Diagnostic gene sequencing panels: from design to report—a technical standard of the American College of Medical Genetics and Genomics (ACMG)

Abstract

Disclaimer: This technical standard is designed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to this standard is voluntary and does not necessarily assure a successful medical outcome. This standard should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with this standard. They also are advised to take notice of the date any particular standard was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. Gene sequencing panels are a powerful diagnostic tool for many clinical presentations associated with genetic disorders. Advances in DNA sequencing technology have made gene panels more economical, flexible, and efficient. Because the genes included on gene panels vary widely between laboratories in gene content (e.g., number, reason for inclusion, evidence level for gene-disease association) and technical completeness (e.g., depth of coverage), standards that address technical and clinical aspects of gene panels are needed. This document serves as a technical standard for laboratories designing, offering, and reporting gene panel testing. Although these principles can apply to multiple indications for genetic testing, the primary focus is on diagnostic gene panels (as opposed to carrier screening or predictive testing) with emphasis on technical considerations for the specific genes being tested. This technical standard specifically addresses the impact of gene panel content on clinical sensitivity, specificity, and validity-in the context of gene evidence for contribution to and strength of evidence for gene-disease association-as well as technical considerations such as sequencing limitations, presence of pseudogenes/ gene families, mosaicism, transcript choice, detection of copynumber variants, reporting, and disclosure of assay limitations.

Analytical validation and performance characteristics of a 48-gene next-generation sequencing panel for detecting potentially actionable genomic alterations in myeloid neoplasms

“…Supplementary single-gene assays are recommended to improve low coverage targets in some clinical assays [29]. In this study, we demonstrated a broad reportable range of the 48-gene panel even in extreme % GC spectrum (Fig 1B).…”

Hypopituitarism in Patients with Blepharophimosis and <b><i>FOXL2</i></b> Mutations

“…About 30 genes have been formally implicated in pituitary deficiencies [4]. Other genes are suspected of involvement in human pituitary pathologies, but the evidence is so far insufficient (limited or disputed) for their inclusion in diagnostic panels according to American College of Medical Genetics and Genomics recommendations [32]. It is therefore possible that our patients' pituitary deficiency was caused by one or several of these genes not included in our panel of 20 genes or by other currently unknown genes.…”

Clinical validity of expanded carrier screening: Evaluating the gene‐disease relationship in more than 200 conditions

“…Notably, HYLS1 was scored at 5.5 points (near the upper bound of the Limited point range), suggesting that it will remain in the supportive clinical validity category. ACMG recently published technical standards, based on the ClinGen evidence categories, for laboratories designing diagnostic sequencing panels (Bean et al, 2020). These technical standards suggest that gene‐disease pairs that fall into the Limited classification should be considered as “genes of uncertain significance” rather than supportive of clinical validity (Bean et al, 2020).…”

“…ACMG recently published technical standards, based on the ClinGen evidence categories, for laboratories designing diagnostic sequencing panels (Bean et al, 2020). These technical standards suggest that gene‐disease pairs that fall into the Limited classification should be considered as “genes of uncertain significance” rather than supportive of clinical validity (Bean et al, 2020). Since the evidence bar for gene‐disease association is generally considered higher for screening an unaffected population than for diagnostic settings in which an individual is already symptomatic, laboratories should evaluate the appropriateness of including genes with a Limited classification on ECS panels.…”