Exome & Genome Sequencing Suggested for Certain Patients

A recent study published by the American College of Medical Genetics and Genomics (ACMG) has recently suggested exome sequencing (ES) and genome sequencing (GS) as strong first- or second-tier tests, for patients with congenital anomalies, developmental delays, or intellectual disabilities.

What is the ACMG?

  • The American College of Medical Genetics and Genomics, also known as ACMG, founded in 1991[1]
  • The “only nationally recognized interdisciplinary professional membership organization,” dedicated and pertaining to improving health through means of medical genetics and/or genomics[1]
  • Collaborated with the Association for Molecular Pathology (AMP) in 2015[2]
  • Widely-considered to be global leader and prominent authoritative figure within field of medical genetics and genomics[3]
  • Pertaining to clinical research, general education, and medical community
  • Used by high percentage of clinical laboratories which perform genetic testing, worldwide

What are the ACMG Guidelines and who uses them?

  • Created in collaboration with the Association for Molecular Pathology (AMP)[4]
  • Serves as a definitive framework for various aspects of clinical genetic testing
  • Recommendations are meant to apply to various breadths of genetic testing
  • Applies standard terminology as descriptors for Mendelian disorders (both common and rare)
  • Evidence-based[5]

Which type of patients apply to this study?

  • The ACMG has strongly recommended the use of ES/GS for patients with the following symptoms: [6]
  • Multiple congenital anomalies (CA)
  • Developmental delay (DD)
  • Intellectual disability (ID)
  • Such symptoms may have potential to be aligned with rare genetic diseases
Analytical Framework
Analytical framework of ES/GS for CA/DD/ID patients, figure courtesy of ACMG

I’m not in that group. What does the study mean for me?

  • Potential for systematic evidence review (SER) being applied to various verticals of patients
  • Ultimately, this means a wider range of symptoms applicable for ES/GS
  • Potential to open up analytical framework (shown above) for wider spectrum of applicable patients, not just CA/DD/ID

Current vs. Suggested

Current Standard
  • ACMG suggests CMA as a first-line test for patients with symptoms which align with CA/DD/ID rare genetic diseases[6]
  • Recent studies show diagnostic rate ranging from 16-28%[4]
Suggested Approach
  • ACMG suggests ES/GS as a first-line test for patients with symptoms which align with CA/DD/ID rare genetic diseases[6]
  • Recent studies show diagnostic rate ranging from 28-68%[4]
  • Another study using a similar vertical of patients concluded WES “provides strong evidence for increased diagnostic and clinical utility”[7]
  • Study focuses on infants with suspected and potentially rare monogenic conditions
  • Yet another study posits a 57% diagnosis rate using WES, compared to 13.5% with standard care[8]
  • Study focuses on children with suspected and potentially rare monogenic conditions

ES or GS: Which test is right for me?


Sources

  1. ACMG Homepage
  2. Standards and guidelines for the interpretation of sequence variants
  3. ACMG Mission Statement
  4. ACMG Guideline for ES/GS for patients …
  5. ACMG Publishes its First Evidence-based Clinical Guideline
  6. ACMG Recommends Sequencing as Test for Children With Intellectual Disability, Congenital Anomalies
  7. A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders
  8. Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions