Preimplantation genetic diagnosis_oct_11

Preimplantation Genetic Diagnosis Oct 11 1
National Medical Policy
Subject: Preimplantation Genetic Diagnosis in Assisted Reproduction
Policy Number: NMP245
Effective Date*: October 2005
Updated: November 2006, November 2007, February 2011, October 2011
This National Medical Policy is subject to the terms in the
IMPORTANT NOTICE
at the end of this document
The Centers for Medicare & Medicaid Services (CMS)
For Medicare Advantage members please refer to the following for coverage guidelines first:
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Source
Reference/Website Link
National Coverage Determination (NCD)
National Coverage Manual Citation
Local Coverage Determination (LCD)
Article (Local)
X
Other
CMS Manual System. Adjudication of Laboratory Tests that are Excluded from Clinical Laboratory Improvement Amendment (CLIA) Edits. (CPT Codes noted)
https://www.cms.gov/transmittals/downloads/R882OTN.pdf
None
Use Health Net Policy
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Current Policy Statement (Update October 2011 – A Medline search failed to reveal any studies that would cause Health Net, Inc. to change its current position)
Many benefit plans specifically exclude in vitro fertilization (IVF) and related procedures. Health Net does not cover IVF services associated with preimplantation genetic diagnosis (PGD) unless the plan specifically covers IVF.
Health Net, Inc. considers preimplantation genetic diagnosis (PGD) as an adjunct to in vitro fertilization (IVF) medically necessary to deselect embryos affected by flawed genetic make-up, when the results of the genetic test will impact clinical decision making and/or clinical outcome, and any of the following are met:
1. Women > 35 years of age to test for suspected aneuploidy - one or a few chromosomes above or below the normal chromosome number, e.g., three number 21 chromosomes or trisomy 21 (characteristic of Down syndrome) is a form of aneuploidy.
2. Couples at high risk for aneuploid pregnancy (e.g., prior aneuploid pregnancy)
3. Couples at high risk for single gene disorders* who meet any of the following:
 One partner has the diagnosis, is a known carrier or has a family history of a single gene, autosomal dominant chromosomal disorder
 Both partners are known carriers of a single gene autosomal recessive chromosomal disorder
 One partner is a known carrier of a single X-linked disorder
4. Couples who already have one child with a genetic problem and are at high risk of having another
5. There have been three or more prior failed attempts at IVF
6. Women with > 2 miscarriages (recurrent pregnancy losses) related to parental structural chromosome abnormality
7. Repeated implantation failure defined as the absence of a gestational sac on ultrasound at 5 weeks post-embryo transfer (e.g., > 3 embryo transfers with high quality embryos or the transfer of 10 embryos in multiple transfers)
8. To determine the sex of an embryo only when there is a documented history of an X-linked disorder, such that deselection of an affected embryo can be made on the basis of sex alone.
9. To evaluate human leukocyte antigen (HLA) status in families with a child with a malignant cancer or genetic disorder who is likely to be cured or whose life expectancy is expected to be substantially prolonged by a cord blood stem cell transplant after all other clinical options have been exhausted, and in whom there is no other source of a compatible bone marrow donor other than an HLA matched sibling.

*Note: Single gene disorders include autosomal recessive diseases (e.g., cystic fibrosis, beta-thalassemia, Tay-Sachs), autosomal dominant diseases (e.g., Marfan's syndrome, myotonic dystrophy) and X-linked diseases (e.g., Duchenne and Becker's muscular dystrophy, hemophilia, fragile-X syndrome).
Note: When the specific criteria noted above are met, we consider the polar
body biopsy / cleavage stage embryo biopsy procedure to obtain the cell and the genetic test associated with PGD medically necessary.
List of Genetically Determined Disorders
Achondroplasia
Adenosine deaminase deficiency
Alpha-1-antitrypsin deficiency
Beta thalassemia
Cystic fibrosis
Epidermolysis bullosa
Fanconi anemia
Gaucher disease
Hemophilia A and B
Huntington disease
Muscular dystrophy (Duchenne and Becker)
Ornithine transcarbamylase (OTC) deficiency
Neurofibromatosis type I
Myotonic dystrophy
Phenylketonuria
Retinoblastoma
Retinitis pigmentosa
Sickle cell disease
Spinal muscular atrophy
Tay Sachs disease
Fragile X syndrome
Lesch-Nyhan syndrome
Rett syndrome
Charcot-Marie-Tooth disease
Barth's syndrome
Turner syndrome
Down's syndrome
Health Net, Inc. considers PGD not medically necessary for any of the following because there is a paucity of peer-reviewed studies:
1. The genetic code associated with the condition is not known to allow diagnosis with current genetic testing techniques
2. Genetic diagnosis is uncertain, e.g., due to genetic/molecular heterogeneity or uncertain mode of inheritance
3. PGD for the purposes of carrier testing to determine carrier status of the embryo (determination of carrier status is performed on individuals contemplating reproduction)
4. PGD for adult-onset/late-onset disorders (e.g., Alzheimer's disease; cancer predisposition)
Health Net, Inc. considers PGD investigational for any of the following because although studies continue to be done, additional peer-reviewed studies are necessary to determine the safety, efficacy and long-term outcomes for these scenarios:

