The Case for Laboratory Developed Procedures: Quality and Positive Impact on Patient Care

Kaul, Karen L.; Sabatini, Linda M.; Tsongalis, Gregory J.; Caliendo, Angela M.; Olsen, Randall J.; Ashwood, Edward R.; Bale, Sherri; Benirschke, Robert; Carlow, Dean; Funke, Birgit H.; Grody, Wayne W.; Hayden, Randall T.; Hegde, Madhuri; Lyon, Elaine; Murata, Kazunori; Pessin, Melissa; Press, Richard D.; Thomson, Richard B.

As the genetic basis for many human diseases became apparent, sequence-based diagnostic testing was implemented as a way to provide definitive diagnoses for patients and their families. Many laboratories began offering sequence-based testing for heritable disorders in the 1990s, using a variety of mutationscanning techniques, such as single-strand conformation polymorphism, denaturing HPLC, MLPA, and others. 102 Sanger-based sequencing was the gold standard, despite being slow and expensive. The multigenic nature of some of these disorders made these sequencing approaches challenging due to the sheer number of genes and size of the sequence requiring analysis. In recent years, however, most of this testing has been converted to NGS, which offers significant advantages in terms of analytic capabilities, quality, speed, and cost. 103 The repetitive sequence reads in a single region ensure an enhanced level of quality, and NGS assays can be designed to interrogate anything from small to large gene panels, whole exomes, and beyond, depending on the clinical need being addressed. Consensus guidelines for NGS assays have been developed by multiple professional societies and address the development, validation, and quality control of these assays. 104, 105 The CAP has developed inspection checklists for laboratories performing NGS for detection of somatic mutations in cancers as well as germline mutations that cause heritable diseases. Progress has also been made in the planning and production of reference materials and proficiency samples. 106 Together, these practices and resources have yielded laboratory-developed assays that can be demonstrated to meet the quality levels needed for patient care.