Critically Ill Rapid Genetic Diagnosis Panel, ~5000 Genes

Mendelian diseases are inherited conditions that are linked to individual genes and can cause critical illness. This test entails rapid sequencing of approximately 5,000 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 approximately 19,000 genes, only the function of approximately 5,000 genes are known.
  • This test only sequences genes with known function.
• See the 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.

• Blood specimens from the proband and both parents
• Completed Informed Consent for Critically Ill Rapid Genetic Diagnosis Panel, ~5000 Genes form for proband
• Completed Patient History for Critically Ill Rapid Genetic Diagnosis Panel, ~5000 Genes form
• Clinical summary from genetic consultation
• Three-generation medical pedigree
• Copy of abnormal results, which may include:
  • Genomic microarray
  • Skeletal survey
  • Magnetic resonance imaging (MRI)

Clinical Sensitivity

50% for infants  

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 Targeted Sequencing (3005867) 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