1. PGD for the purpose of HLA typing of an embryo to identify a future suitable stem cell, tissue or organ transplantation donor; PGD has not been established as the standard of care for assessing the suitability of embryos for stem cell transplantation.
2. Testing of embryos for non-medical gender selection or non-medical traits
3. The affected or sick child has an acute medical condition prohibiting safe stem cell transplantation or has extremely low life expectancy, such that there isn‟t enough time for the PGD test to be developed, applied and the birth of the HLA- matched sibling.
Codes Related To This Policy
ICD-9 Codes
270.0-279.9 Other metabolic and immunity disorders
277.00-277.09 Cystic fibrosis
282.41-282.49 Thalassemias
282.60-282.69 Sickle-cell disease
284.0 Constitutional aplastic anemia
298.81 Primary hypercoagulable state
330.1 Cerebral lipidoses
359.0 Congenital hereditary muscular dystrophy
359.1 Hereditary progressive muscular dystrophy
653.70 Other fetal abnormality causing disproportion; unspecified as to episode of care or not applicable, delivered, with or without mention of antepartum condition, or antepartum condition or complication
655.00-655.90 Known or suspected fetal abnormality affecting management of mother; unspecified as to episode of care or not applicable, delivered, with or without mention of antepartum condition, or antepartum condition or complication
569.89.1 Elderly primigravida; unspecified as to episode of care or not
applicable, delivered, with or without mention of antepartum condition, or antepartum condition or complication
659.60, 1, 3 Elderly multigravida
741.00-742.9 Spina bifida and other congenital anomalies of nervous system
758.0 - 758.9 Chromosomal anomalies
759.82 Marfan syndrome
793.9 Other nonspecific abnormal findings on radiological and other examination of body structure
V17.2 Family history of other neurological diseases
V18.1 Family history of other endocrine and metabolic diseases
V18.2 Family history of anemia
V18.3 Family history of other blood disorders
V18.4 Family history of mental retardation
V19.5 Family history of congenital anomalies
V19.8 Family history of other condition
V23.81 Supervision of elderly primigravida
V23.82 Supervision of elderly multigravida
V23.89 Supervision of other high-risk pregnancy
V28.0 Screening for chromosomal anomalies by amniocentesis

V28.1 Screening for raised alpha-fetoprotein levels in amniotic fluid
V28.2 Other screening based on amniocentesis
V28.8 Other specified antenatal screening
V82.4 Maternal postnatal screening for chromosomal anomalies
V83.31 Cystic fibrosis gene carrier
V83.89 Other genetic carrier status
CPT Codes
83898 Molecular diagnostics; amplification of patient nucleic acid (e.g. PCR, LCR), single primer pair, each primer pair
88365 Tissue in situ hybridization, interpretation and report
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
HCPCS Codes
S3625 Maternal serum triple marker screen including alpha-fetoprotein (AFP), estriol, and human chorionic gonadotropin (hCG)
S3835 Complete gene sequence analysis for cystic fibrosis genetic testing
S3837 Complete gene sequence analysis for hemochromatosis genetic testing
S3840 DNA analysis for germline mutations of the ret proto-oncogene for susceptibility to multiple endocrine neoplasia type 2
S3841 Genetic testing for retinoblastoma
S3842 Genetic testing for von Hippel-Lindau disease
S3843 DNA analysis of the F5 gene for susceptibility to Factor V Leiden thrombophilia
S3845 Genetic testing for alpha-thalassemia
S3846 Genetic testing for hemoglobin E beta-thalassemia
S3847 Genetic testing for Tay-Sachs disease
S3848 Genetic testing for Gaucher disease
S3849 Genetic testing for Niemann-Pick disease
S3851 Genetic testing for Canavan disease
S3853 Genetic testing for myotonic muscular dystrophy
S4011-S4022 In vitro fertilization
Scientific Rationale Update – October 2011
Colls et al. (2009) Preimplantation genetic diagnosis (PGD) for gender selection for non-medical reasons has been considered an unethical procedure by several authors and agencies in the Western society on the basis that it could disrupt the sex ratio, that it discriminates against women and that it leads to disposal of normal embryos of the non-desired gender. In this study, the analysis of a large series of PGD procedures for gender selection from a wide geographical area in the USA shows that, in general, there is no deviation in preference towards any specific gender except for a preference of males in some ethnic populations of Chinese, Indian and Middle Eastern origin that represent a small percentage of the US population. In cases where only normal embryos of the non-desired gender are available, 45.5% of the couples elect to cancel the transfer, while 54.5% of them are open to have embryos transferred of the non-desired gender, this fact being strongly linked to cultural and ethnic background of the parents. In addition this study adds some

