- Large deletions/duplications
- Noncoding transcripts
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
- Pathogenic ACMG variants that cannot be detected by massively parallel sequencing
- Low-level mosaic variants
Analytic Sensitivity
For massively parallel sequencing:
Variant Class |
Analytical Sensitivity (PPA) Estimatea (%) |
Analytical Sensitivity (PPA) 95% Credibility Regiona (%) |
---|---|---|
SNVs |
99.2 |
96.9-99.4 |
Deletions 1-10 bp |
93.8 |
84.3-98.2 |
Deletions 11-44 bp |
100 |
87.8-100 |
Insertions 1-10 bp |
94.8 |
86.8-98.5 |
Insertions 11-23 bp |
100 |
62.1-100 |
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants |
References
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25937001
Willig LK, Petrikin JE, Smith LD, et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015;3(5):377-387.
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27241786
Daoud H, Luco SM, Li R, et al. Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit. CMAJ. 2016;188(11):E254-E260.
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27854360
Kalia SS, Adelman K, Bale SJ, et al. 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 [published correction appears in Genet Med. 2017 Apr;19(4):484]. Genet Med. 2017;19(2):249-255.
Order for rapid diagnosis of a critically ill individual suspected to be affected with a Mendelian genetic condition