Code Description CPT
81200 ASPA (aspartoacylase) (eg, Canavan disease) gene analysis, common variants (e.g., E285A, Y231X)
81223 CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; full gene sequence
81255 HEXA (hexosaminidase A [alpha polypeptide]) (eg, Tay-Sachs disease) gene analysis, common variants (eg, 1278insTATC, 1421+1G>C, G269S)
81257 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis, for common deletions or variant (eg, Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2,
81599 Unlisted multianalyte assay with algorithmic analysis
89290 Biopsy, oocyte polar body or embryo blastomere, microtechnique (for preimplantation genetic diagnosis); less than or equal to 5 embryos
89291 Biopsy, oocyte polar body or embryo blastomere, microtechnique (for preimplantation genetic diagnosis); greater than 5 embryos
89398 Unlisted reproductive medicine laboratory procedure
Specific CPT codes describe the embryo biopsy procedure (89290-89291). Additional CPT codes will be required for the genetic analysis and will vary by technique used to perform the genetic analysis.
Preimplantation Genetic Testing in Embryos
In vitro fertilization is the process of combining eggs and sperm in a lab dish to create a fertilized egg (an embryo) and later implanting it into the uterus to complete the pregnancy. Before implantation, one or more cells from the embryo may be tested to see if there are problems with its genes or chromosomes. “Preimplantation genetic diagnosis” testing looks at the genes to see if the embryo carries a genetic disease such as cystic fibrosis. “Preimplantation genetic screening” looks to see if there are too few or too many chromosomes. This policy describes when either type of preimplantation genetic testing may be considered medically necessary.
Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.
Policy Coverage Criteria
Procedure Medical Necessity
Preimplantation genetic diagnosis (PGD)
The procedure to obtain the cell sample for PGD (ie, the embryo biopsy) is considered medically necessary when the criteria below for PGD are met. However, the IVF procedure (ie, the procedures and services, including intracytoplasmic sperm injection [ICSI], required to create the embryos to be tested and the transfer of the appropriate embryos back to the uterus after testing) is covered only for persons with assisted fertility benefits for IVF. Please check the member contract and benefit descriptions for coverage of assisted fertility techniques such as IVF. Preimplantation genetic diagnosis (PGD) may be considered medically necessary as an alternative to amniocentesis or chorionic villus sampling in couples undergoing IVF who meet one of the following criteria: * For evaluation of an embryo at an identified elevated risk of a
genetic disorder such as when: o Both partners are known carriers of a single-gene
autosomal recessive disorder o One partner is a known carrier of a single-gene autosomal
recessive disorder and the partners have an offspring who has been diagnosed with that recessive disorder
o One partner is a known carrier of a single-gene autosomal dominant disorder
o One partner is a known carrier of a single X-linked disorder OR * For evaluation of an embryo at an identified elevated risk of
structural chromosomal abnormality such as if one parent has a balanced or unbalanced chromosomal translocation.
Procedure Medical Necessity
Preimplantation genetic screening (PGS), gender selection
Note: When the specific criteria noted above are met, the Plan will cover the embryo biopsy procedure to obtain the cell and genetic test associated with PGD under the medical benefit.
Preimplantation genetic screening (PGS) is considered not medically necessary when testing embryos solely for nonmedical gender selection or selection of other nonmedical traits.
Preimplantation genetic diagnosis (PGD)
Preimplantation genetic screening (PGS)
Preimplantation genetic diagnosis (PGD) as an alternative to amniocentesis or chorionic villus sampling is considered investigational in patients/couples who are undergoing IVF in all situations other than those specified above.
Preimplantation genetic screening (PGS) as an alternative to amniocentesis or chorionic villus sampling is considered investigational in patients/couples who are undergoing IVF in all situations when used to screen for potential genetic abnormalities in couples without a specific known inherited disorder.
In some cases involving a single X-linked disorder, determination of the gender of the embryo provides sufficient information for excluding or confirming the disorder.