evidence to the proposition that, in couples with previous children of a given gender, there is no biological predisposition towards producing embryos of that same gender.
El-Toukhy et al. (2010) completed a review to inform the clinician about the application, success rates and limitations of preimplantation genetic diagnosis (PGD) for hematologic disease to enable clinicians to offer couples with reproductive risk a realistic view of possible treatments. The history and ethics involved in performing PGD together with human leukocyte antigen (HLA) testing (PGD-H) to create matched siblings suitable for hematopoietic stem cell transplant (HSCT) are discussed. The greatest diagnostic hurdle in PGD is the paucity of molecular material in the single embryonic cell. PGD to exclude embryos carrying serious hematologic disease is a viable alternative to prenatal diagnosis for couples whom wish to avoid having affected children and for whom therapeutic termination of affected pregnancies is unacceptable. PGD is not available for all hematologic mutations, is expensive, time consuming and does not guarantee a pregnancy. PGD-H is more diagnostically and ethically challenging, especially when there is the time constraint of urgent provision of HLA-matched stem cells for a sick sibling. To date there is only a handful of reported cases of successful HSCT from siblings created by embryo selection.
Pre-implantation genetic diagnosis (PGD) has been proposed as a method for selecting HLA-matched embryos in order to create a tissue matched child that can serve as a stem cell donor. After delivery of the HLA-matched baby, umbilical cord blood (UCB) cells can be collected and cryopreserved for transplantation to the sick sibling or the affected child. Using pre-implantation HLA typing to have a tissue- matched child that can serve as a haematopoietic stem cell donor to save a loved one‟s life. This is generally known as the creation of „saviour siblings‟. Haematopoietic stem cells are found in the umbilical cord blood, bone marrow and peripheral blood. Despite recent promising results of using stem cells from the umbilical cord blood of so called saviour siblings for curing patients with blood diseases and certain types of cancer, this method has been met with much opposition. Concerns related to the risks of preimplantation genetic diagnosis (PGD) for the child to be born, the intention to have a donor child, the limits that should be placed on what cells or organs can be used from the child and whether the recipient can be someone other than a sibling). Preimplantation tissue typing has been proposed as a method for creating a tissue matched child that can serve as a haematopoietic stem cell donor to save its sick sibling in need of a stem cell transplant. Despite recent promising results, many people have expressed their disapproval of this method.
Scientific Rationale Update – February 2011
Tay Sachs Disease
Per Hayes Genetic Testing Overview, (2008) “New molecular technologies for gene amplification and detection are emerging. These new technologies may improve preimplantation genetic diagnosis of Tay Sachs Disease (TSD), which employ single cells to detect specific alleles on single chromosomes”. In order to develop a reliable, robust test to generate stronger signals for single-cell preimplantation genetic diagnosis of TSD, a new single-reaction primer system to amplify two mutation sites
simultaneously was developed. New nested primers were designed to optimize detection of two major TSD mutations. Based on PCR-amplified product analysis, a total efficiency of amplification was 85.3%, with an allele dropout rate (ADO) of 4.8% and 5.8% for both mutations. Although there is no evidence to suggest that

DNA mutation analysis would not be feasible for standard prenatal diagnosis or for preimplantation analysis prior to implantation of embryos during assisted
reproduction, no clinical trials addressing this application were identified in the literature search.
Per Hayes, the genetic test overview of the „Ashkenazi Jewish Genetic Screening Panel for Risk Assessment‟:
 For the inclusion of Tay-Sachs disease – Rated „A‟ for the Hayes Genetic Test Rating. (i.e. A - Established benefit. A high level of positive published evidence regarding safety and efficacy supports use of the technology for the cited application(s). Drugs, biologics, and devices with an A rating have FDA approval, but not necessarily for the specific clinical application).
Altaruscu et al. (2007) Preimplantation genetic diagnosis (PGD) for single gene defects is described for a family in which each parent is a carrier of both Tay-Sachs (TS) and Gaucher disease (GD). A multiplex fluorescent polymerase chain reaction protocol was developed that simultaneously amplified all four familial mutations and 10 informative microsatellite markers. In one PGD cycle, seven blastomeres were analysed, reaching a conclusive diagnosis in six out of seven embryos for TS and in five out of seven embryos for GD. Of the six diagnosed embryos, one was wild type for both TS and GD, and three were wild type for GD and carriers of TS. Two remaining embryos were compound heterozygotes for TS. Two transferable embryos developed into blastocysts (wt/wt and wt GD/carrier TS) and both were transferred on day 5. This single cycle of PGD resulted in a healthy live child. Allele drop-out (ADO) was observed in three of 34 reactions, yielding an 8% ADO rate. The occurrence of ADO in single cell analysis and undetected recombination events are primary causes of misdiagnosis in PGD and emphasize the need to use multiple polymorphic markers. So far as is known, this is the first report of concomitant PGD for two frequent Ashkenazi Jewish recessive disorders.
Fragile X Syndrome
Per Hayes (2008) Current evidence suggests that the use of the genetic test to identify carriers of the premutation, or for preimplantation and prenatal genetic testing may benefit carriers and assist family planning. There is no evidence for the clinical utility of a general population-screening program.
Preimplantation and prenatal genetic testing for fragile X syndrome has been investigated in several studies that provide sufficient evidence to support the validity of the test. Furthermore, there is evidence that prenatal genetic testing informs decision-making and provides the option of terminating affected pregnancies. Successful unaffected pregnancies have also been achieved using preimplantation genetic diagnosis.
Hayes rating for genetic testing for fragile x syndrome:
 B – for preimplantation testing for CGG repeat length in embryos from carrier mothers with a known premutation in the FMR1 gene.
Malcov et al. (2007) Fragile X syndrome is caused by a dynamic mutation in the FMR1 gene. Normal individuals have <55 CGG repeats in the 5 untranslated region, premutation carriers have 55-200 repeats and a full mutation has >200 repeats. Female carriers are at risk of having affected offspring. A multiplex nested polymerase chain reaction protocol is described for preimplantation genetic diagnosis (PGD) of fragile X syndrome with simultaneous amplification of the CGG-repeat

