Reviewer #3: Diagnosis: Cystic Fibrosis Treatment: CPT codes 88299 [Unlisted cytogenetic study] and 81228 [cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CHG] microarray analysis)] The insurer denied coverage for CPT codes 88299 [Unlisted cytogenetic study] and 81228 [cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CHG] microarray analysis)]. The denial is upheld. The patient is a female with a history of infertility and cystic fibrosis (CF) carrier. The patient underwent genetic testing (CPT codes 88299 - cytogenetic study. Traditionally, morphology-based grading had been the primary technique used for in vitro fertilization (IVF) to evaluate and select the most competent embryos for transfer. Technologies have been developed in the fields of genomics, transcriptomics, proteomics, metabolomics, and time-lapse imaging to try to assist in the selection of the best embryos. However, a focus has been on analysis of 24-chromosome copy number for evaluation and transfer of only diagnosed euploid embryos, also known as preimplantation genetic testing for aneuploidy (PGT-A). Several molecular techniques have been utilized during IVF cycles to determine ploidy including fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), array CGH (aCGH),digital polymerase chain reaction (dPCR), single-nucleotide polymorphism (SNP)array, real-time quantitative PCR (qPCR), and next-generation sequencing (NGS). In both the United States and Europe, preimplantation genetic diagnosis for monogenic disorders (PGT-M) has been used with increasing frequency for preconception management. Prenatal diagnosis and pregnancy termination are also employed for the management of serious single-gene diseases. In 2018, the Practice Committee of the American Society for Reproductive Medicine (ASRM) recommended PGT-M with IVF as a significant advance over post-conception diagnosis and pregnancy termination in the case of single-gene (monogenic) disorders. The ASRM, in its Practice Committee Opinion, does not support co-testing of PGT-M and PGT-A at this time due to the need for further studies. Therefore codes 88299 and 81228 do not have final approval from the appropriate regulatory bodies for this patient's diagnosis. Thus, the requested service is not likely to be more beneficial than any of the standard treatments/procedures for this patient. The carrier's denial of coverage for CPT codes 88299 [Unlisted cytogenetic study] and 81228 [cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CHG] microarray analysis)]; testing performed should be upheld.

Reviewer #2: Diagnosis: Carrier of cystic fibrosis Treatment: CPT codes 88299 [Unlisted cytogenetic study] and 81228 [cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CHG] microarray analysis)] The insurer denied coverage for CPT codes 88299 [Unlisted cytogenetic study] and 81228 [cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CHG] microarray analysis)]. The denial is upheld. This case involves female who underwent the requested genetic testing. The submitted documentation indicated that the patient experienced fertility issues and underwent the process of in vitro fertilization (IVF). The documentation detailed the patient and her husband were both carriers of cystic fibrosis. As a result, a fertility specialist recommended that the samples of the embryos be tested to see which embryos may have cystic fibrosis given the offspring would have a 1 in 4 chance of having cystic fibrosis. The documentation indicated that the patient underwent testing initially where it was noted that none of the embryos were viable. Additional embryos were tested and only 1 embryo was viable for future pregnancy. The two CPT codes requested for review were: 81228 which was PGT-M, screening for cystic fibrosis, and 88299 which was PGT-A, screening for aneuploidy. As per the American College of Obstetricians and Gynecologists (ACOG), the clinical utility of preimplantation genetic testing-monogenic and preimplantation genetic testing-structural rearrangements is firmly established; however, the best use of preimplantation genetic testing-aneuploidy remains to be determined. Future research is necessary to establish the overall clinical utility for preimplantation genetic testing-aneuploidy, the subset of patients that may benefit from preimplantation genetic testing-aneuploidy, the clinical significance of mosaicism, and residual risk for aneuploidy in preimplantation genetic testing-aneuploidy screened embryos. PGT-M may be considered in this patient since both parents are CF carriers. However, usually the parents have to undergo genetic counseling first to understand whether the results of this testing would change overall health outcome. In this case there was no counseling documented, thus it is unclear whether the testing would change health outcome. Preimplantation genetic testing encompasses preimplantation genetic screening (PGS) and preimplantation genetic diagnosis (PGD). PGS improves success rates of in vitro fertilization by ensuring the transfer of euploid embryos that have a higher chance of implantation and resulting in a live birth. PGD enables the identification of embryos with specific disease-causing mutations and transfer of unaffected embryos. However, ACOG does not support the use of PGT-A at this time. And this patient did not undergo genetic counseling to understand if PGT-M would change the health outcome. ACOG is unclear as to the best use of PGT-A at this time. Thus, the requested service is not likely to be more beneficial than any of the standard treatments/procedures for this patient. The carrier's denial of coverage for CPT codes 88299 [Unlisted cytogenetic study] and 81228 [cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CHG] microarray analysis)]; testing performed should be upheld.

Reviewer#1 Diagnosis: Carrier of cystic fibrosis Treatment: CPT codes 88299 [Unlisted cytogenetic study] and 81228 [cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CHG] microarray analysis)] The insurer denied coverage for CPT codes 88299 [Unlisted cytogenetic study] and 81228 [cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CHG] microarray analysis)]. The denial is upheld. This patient is a female with a history of infertility and cystic fibrosis (CF) carrier. Her partner was also a carrier of cystic fibrosis. To prevent the birth of a child affected by this condition, the patient underwent in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD). CPT 88299 was performed to develop a probe against this couples' mutation. Testing was performed on the cells retrieved from the embryos. Testing was performed to evaluate the embryos for cystic fibrosis status but also for aneuploidy (CPT 81228 and CPT 99000). Of note, the patient was not a carrier of any chromosomal anomaly. According to literature review, CPT codes 88299 [Unlisted cytogenetic study] has final approval from the appropriate regulatory bodies for this diagnosis. CPT code 81228 [cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CHG] microarray analysis)] has final approval from the appropriate regulatory bodies for this diagnosis. Both the patient and her partner are carriers of the cystic fibrosis genes so IVF and PGD was done to prevent the birth of a child affected by this condition. In addition, genetic testing and probe preparation was appropriate prior to proceeding with IVF. Thus, this patient would be considered a good candidate for CPT codes 88299 [Unlisted cytogenetic study] and 81228 [cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CHG] microarray analysis)] as long as 81228 was used to evaluate for cystic fibrosis and not for aneuploidy. The embryos biopsies underwent testing for cystic fibrosis PGT-M (preimplantation genetic testing for monogenic/single gene defects) but also for chromosomal anomaly PGTA (preimplantation genetic testing for aneuploidies formerly known as PGS). While testing the embryos for cystic fibrosis PGT-M was appropriate, there was no indication for PGTA. The patient did not have any chromosomal anomaly and neither the American College of Obstetricians and Gynecologists (ACOG) nor the American Society for Reproductive Medicine (ASRM) recommend routine screening of embryos for aneuploidy prior to transfer. In this case, the code 81228 includes both PGT-M and PGT-A. While PGT-M was required PGT-A is not likely to be more beneficial than any of the standard treatments/procedures for this patient. The carrier's denial of coverage for CPT codes 88299 [Unlisted cytogenetic study] and 81228 [cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CHG] microarray analysis)]; testing performed should be upheld.

1) The Practice Committee of the American Society for Reproductive Medicine (ASRM)

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