The severity of the genetic disorder is also a consideration. At present, many cases of preimplantation genetic diagnosis (PGD) have involved lethal or severely disabling conditions with limited treatment opportunities, such as Huntington chorea or Tay-Sachs disease. Cystic fibrosis is another condition for which PGD has been frequently performed. However, cystic fibrosis has a variable presentation and can be treatable. The range of genetic testing that is performed on amniocentesis samples as a possible indication for elective abortion may serve as a guide.
This policy does not address the myriad ethical issues associated with preimplantation genetic testing (PGT) that, it is hoped, have involved careful discussion between the treated couple and the physician. For some couples, the decision may involve the choice between the risks of an in vitro fertilization procedure and deselection of embryos as part of the PGT treatment versus normal conception with the prospect of amniocentesis and an elective abortion.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.
Table 1. Nomenclature to Report on Variants Found in DNA Previous Updated Definition
Mutation Disease-associated variant Disease-associated change in the DNA sequence Variant Change in the DNA sequence
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex.
Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Preimplantation genetic testing (PGT) involves analysis of biopsied cells as part of an assisted reproductive procedure. It is generally considered to be divided into 2 categories:
1. Preimplantation genetic diagnosis (PGD) is used to detect a specific inherited disorder in conjunction with in vitro fertilization (IVF) and aims to prevent the birth of affected children to couples at high risk of transmitting a disorder
2. Preimplantation genetic screening (PGSin conjunction with in vitro fertilization (IVF) involves testing for potential genetic abnormalities for couples without a specific known inherited disorder.
Preimplantation Genetic Testing
Preimplantation genetic testing (PGT) describes various adjuncts to an assisted reproductive procedure in which either maternal or embryonic DNA is sampled and genetically analyzed, thus permitting deselection of embryos harboring a genetic defect before implantation of an embryo into the uterus. The ability to identify preimplantation embryos with genetic defects before implantation provides an alternative to amniocentesis, chorionic villus sampling(CVS), and selective pregnancy termination of affected fetuses. Preimplantation genetic testing is generally categorized as either diagnostic (preimplantation genetic diagnosis [PGD]) or screening (preimplantation genetic screening [PGS]). PGD is used to detect genetic evidence of a specific inherited disorder, in the oocyte or embryo, derived from mother or couple, respectively, that has a high risk of transmission. PGS is not used to detect a specific abnormality but instead uses similar techniques to identify a number of genetic abnormalities in the absence of a known heritable disorder. This terminology, however, is not used consistently (eg, some authors use PGD when testing for a number of possible abnormalities in the absence of a known disorder).
Biopsy for PGD can take place at 3 stages: the oocyte, cleavage stage embryo, or the blastocyst. In the earliest stage, both the first and second polar bodies are extruded from the oocyte as it completes the meiotic division after ovulation (first polar body) and fertilization (second polar body). This strategy thus focuses on maternal chromosomal abnormalities. If the mother is a known carrier of a genetic defect and genetic analysis of the polar body is normal, then it is assumed that the genetic defect was transferred to the oocyte during meiosis.
Biopsy of cleavage stage embryos or blastocysts can detect genetic abnormalities arising from either the maternal or paternal genetic material. Cleavage stage biopsy takes place after the first few cleavage divisions when the embryo is composed of 6 to 8 cells (ie, blastomeres). Sampling involves aspiration of one and sometimes 2 blastomeres from the embryo. Analysis of 2 cells may improve diagnosis but may also affect the implantation of the embryo. In addition, a potential disadvantage of testing at this phase is that mosaicism might be present. Mosaicism refers to genetic differences among the cells of the embryo that could result in an incorrect interpretation if the chromosomes of only a single cell are examined.
The third option is sampling the embryo at the blastocyst stage when there are about 100 cells. Blastocysts form 5 to 6 days after insemination. Three to 10 trophectoderm cells (outer layer of the blastocyst) are sampled. A disadvantage is that not all embryos develop to the blastocyst phase in vitro and, when they do, there is a short time before embryo transfer needs to take place. Blastocyst biopsy has been combined with embryonic vitrification to allow time for test results to be obtained before the embryo is transferred.