region, the Sry gene and several flanking polymorphic markers. The amplification efficiency was > or =96% for all loci. The allele dropout rate in heterozygotic females was 9% for the FMR1 CGG-repeat region and 5-10% for the polymorphic markers. Amplification failure for Sry occurred in 5% of single leukocytes isolated from males. PGD was performed in six patients who underwent 15 cycles. Results were confirmed in all cases by amniocentesis or chorionic villous sampling. Five clinical pregnancies were obtained (31% per cycle), four of which resulted in a normal delivery and one miscarried. This technique is associated with high efficiency and accuracy and may be used in carriers of full mutations and unstable high-order premutations.
Spinal Muscular Atrophy (SMA)
Hayes (2008) Prenatal diagnosis is typically performed by PCR-RFLP, but may also involve sequence analysis and/or linkage studies. To avoid false-negative results, testing for maternal cell contamination is often performed by analysis of polymorphic markers. Preimplantation genetic diagnosis (PGD) has also been carried out using PCR-RFLP or allele-specific PCR.
The confirmation of SMA in an individual by genetic testing may also affect the reproductive decision-making of family members. Meldrum et al. (2007) inquired about the effect of a child‟s SMA diagnosis on the future reproductive decisions of the parents. Of 103 respondents questioned in this retrospective analysis, 53% reported that they chose to limit future pregnancies, while 21% chose to undergo prenatal diagnosis in a subsequent pregnancy, either by CVS, amniocentesis, and/or PGD. In addition to affecting future pregnancies, families perceived that the genetic diagnosis of SMA also helped them connect with appropriate support resources.
A total of 11 open studies involving SMA patients are listed on the ClinicalTrials.gov website. Of these, 9 are designed to study disease progression, prognosis, or treatment. Two studies are examining specific methodologies for the genetic diagnosis of SMA; these are listed below:
 Quantitative Analysis of SMN1 and SMN2 Gene Based on DHPLC System: Establishing a Novel Highly Efficient and Reliable SMA Carrier Screening Test (NCT00155168)
 Establishing Novel Detection Techniques for Various Genetic-Related Diseases by Applying DHPLC Platform (NCT00154960)
Hayes (2009) rates Spinal Muscular Atrophy (SMA) for Progressive Muscle Weakness as noted below:
 For the prenatal diagnosis or preimplantation genetic diagnosis of SMA in the pregnancy of two known carriers – Rated as B
Giardet et al. (2008) Two multiplex PGD protocols were developed allowing the detection of the common homozygous deletion of the telomeric spinal muscular atrophy gene (SMN1), together with two microsatellites located on each side of SMN1. The molecular genetics laboratory of the university hospital in Montpellier. PATIENT(S): A couple who had already given birth to a child affected with SMA.) In vitro fertilization using intracytoplasmic sperm injection (ICSI) and blastomere biopsy. MAIN OUTCOME MEASURE(S): Improvement of PGD for SMA. Two different multiplex protocols were set up on 81 (multiplex A) and 64 single cells (multiplex B) from normal controls, affected patients, and individuals with homozygous SMN2 deletion. In one PGD cycle that used one of these protocols, two embryos were

