Pathology/Lab Coding Alert

Don’t miss new code for low-pass sequencing analysis.

Lots of small changes come together in CPT^® 2022 to increase options for reporting constitutional disorder laboratory testing.

Read on to explore the changes you need to know in Category I codes, section instructions, and Proprietary Laboratory Analyses (PLA) codes.

Ground Your Understanding: Terms and Methods

Recent coding revisions reflect changes in both laboratory methods and a growing understanding of how genetics impact human health. Digest the following basic information to help you better understand the CPT^® 2022 changes.

Glossary: First you need to know the definitions of the following terms.

• Cytogenomics: The study of all genes (whole genome) and chromosomes and how their structure, function, and aberration influence a person.
• Constitutional disorder: A condition stemming from a person’s innate genomic structure and function; also called germline disorder.
• Chromosome: Found in the nucleus of cells, a chromosome is a group of genes (DNA) that appears as a threadlike structure, especially during cell division.

Lab methods: Over time, cytogenomic tools have changed, beginning with visual representations of chromosome number and appearance using methods such as karyotype and Giemsa banding. Newer tests allowed identification of the location of specific DNA sequences on a chromosome using fluorescence in situ hybridization (FISH).

Labs now commonly use more sensitive methods of chromosomal microarray analysis (CMA), such as comparative genomic hybridization (CGH). These methods allow labs to find chromosomal aberrations such as large repeated or deleted DNA regions (copy number variants, called CNVs) or specific DNA sequence changes (single nucleotide polymorphisms, or SNPs).

The latest analytical development is low-pass sequencing analysis using next generation sequencing (NGS). This method can identify with high sensitivity CNVs and chromosomal structural variations, such as long homozygous (same small repeating sequence) DNA regions called loss of heterozygosity (LOH).

Learn New and Revised Category I Codes

CPT^® 2022 revises and expands the 81228 (Cytogenomic (genome-wide) analysis for constitutional chromosomal abnormalities; interrogation of genomic regions for copy number variants, comparative genomic hybridization [CGH] microarray analysis) code family to include the following codes:

• 81229 (… interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants, comparative genomic hybridization (CGH) microarray analysis)
• 81349 (… interrogation of genomic regions for copy number and loss-of-heterozygosity variants, low-pass sequencing analysis)

Revision: Changes to existing codes 81228 and 81229 clarify that the tests are “for constitutional chromosomal abnormalities,” and provide a distinction between the codes based on whether the CGH microarray analysis involves only CNV, or CNV and SNPs.

Addition: New code 81349 provides a specific way to report a cytogenomic analysis for constitutional chromosomal abnormalities that uses low-pass sequencing methodology to identify CNVs and LOH variants.

“Low-pass cytogenomics will be at least a competing standard of care” with microarrays for the detection of copy number variants, according to Bruce Quinn, MD, PhD, principal of Bruce Quinn Associates, representing Invitae at the Clinical Laboratory Fee Schedule Annual Laboratory Meeting about the new codes. The method provides “high resolution mapping of chromosome structure,” he said.

Notes: New CPT^® text notes provide the following direction about how to use these codes:

• Don’t report any codes from this family together for the same analysis.
• Don’t use these codes for targeted exome (not genome-wide) analysis, but turn instead to an appropriate code such as 81405 (Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis)… Cytogenomic constitu­tional targeted microarray analysis of chromosome 22q13 by interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities…) or 81479 (Unlisted molecular pathology procedure).
• Don’t report 81349 for constitutional chromosomal abnormalities testing by sequence analysis; instead see 81425 (Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis).
• For a specific analyte included in the 81228, 81229, or 81349 test, don’t additionally report analyte-specific molecular pathology code(s).

Follow GSP Section Notes to Know When These Codes Apply

The following codes in the CPT^® section Genetic Sequencing Procedures [GSPs] and Other Molecular Multianalyte Assays section describe sequence analysis methods for constitutional disorder testing:

• 81425 code family (+81426 for comparator analysis, such as parent or sibling)
• 81415 (Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis) code family (+81416 for comparator analysis, such as parent or sibling)

To help distinguish 81425 and 81415 sequence analysis tests from the 81228 family, CPT^® 2022 adds text notes directing you to the cytogenomic tests, when appropriate.

The GSP introduction also contains this definition of low-pass sequencing: “a method of genome sequencing intended for cytogenomic analysis of chromosomal abnormalities, such as that performed for trait mapping or copy number variation, typically performed to an average depth of sequencing ranging from 0.1 to 5X.” Sequencing depth is the proportion of times a DNA base is found in all the times the same sequence is read.

Notice Constitutional Disorder PLA Codes

The following PLA codes describe tests for constitutional disorders and make their debut in the CPT^® 2022 manual:

• 0260U (Rare diseases (constitutional/heritable disorders), identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping)
• 0264U (Rare diseases (constitutional/heritable disorders), identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping)
• 0265U (Rare constitutional and other heritable disorders, whole genome and mitochondrial DNA sequence analysis, blood, frozen and formalin-fixed paraffin-embedded (FFPE) tissue, saliva, buccal swabs or cell lines, identifi­cation of single nucleotide and copy number variants)
• 0266U (Unexplained constitutional or other heritable disorders or syndromes, tissue-specific gene expression by whole-transcriptome and next-generation sequencing, blood, formalin-fixed paraffin-embedded (FFPE) tissue or fresh frozen tissue, reported as presence or absence of splicing or expression changes)
• 0267U (Rare constitutional and other heritable disorders, identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping and whole genome sequencing)

Some of these tests use a unique laboratory method called optical genome mapping (OGM) performed using the Saphyr^® System from Bionano Genomics Inc. to evaluate the patient’s chromosomes for large scale changes in DNA, such as copy number variations, inversions, insertions, deletions, and translocations.

This method is able to “identify all structural variant types [that] could be associated with a genetic disorder,” according to Ravindra Kolhe, MD, PhD, FCAP, in a press release for Georgia Esoteric and Molecular Laboratory that performs the 0260U test.

Key: To report a PLA code, the test must match both the code descriptor and the specific proprietary clinical lab or manufacturer. If a PLA code exists that describes a specific lab test, you must use that code because PLA codes take precedence over any other code that describes the test, even a Category I code.