Current guidelines from key medical societies
Indications for WES/WGS1,27
ACMG published an evidence-based guideline in 2021 which strongly recommends exome and genome sequencing as a first- or second-tier test in:
- Patients with one or more congenital anomalies prior to 1 year of age
- Patients with intellectual disability/developmental delay prior to 18 years of age
In addition, ACMG has published recommendations to consider exome or genome sequencing in a phenotypically affected individual when:
- Phenotype or family history data strongly implicate a genetic etiology, but the phenotype does not correspond with a specific disorder for which a genetic test targeting a specific gene is available on a clinical basis.
- A patient presents with a defined genetic disorder that demonstrates a high degree of genetic heterogeneity, making WES or WGS analysis of multiple genes simultaneously a more practical approach.
- A likely genetic disorder but specific genetic tests available for that phenotype have failed to arrive at a diagnosis.
- When a fetus presents with a likely genetic disorder in which specific genetic tests, including targeted sequencing tests, available for that phenotype have failed to arrive at a diagnosis.
Tools and Methods for Variant Classification2,3
ACMG and others note that a careful review of the evidence for and against pathogenicity are important in variant classification. Use of sequence, population, and disease databases can be useful when classifying variants, however, clinical laboratories should be aware of potential limitations. In addition, laboratories are encouraged to contribute to variant databases and to form collaborations with clinicians.
Genomic Interpretation and Reporting2,3,4
ACMG recommends that genetic reports should be concise, easy to understand and contain all essential testing elements, supporting evidence for variants and follow up recommendations, if indicated. Careful review of the patient’s phenotype and the method of ascertainment are important in test interpretation.
The ACMG has published lists of medically actionable genes recommended for return if a pathogenic variant is detected as a secondary finding in clinical genomic sequencing, based on conditions with the potential for intervention and improved outcomes if caught early. They also created a secondary findings working group to maintain the list of medically actionable secondary findings (currently 73 genes). Several other groups recommend that laboratories and clinics offering WGS/WES should have clear policies in place related to disclosure of secondary findings. Informed consent should indicate an option to opt-in or opt-out of receiving secondary findings and include a discussion about ramifications of either decision.
Clinical Data Sharing2,11-13
Clinical genomic data sharing is an important aspect of genomic sequencing that has been addressed by multiple societies, including ACMG, AMP, CCMG, ESHG and NSGC. Data-sharing is essential to reduce the number of variants of uncertain significance and to improve consistency and accuracy of variant interpretation.
There are a range of opinions from ACMG, AMP and CAP about whether confirmation of all pathogenic or likely pathogenic sequence variants is recommended.
Variant Reevaluation and Reanalysis17
Requests for variant reanalysis can come from the patient, healthcare provider or laboratory. Clinical laboratories should have separate policies and protocols for initial variant classification, variant-level reclassification, and case-level reanalysis, which should be periodically reviewed and updated.
The American College of Medical Genetics and Genomics developed a standard for the development of next-generation sequencing tests for constitutional variants. The following points are covered in this publication: clinical use of testing, technology and processes, test development and validation, reporting standards, data management, ongoing quality management and proficiency testing. This document does not apply to cell-free DNA analysis, infections disease testing or RNA applications of NGS.
The Euro-Gentest Working Group within the European Society of Human Genetics reviewed the 2016 published guidelines which focused on whole-exome sequencing and targeted panel testing. The original 38 recommendations were re-evaluated in the context of whole-genome sequencing (WGS) resulting in a total of 44 original, updated and new recommendations. These 44 recommendations cover general considerations, evaluation and rationale for NGS applications, quality control, bioinformatics, ethical considerations, variant interpretation, data banking and result reporting.
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