transferred, which resulted in the birth of a healthy baby. Analysis of microsatellite markers in addition to the SMN1 deletion allows the detection of contamination, the study of ploidy of the biopsied blastomeres, and the performance of an indirect genetic diagnosis, thereby increasing the reliability of the results. This PGD assay may be applied to all families with the common deletion of SMN1 and also to couples in whom one of the partners carries a small intragenic mutation in SMN1, identified in about 6% of affected individuals who do not lack both copies of SMN1.
Shaw et al. (2008) Thirty-three members of 7 families participated in carrier test and disease detection of SMA. Prenatal genetic diagnosis was performed if both parents were carriers or any family members had SMA. DNA extracted from blood, chorionic villi and amniotic fluid was amplified and used for DHPLC. Twenty SMA carriers, seven SMA affected cases, and six normal individuals were identified. SMA status was demonstrated by genotyping and total copy number determinations of SMN1 and SMN2. Families 1-3 were classified as group one (SMA affecting previously born child). Group two, comprising families 4 and 5, had lost a child due to an unknown muscular disease. Group three (SMA-affected parent) comprised families 6 and 7; carrier testing was done. DHPLC prenatal genetic diagnosis was made in seven pregnancies, one in each family (affected, n=2; carrier, n=3; normal, n=2). Pregnancy was terminated for the two affected fetuses. The others were delivered uneventfully and SMA free. DHPLC prenatal diagnosis of SMA and determination of SMA status in adults is possible, and SMN1 and SMN2 copy numbers can be determined.
Alpha-1-antitrypsin deficiency
Alpha-1 antitrypsin (AAT) deficiency emphysema is an inherited disorder affecting approximately 100,000 Americans. Affected patients have little or no blood and tissue levels of AAT (also called alpha-1 protease inhibitor, alpha1-PI, or A1-PI), which protects the lung from destruction by enzymes in the lung that normally digest bacteria and other invaders. Unchecked, this enzyme progressively damages healthy lung tissue leading to decreased lung function and emphysema. The prognosis for patients with high-risk phenotypes for AAT deficiency emphysema is poor although symptomatic treatments and more definitive lung surgery are options.
Cystic Fibrosis
Norton et al. (2008) Recent advances in genetic technology have substantial implications for prenatal screening and diagnostic testing. The past year has also seen important changes in recommendations surrounding the genetic counseling that occurs in the provision of such testing. Multiple screening tests for single gene disorders, chromosomal abnormalities, and structural birth defects are now routinely offered to all pregnant women. Ethnicity-based screening for single gene disorders includes Tay Sachs disease, cystic fibrosis, and hemoglobinopathies. Recent discussions have involved, not only additional disorders that warrant screening, but a re-evaluation of the paradigm of selecting disorders for population-based screening. Testing for chromosomal abnormalities has seen the introduction of first-trimester screening, as well as strategies to improve detection through sequential testing. Changes in recommendations for screening compared with diagnostic testing, and a move away from maternal age-based dichotomizing of testing, have had major implications for provision of genetic counseling by providers of prenatal care. Advances in genetic testing have resulted in tremendous benefits to patients, and challenges to providers. New approaches to education and counseling are needed to assure that all patients receive a complete and balanced review of their prenatal genetic-testing options.

Fanconi Anemia
Modern Ashkenazi Jewish (AJ) populations (Ashkenazic Jews or Ashkenazim) descended from the Jewish communities of Germany, Poland, Austria, and Eastern Europe. Approximately 90% of the 5.7 million individuals of Jewish descent in the USA today are of AJ origin. Certain childhood-onset autosomal recessive genetic disorders are more common among the AJ community including Tay-Sachs disease, Canavan disease, familial dysautonomia, Bloom syndrome, Fanconi anemia group C, Gaucher disease, mucolipidosis type IV, Niemann-Pick disease type 1A, cystic fibrosis, and primary dystonia type 1 (torsion dystonia). Over the last few decades, the molecular basis of these diseases has been elucidated providing the tools and the opportunity to perform preconceptual carrier screening for these disorders in this ethnic group. The relatively homogeneous genetic make-up of the AJ population has resulted in there being a relatively limited number of disease-causing sequence variants accounting for the majority of cases of each disease which has allowed for the development of screening panels with a high level of sensitivity and specificity for the AJ population. As a result of the autosomal recessive mode of inheritance for these disorders, if both members of a couple are carriers, they have a 25% chance of having a child with the disorder. Fifteen autosomal recessive disorders were reviewed in order to determine whether or not they should be included in an AJ screening panel. The 15 disorders are: alpha-1-antitrypsin deficiency (AAD), Bloom syndrome (BLM), Canavan disease (CD), CF, deafness neurosensory autosomal recessive 1 (DFNB1), FD, familial hyperinsulinism (FHI), Fanconi anemia type C (FAC), Gaucher disease type 1 (GD), glycogen storage disease type 1A (GSD), maple syrup urine disease type 1b (MSUD), mucolipidosis type IV (MLIV), Niemann-Pick disease types A and B (NPDA&B), nonclassical congenital adrenal hyperplasia (NCAH), and Tay-Sachs disease (TSD). There is controversy, however, surrounding which diseases should be included in such screening panels. While serious, generally fatal disorders such as Tay-Sachs disease and Canavan disease are clear candidates for screening; the argument is not as clear for disorders with variable clinical presentation and reduced penetrance such as Gaucher disease or primary dystonia.
Fares et al. (2008) completed a study, with a database containing the results of 410 genotyping assays was screened. Ten thousand seventy eight nonselected healthy members of the AJ population were tested for carrier status for the following diseases; Gaucher disease (GD), cystic fibrosis (CF), Familial dysautonomia (FD), Alpha 1 antitrypsin (A1AT), Mucolipidosis type 4 (ML4), Fanconi anemia type C (FAC), Canavan disease (CD), Neimann-Pick type 4 (NP) and Bloom syndrome (BLM). The results demonstrated that 635 members were carriers of one mutation and 30 members were found to be carriers of two mutations in the different genes related to the development of the above mentioned diseases. GD was found to have the highest carrier frequency (1:17) followed by CF (1:23), FD (1:29), A1AT (1:65), ML4 (1:67) and FAC (1:77). The carrier frequency of CD, NP and BLM was 1:82, 1:103 and 1:157, respectively. The frequency of the disease-causing mutations screened routinely among the AJ population indicated that there are rare mutations with very low frequencies. The screening policy of the disease-causing mutations should be reevaluated and mutations with a high frequency should be screened, while rare mutations with a lower frequency may be tested in partners of carriers.
Hemophilia A for Hemophilia A/Factor 8 Deficiency
Laurie et al. (2010) Preimplantation genetic diagnosis (PGD) is an option for couples at risk of having a child with hemophilia A (HA). Although many clinics offer PGD for HA by gender selection, an approach that detects the presence of the underlying F8

