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Key Points

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  • Genomic technology:

    • Advances in DNA sequencing technology have led to improved accuracy as well as decreased costs and have resulted in the recent introduction of individual whole genome, whole exome, and large gene panel sequencing from certified reference laboratories for clinical molecular diagnosis.

  • Data filtering:

    • Bioinformatic filtering of the over 3 billion nucleotide base pairs found in any genome is required to identify causal mutations. Currently, most analysis focuses on the estimated 4000 genes (out of a total of ~20,000 genes) in the human genome implicated in human disease.

  • Informed consent:

    • Prior to testing patients should be informed of (a) potential disclosure of nonpaternity, consanguinity, and/or unrelatedness to one or more family members, (b) the possibility of finding either a diagnosis or predisposition to a disease unrelated to the reason that sequencing was ordered, (c) limitations of current sequencing approaches (even when genetic etiology is strongly suspected), and (d) potential risk of genetic discrimination affecting either insurability and employment. They should also be informed of the US Federal law (GINA) which seeks to protect against the existing genetic discrimination.

  • Incidental findings:

    • Diagnostic use of this technology is made more complex by the uncovering of numerous incidental findings (some with unknown significance and others with an established pathogenic effect) present in any individual genome. Recent ACMG recommendations on release of incidental findings advises the return of “known pathogenic” and “expected pathogenic” variants identified across 56 well curated genes.

  • Genetic counseling:

    • Appropriate genetic counseling to address incidental findings and informed consent issues is necessary both prior to as well as following medical genomic testing in a patient.

  • Periodic reanalysis:

    • The rapidly evolving knowledge base allows providers to discuss with patients the expectation that future reanalysis of the same genomic dataset will yield additional valuable insights into the health implications of the data for the patient. Many predict that annual reanalysis will become the norm.

  • Results disclosure:

    • Allowing patients to “opt out” for disclosure of abnormal results (even when findings are incidental or secondary) is generally not the norm in medicine. While controversial, there may be special instances in medical genomics where providing an “opt out” option for abnormal results is appropriate - such as when incidental findings for an adult-onset disease in a pediatric patient is discovered. Even in these cases, however, disclosure to the parents/guardians is generally favored over suppression of these results.

  • Sanger sequencing:

    • The use of traditional DNA sequencing approaches to genetic diagnosis (ie, Sanger sequencing) continues to have a clinical role in the diagnosis of many well-studied conditions. Currently, pathogenic mutations generated from next-generation sequencing (NGS) are usually confirmed with an alternative method of clinical sequencing before being medically acted upon and Sanger sequencing is often considered the “gold standard” for confirmation.

  • Limitations of NGS:

    • Current technology does not perfectly represent the complete genome or exome due to technical limitations. At this time, clinical exome sequencing on average covers 92-99% or more of targeted coding areas of genes and ...

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