Analysis and Testing
The biopsied material can be analyzed in a variety of ways. Polymerase chain reaction or other amplification techniques can be used to amplify the harvested DNA with subsequent analysis for single genetic defects. This technique is most commonly used when the embryo is at risk for a specific genetic disorder such as Tay-Sachs disease or cystic fibrosis. Fluorescent in situ hybridization (FISH) is a technique that allows direct visualization of specific (but not all) chromosomes to determine the number or absence of chromosomes. This technique is most commonly used to screen for aneuploidy, sex determination, or to identify chromosomal translocations. FISH cannot be used to diagnose single genetic defect disorders. However, molecular techniques can be applied with FISH (eg, microdeletions, duplications) and, thus, single-gene defects can be recognized with this technique. Performing PGS using FISH is known as PGS version 1.
Another more recent approach is array comparative genome hybridization testing at either the 8-cell or, more often, the blastocyst stage, also known as PGS version 2. Unlike FISH analysis, hybridization allows for 24 chromosome aneuploidy screening, as well as more detailed screening for unbalanced translocations and inversions and other types of abnormal gains and losses of chromosomal material. Other PGS version 2 methods include single nucleotide variant microarrays and quantitative polymerase chain reaction.
Next-generation sequencing such as massively parallel signature sequencing has potential applications to prenatal genetic testing and is grouped with PGS version 2 techniques in some literature and referred to as PGS version 3 in other literature.
Three general categories of embryos have undergone preimplantation genetic testing, which are discussed in the following subsections.
Embryos at Risk for a Specific Inherited Single Genetic Defect
Inherited single-gene defects fall into 3 general categories: autosomal recessive, autosomal dominant, and X-linked. When either the mother or father is a known carrier of a genetic defect, embryos can undergo PGD to deselect embryos harboring the defective gene. Sex selection of a female embryo is another strategy when the mother is a known carrier of an X-linked disorder for which there is no specific molecular diagnosis. The most common example is female carriers of fragile X syndrome.
In this scenario, PGD is used to deselect male embryos, half of which would be affected. PGD could also be used to deselect affected male embryos. While there is a growing list of single genetic defects for which molecular diagnosis is possible, the most common indications include cystic fibrosis, ß-thalassemia, muscular dystrophy, Huntington disease, hemophilia, and fragile X disease. It should be noted that when PGD is used to deselect affected embryos, the treated couple is not technically infertile but is undergoing an assisted reproductive procedure for the sole purpose of PGD. In this setting, PGD may be considered an alternative to selective termination of an established pregnancy after diagnosis by amniocentesis or chorionic villus sampling.
Embryos at a Higher Risk of Translocations
Balanced translocations occur in 0.2% of the neonatal population but at a higher rate in infertile couples or in those with recurrent spontaneous abortions. PGD can be used to deselect embryos carrying the translocations, thus leading to an increase in fecundity or a decrease in the rate of spontaneous abortion.
Identification of Aneuploid Embryos
Implantation failure of fertilized embryos is common in assisted reproductive procedures; aneuploidy of embryos is thought to contribute to implantation failure and may also be the cause of recurrent spontaneous abortion. The prevalence of aneuploid oocytes increases in older women. These age-related aneuploidies are mainly due to nondisjunction of chromosomes during maternal meiosis. Therefore, PGS has been explored as a technique to deselect aneuploid oocytes in older women and is also known as PGD for aneuploidy screening. FISH analysis of extruded polar bodies from the oocyte or no blastomeres at day 3 of embryo development was initially used to detect aneuploidy (PGS version 1). A limitation of FISH is that analysis is limited to a restricted number of proteins. More recently, newer PGS methods have been developed and are known collectively as PGS version 2. These methods allow for all chromosomes analysis with genetic platforms including array comparative genomic hybridization and single-nucleotide variant chain reaction analysis. Moreover, in addition to older women, PGS has been proposed for women with repeated implantation failures.