mutation has several advantages. The objection was to develop and validate analysis protocols combining indirect and direct methods for identifying F8 mutations in single cells, and to apply these protocols clinically for PGD. A panel of microsatellite markers in linkage disequilibrium with F8 were validated for single-cell multiplex polymerase chain reaction. For point mutations, a primer extension genotyping assay was included in the multiplex. Amplification efficiency was evaluated using buccal cells and blastomeres. Four clinical PGD analyses were performed, for two families. Results: Across all validation experiments and the clinical PGD cases, approximately 80% of cells were successfully genotyped. Following one of the PGD cycles, healthy twins were born to a woman who carries the F8 intron 22 inversion. The PGD analysis for the other family was complicated by possible germline mosaicism associated with a de novo F8 mutation, and no pregnancy was achieved. Conclusions: PGD for the F8 intron 22 inversion using microsatellite linkage analysis was validated by the birth of healthy twins to one of the couples. The other family's situation highlighted the complexities associated with de novo mutations, and possible germline mosaicism. As many cases of HA result from de novo mutations, these factors must be considered when assessing the reproductive options for such families.
Neurofibromatosis Type 1 (NF1)
Per Hayes (2010) NF1 gene testing is a complex, multistep process that may involve protein truncation testing (PTT) to identify variants leading to premature truncation of the NF1 protein, and sequence analysis of genomic DNA and/or messenger RNA (mRNA) to look for base-pair substitutions, small deletions or insertions, and variants affecting splicing of the NF1 gene. It may also involve multiplex ligation-dependent probe amplification (MLPA), fluorescence in situ hybridization (FISH), and/or array- based comparative genomic hybridization (aCGH) to test specifically for larger genomic imbalances such as multiexon or whole-gene deletions. NF1 gene testing may be considered for patients exhibiting the classic signs of NF1, for either diagnostic confirmation or for identification of the causative gene variant in cases where the testing of family members (including at-risk fetuses) is desired. It may also be used to establish a diagnosis in patients demonstrating features of NF1 who do not yet fulfill the clinical diagnostic criteria (including infants and children who have not yet developed enough features for a diagnosis, or patients with an atypical clinical presentation). In addition, prenatal and preimplantation genetic diagnosis may be used to diagnose NF1 in the offspring of affected individuals.
Currently, genetic testing is considered unnecessary for confirming a diagnosis of NF1 in clinically diagnosed individuals or for managing their care. However, it has been suggested that NF1 gene testing may be useful in cases with an atypical presentation or in individuals who are suspected of having NF1 but do not fulfill the criteria for a clinical diagnosis (for example, in young children who have not yet developed enough features to establish a diagnosis). In these cases, a positive gene test may also allow for earlier genetic counseling and risk assessment, earlier monitoring for complications, and earlier initiation of interventions for developmental delays or intellectual disabilities. While data supporting the utility of NF1 gene testing in the above cases were not identified, studies do support the use of NF1 gene testing in patients desiring prenatal or preimplantation genetic diagnosis.
The main limitation of studies demonstrating the clinical utility of NF1 gene testing in reproductive decision making is that most were case series involving few NF1 patients, although obtaining larger patient populations is unlikely due to the nature

of the testing (i.e., prenatal and preimplantation genetic diagnosis are much less common than the testing of symptomatic individuals)
HAYES RATING FOR GENETIC TEST for Neurofibromatosis Type 1 (NF1)
 For identification of the causative gene variant in NF1 patients desiring prenatal or preimplantation genetic diagnosis (or the testing of other at-risk family members) – rated C.
 For the prenatal or preimplantation genetic diagnosis of NF1 in the pregnancies of affected individuals – Rated C
Huntington’s Disease (HD)
Per Hayes (2008) Genetic testing for HD is used for diagnostic, predictive, and prenatal or preimplantation genetic diagnosis purposes. Symptomatic patients with or without a family history may benefit from diagnostic testing for HD. Asymptomatic individuals with a family history may undergo predictive testing to define personal risk or risk of transmission. Prenatal testing for HD may be indicated for asymptomatic couples with a family history of HD. Preimplantation testing to deselect embryos with HD allele(s) may be indicated for couples carrying penetrant HD alleles.
Genetic testing for HD may be categorized by three purposes, which include diagnostic (with or without family history), predictive (personal or risk of transmission), and prenatal or preimplantation; in all, six groups of patients may benefit:
Diagnostic:
 Patients (probands) suspected of having HD in the absence of a family history of HD to confirm diagnosis.
 Patients (probands) suspected of having HD from families in which there is a history of HD to confirm diagnosis.
Predictive:
 Asymptomatic individuals from families in which there is a history of HD to define personal risk.
 Asymptomatic individuals from families in which there is a history of HD to define risk of transmission.
Prenatal or preimplantation:
 Fetuses from families in which there is a history of HD to define risk by prenatal testing.
 Embryos from parents with penetrant genetic variation for HD to avoid risk for offspring by preimplantation testing
Genetic Test Evaluation Overview (April 29, 2008)
 For testing for CAG repeat length for diagnosis of HD in patients (probands) suspected of having HD in the absence of a family history of HD - rated C
 For testing for CAG repeat length for diagnosis of HD in patients (probands) suspected of having HD from families in which there is a history of HD – Rated D1
 For predictive testing for CAG repeat length in asymptomatic individuals from families in which there is a history of HD to define personal risk - rated D2

