A few weeks ago, I had the chance to write and post a 25-page white paper on advanced genomics coding and reimbursement, focusing on the evolving position of PLA codes - here.
Looking at genome-wide services, like exome, genome, and cytogenomics, I noticed something unusual. There were at least three codes for germline (constitutional) cytogenomics using NGS, but there was no corresponding Category 1 CPT code. This is in contrast to various codes for pharmacogenetics, hereditary panels, exome or genome, where the PLA codes are at least related to an existing CPT code. IO was pulled back to this topic last week, when AMA posted proposed CPT codes for May 2021, and there is now a proposal for a low-pass NGS Category I code (here).
There are several cytogenomics codes today, but all specify "microarray" cytogenomics as the technological method. These are 81228, 81229 (microarray with SNPs), and 81277 (tumor microarray), all designed to report chromosomal abnormalities rather than point mutations. They're priced by CMS at $900, $1160,. and $1160.
In the PLA world, there are codes for sequencing-based cytogenomics, of which I count at least three for germline tests, being 0012U (Mayo), 0156U (NY Genome Center), and 0209U (Perkin-Elmer). The Mayo code is priced by CMS at $2515, while the NYGC and Perkin codes are newer and still in the 2021 gapfill process at the MACs.
In 2020, ACMG published technical standards for interpretation and reporting of constitutional (germline) copy-number variants (Riggs et al.), and remark,
"Tremendous strides have been made in understanding the effects of copy-number variants (CNVs) in both affected individuals and the general population...continued broad implementation of array and next-generation sequencing–based technologies will expand the types of CNVs encountered in the clinical setting."
(I recall the first time I read a headline about NGS-based chromosome analysis 6 or 8 years ago, and in the interim it sounds like it's clearly come of age.)
New to me is Chaubey et al., J Molec Diagn 22:823-40 (2020). This team at Perkin-Elmer assessed 409 cases for microarray and low pass genome sequencing for CNV, and suggest that NGS methods are economical at scale and potentially more accurate (depending on copy depth; they use 5X) than microarray. Find it open access here.
Chaubey et al. conclude,
Several cases with pathogenic CNVs were detected that were missed by CMA. This study demonstrates that LP-GS (5X GS) was able to reliably detect absence of heterozygosity, microdeletion/microduplication syndromes, and intragenic CNVs with higher coverage and resolution over the genome. Because of lower cost, higher resolution, and greater sensitivity of this test, our study in combination with other reports could be used in an evidence-based review by professional societies to recommend replacing CMAs.
A lab that is new to me is Gencove, whose website headline is "Industrial-scale genome sequencing." They cite collaborations with Broad, Coriell, and others. The website states, "Gencove’s low-pass sequencing platform is setting the new standard for high-throughput genomics research and diagnostics applications."
See a new open-access publication Li et al. using 0.5X and 1X LP-NGS and published in Genome Research, February 2021 - here. These authors summarize, "We conclude that low-pass sequencing plus imputation, in addition to providing a substantial increase in statistical power for genome wide association studies, provides increased accuracy for polygenic risk prediction at effective coverages of ~0.5× and higher compared to the Illumina Global Screening Array."
Traditionally in tumors, we've used NGS to detect mutations or indels in 50 to 500 genes. Another aspect of tumor biology is "chromothripsis," the widespread disruption of chromosomal structure in some cancers. See a March 2021 paper in Nature by Shoshani et al. here. See a new March 2021 paper in NEJM on the need for whole-genome sequencing in myeloid cancers, Duncavage et al., here.