Exome Sequencing

Parental specimens are necessary to identify de novo variants and the chromosomal phase of variants and to optimally interpret patient results.

• The exome accounts for 1-2% of the human genome but harbors approximately 85% of pathogenic variants.
• The function of only approximately 4,500 genes is currently known.
• Exome sequencing may or may not
  • Determine etiology of patient’s medical condition
  • Predict prognosis or severity
  • Guide medical management

Information Required for Testing

• Completed Informed Consent for Exome Sequencing form for patient and parents
• Completed Patient History for Exome Sequencing form for proband and parents
• Three-generation medical pedigree
• Results of genomic microarray, magnetic resonance imaging (MRI), and other relevant tests
• Summary notes from genetic and specialist consultations

Clinical Sensitivity

Unpublished internal data

• Approximately 20% when only the proband sample is sequenced and one or both parental samples are unavailable
• Approximately 35% when only performing targeted sequencing of parental samples based on variants identified by sequencing the proband’s exome
• Approximately 45% when the proband and both parents undergo exome sequencing

Reporting

• Tens of thousands of genetic variants are identified.
  • Variants may be pathogenic, benign, or of unknown clinical significance.
  • American College of Medical Genetics and Genomics (ACMG) recommends reporting secondary findings in genes not associated with the patient’s clinical phenotype. (See table below.)
• Only the following variants are reported:
  • Those predicted to be related to the patient’s phenotype
  • De novo and rare compound heterozygous variants in genes of unknown function, if a causative variant is not identified that explains the patient’s medical condition
  • Pathogenic variants in genes recommended by ACMG, or other medically actionable incidental variants in non-ACMG genes if elected on the consent form
• Single disease-causing variants in autosomal recessive ACMG genes are not reported.
• Family members undergoing exome sequencing who complete a consent form requesting ACMG variants will receive a separate report describing pathogenic secondary findings.

Interpretation/Storage/Reanalysis/Data Sharing

• Accurate representation of biological relationships between family members is imperative for correct test interpretation.
• Test interpretation is based on information available at the time of testing and may change in the future.
• Exome sequencing data will be stored for a minimum of 5 years in compliance with ARUP’s data retention policy, but many samples are discarded after testing is complete.
• Samples may be stored indefinitely for test validation or education purposes after personal identifiers are removed. All New York samples are discarded 60 days following test completion. Patients may request disposal of their sample by calling ARUP Laboratories at 800-242-2787, ext. 3301.
• The first request for data reanalysis is available at no cost; subsequent reanalysis requests will be associated with charges.
• Deidentified information about genetic variants and clinical findings may be published in international databases unless declined on consent form.
• Patients may also contact ARUP Laboratories at 800-242-2787, ext. 3301, and request that their test result not be shared with public databases.
• Patients have the opportunity to participate in patient registries and research. For more information, see www.aruplab.com/genetics/resources.
• Raw exome sequencing data may be requested by the ordering healthcare provider and hospital that submitted the test to ARUP.

Limitations

• A negative result does not exclude a genetic cause for the patient’s disorder.
• Diagnostic errors can occur due to rare sequence variations.
• Result interpretation may be impacted if this individual has had an allogeneic stem cell transplantation.
• The human exome is not able to be completely analyzed as some genes have not been identified, whereas others, due to technical limitations, cannot be either sequenced or interpreted.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries
  • Large deletions/duplications
  • Mitochondrial DNA (mtDNA)
• The following may not be detected:
  • Deletions/duplications/insertions of any size by massively parallel sequencing
  • Some variants due to the presence of pseudogenes, repetitive, or homologous regions
  • Low-level somatic variants
  • Chromosomal phase of identified variants
  • Pathogenic ACMG variants that cannot be detected by routine exome analysis

Analytic Sensitivity

The analytic sensitivity of this test is approximately 98% for single nucleotide variants (SNVs) and greater than 93% for insertions/duplications/deletions from 1-10 base pairs in size. Deletions/duplication greater than 10 base pairs may be detected, but the analytic sensitivity may be reduced.