In some cases involving a single X-linked disorder, determination of the sex of the embryo provides sufficient information for excluding or confirming the disorder.

This policy does not address the myriad of ethical issues associated with preimplantation genetic testing that should be carefully discussed between the treated individual or couple and the physician.

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. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG1). The Society's nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and 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 PG2 shows the recommended standard terminology-"pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"-to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Genetic counseling is primarily aimed at individuals 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.

Background

Preimplantation Genetic Testing

Preimplantation genetic testing describes various adjuncts to an assisted reproductive procedure (see evidence review 4.02.04) 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, and selective pregnancy termination of affected fetuses. Preimplantation genetic testing is generally categorized as either diagnostic (preimplantation genetic diagnosis) or screening (preimplantation genetic screening). Preimplantation genetic diagnosis 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. Preimplantation genetic screening 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 preimplantation genetic diagnosis when testing for a number of possible abnormalities in the absence of a known disorder), following a terminology change from 'preimplantation genetic screening' to 'preimplantation genetic testing' in 2017.^1,

Biopsy

Biopsy for preimplantation genetic diagnosis 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 1 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. Fluorescent in situ hybridization 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.

A more recent approach for preimplantation genetic screening is with comprehensive chromosome screening using techniques such as array comparative genome hybridization and next generation sequencing.

Embryo Classification

Three general categories of embryos have undergone preimplantation genetic testing, which is discussed in the following subsections.

Embryos at Risk for a Specific Inherited Single-Gene 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 preimplantation genetic diagnosis 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, preimplantation genetic diagnosis is used to deselect male embryos, half of which would be affected. Preimplantation genetic diagnosis could also be used to deselect affected male embryos. While there is a growing list of single-gene defects for which molecular diagnosis is possible, the most common indications include cystic fibrosis, β-thalassemia, muscular dystrophy, Huntington disease, hemophilia, and fragile X disease. It should be noted that when preimplantation genetic diagnosis 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 preimplantation genetic diagnosis. In this setting, preimplantation genetic diagnosis 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 those with recurrent spontaneous abortions. Preimplantation genetic diagnosis 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, preimplantation genetic screening has been explored as a technique to deselect aneuploid oocytes in older women and is also known as preimplantation genetic diagnosis for aneuploidy screening. Analysis of extruded polar bodies from the oocyte or no blastomeres at day 3 of embryo development using FISH was initially used to detect aneuploidy. A limitation of FISH is that analysis is restricted to a number of proteins. More recently, newer preimplantation genetic screening methods have been developed. 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, preimplantation genetic screening has been proposed for women with repeated implantation failures.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.