 For predictive testing for CAG repeat length in asymptomatic individuals from families in which there is a history of HD to define risk of transmission – rated B
 For prenatal testing for CAG repeat length in fetuses from families in which there is a history of HD - rated B
 For preimplantation testing for CAG repeat length in embryos from parents with penetrant genetic variation for HD- rated C
Myotonic Dystrophy Types 1 and 2 (DM1 / DM2)
Per Hayes (2009) The clinical circumstances in which genetic testing for DM1 and DM2 may be appropriate are: when DM is suspected, or to definitively confirm a clinical diagnosis; for asymptomatic adults at risk for DM through a family history of the disorder; prenatal diagnosis in pregnant women at risk for offspring with congenital DM; and preimplantation genetic diagnosis (PGD) of DM.
Genetic Test Evaluation Overview Hayes (2009, updated 2010)
 For prenatal diagnosis or preimplantation genetic diagnosis of DM1 in couples in which one or more members have been confirmed to be affected with, or be a presymptomatic carrier of, DM1 through genetic testing – rated B
 For prenatal diagnosis or preimplantation genetic diagnosis of DM2 – rated D2
Charcot-Marie-Tooth Type 1A (CMT1)
Per Hayes (2009) Individuals with a differential diagnosis of CMT1 may undergo this test to confirm the diagnosis and establish CMT subtype. Asymptomatic individuals with a family history of CMT1A may pursue testing to clarify their personal risk and risk of transmission to offspring. Prenatal diagnosis and preimplantation genetic diagnosis for CMT1A provides options for couples at risk to pass on a CMT1A duplication.
Identifying the genetic cause can also provide reproductive options such as prenatal diagnosis or preimplantation genetic diagnosis, which could prevent the birth of an affected offspring if desired. CMT1A duplication testing can confirm the presence of a familial deletion and could be the first step in the process of identifying asymptomatic family members at risk to pass the duplication on to their children. Prenatal and preconception testing for CMT1A has been shown to potentially have clinical utility. Prenatal diagnosis for a variable, adult-onset disorder such as CMT1A is not commonly requested, although this decision is patient-specific. On the other hand, preimplantation genetic diagnosis has been shown to be successful for couples at risk of having a child with CMT1A, and has clinical utility for individuals with CMT1A in the process of family planning.
Molecular genetic testing for CMT1A may be appropriate for the following individuals:
 For a couple planning a pregnancy and interested in prenatal or preimplantation genetic diagnosis.
Genetic Test Evaluation Overview Hayes (2010 updated)
 For prenatal or preimplantation genetic diagnosis of CMT1A – rated B.
Per the American Congress of Obstetricians and Gynecologists (ACOG). ACOG Committee Opinion. Number 430 • March 2009. Preimplantation Genetic Screening for Aneuploidy states the following:
“Preimplantation genetic screening differs from preimplantation genetic diagnosis for single gene disorders and was introduced for the detection of chromosomal

