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

• Published in: Genetics in medicine Vol. 22; no. 3; pp. 453 - 461
• Main Authors: Bean, Lora, Funke, Birgit, Carlston, Colleen M., Gannon, Jennifer L., Kantarci, Sibel, Krock, Bryan L., Zhang, Shulin, Bayrak-Toydemir, Pinar
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.03.2020; Nature Publishing Group US
• Subjects: ACMG Technical Standards; Biomedical and Life Sciences; Biomedicine; design; gene panel sequencing; genetic testing; Genetic Testing - standards; Genetic Testing - trends; Genetics, Medical - standards; Genetics, Medical - trends; Genomics - standards; Genomics - trends; High-Throughput Nucleotide Sequencing - standards; Human Genetics; Humans; Laboratories; Laboratory Medicine; Molecular Diagnostic Techniques - standards; Molecular Diagnostic Techniques - trends; Mutation - genetics; next-generation sequencing (NGS); technical standard; United States; United States; gene panel sequencing; technical standard; genetic testing; next-generation sequencing (NGS); design
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/s41436-019-0666-z

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 copy-number variants, reporting, and disclosure of assay limitations.