aneuploidy. Current data does not support a recommendation for preimplantation genetic screening for aneuploidy using fluorescence in situ hybridization solely because of maternal age. Also, preimplantation genetic screening for aneuploidy does not improve in vitro fertilization success rates and may be detrimental. At this time there are no data to support preimplantation genetic screening for recurrent unexplained miscarriage and recurrent implantation failures; its use for these indications should be restricted to research studies with appropriate informed consent. Preimplantation genetic screening differs from preimplantation genetic diagnosis (PGD) for single gene disorders. In order to perform genetic testing for single gene disorders, PGD was introduced in 1990 as a component of in vitro fertilization programs. Such testing allows the identification and transfer of embryos unaffected by the disorder in question and may avoid the need for pregnancy termination. Assessment of polar bodies as well as single blastomeres from cleavage stage embryos has been reported, although the latter is the approach most widely practiced. Preimplantation genetic diagnosis has become a standard method of testing for single gene disorders, and there have been no reports to suggest adverse postnatal effects of the technology. Preimplantation genetic diagnosis has been used for diagnosis of translocations and single-gene disorders, such as cystic fibrosis, X- linked recessive conditions, and inherited mutations, which increase one‟s risk of developing cancer.
In contrast, in the latter half of the 1990s, preimplantation genetic screening was introduced for the detection of chromosomal aneuploidy (2–4). Aneuploidy leads to increased pregnancy loss with increasing maternal age and also was thought to be a major cause of recurrent pregnancy loss in patients using assisted reproductive technologies. However, when compared with the molecular diagnostics available for PGD of single gene disorders, the current technologies available for preimplantation genetic screening for aneuploidy are more limited. Preimplantation genetic screening using fluorescence in situ hybridization is constrained by the technical limitations of assessing the numerical status of each chromosome. Typically assessed are the chromosome abnormalities associated with common aneuploidies found in spontaneous abortion material, and because of this, and other limitations noted in this Committee Opinion, a significant false-negative rate exists. Therefore, this form of testing should be considered a screening test, and not a diagnostic test, as is the case for PGD for single gene disorders.
Because preimplantation chromosome assessment tests a single cell, there are certain limitations:
 Testing a single cell prohibits confirmation of results.
 There is a limit to the number of tests that can be done with a single cell.
 Embryo mosaicism of normal and aneuploid cell lines may not be clinically significant.
Guidelines for counseling on limitations of this screening have been developed by the American Society for Reproductive Medicine.
Recommendations of ACOG:
 Current data does not support a recommendation for preimplantation genetic screening for aneuploidy using fluorescence in situ hybridization solely because of maternal age.
 Preimplantation genetic screening for aneuploidy does not improve in vitro fertilization success rates and may be detrimental.

 At this time there are no data to support preimplantation genetic screening for recurrent unexplained miscarriage and recurrent implantation failures; its use for these indications should be restricted to research studies with appropriate informed consent.
Scientific Rationale Initial
With recent advances in genetics, there are a good number of inherited disorders, which can now be diagnosed at a molecular level. For couples who are carriers or affected by any of a variety of genetic diseases and are at high risk for transmitting it to their offspring, it is currently possible to detect the disorder during pregnancy. This is done by one of two approaches: chorionic villus sampling in the first trimester or amniocentesis in the second trimester. However the couples have the dilemma of whether or not to terminate the pregnancy if the genetic abnormality is present. In some cases this may also not be a viable option for religious or moral reasons. An alternative would then be to diagnose the condition in embryos before the pregnancy is established. Only the unaffected embryos would then be transferred to the uterus. This new technique that combines advances in molecular genetics and assisted reproductive technologies is referred to as preimplantation genetic diagnosis (PGD). It does not involve the manipulation of genes in embryos; rather, it selects among embryos. PGD involves several steps: the creation of an embryo via IVF; the removal of one or two cells from the embryo; the genetic testing of these cells for specific genetic conditions; and the subsequent transfer of unaffected embryos to a woman‟s uterus.
Currently, IVF is the only available technique for obtaining an embryo in the very early stages of development. One to two single cells, blastomeres, are removed from early cleavage stage embryos (6–8-cell stage) at approximately 3 days' post- fertilization. The blastomere contains genetic material that can be analyzed to identify three categories of disorders, including aneuploidy and structural chromosomal abnormalities, single-gene disorders, and X-linked disorders. Although couples with a high risk of transmitting a genetic defect to their offspring may have normal fertility, they would need to go through the IVF procedure to provide embryos for screening. Fertility specialists can use the results of this analysis to select only mutation-free embryos for implantation into the mother's uterus, hence preventing the physical and psychological trauma associated with possible termination. Clinical and practical considerations include that the embryo must be healthy enough to survive the procedure. It is estimated that only 2.5% of eggs collected will form a viable unaffected pregnancy. Maternal age is an important factor, particularly for aneuploidy screening in women older than 35 years of age, as this increases the likelihood of finding a chromosomal abnormality and decreases the success rate of IVF. With PGD, couples are much more likely to have healthy babies. Although PGD has been practiced for years, only a few specialized centers worldwide offer this procedure.
PGD should be offered for 3 major groups of disease, including (1) sex-linked disorders, (2) single gene defects, and (3) chromosomal disorders. X-linked diseases are passed to the child through a mother who is a carrier. They are passed by an abnormal X chromosome and manifest in sons, who do not inherit the normal X chromosome from the father. Affected fathers have sons who are not affected, and their daughters have a 50% risk of being carriers if the mother is healthy. Sex-linked recessive disorders include hemophilia, fragile X syndrome, most of the neuromuscular dystrophies (currently > 900 neuromuscular dystrophies are known), and hundreds of other diseases. Sex-linked dominant disorders include Rett

syndrome, incontinentia pigmenti, pseudohyperparathyroidism, and vitamin D– resistant rickets. This genetic test is currently available to couples whose offspring are at a high risk (25-50%) for a specific genetic condition due to one or both parents being carriers or affected by the disease. Also the genetic code associated with the condition must be known in order to allow diagnosis. Currently, it is not feasible to routinely screen women at lower risks, such as women over age 35 for Downs Syndrome, since the means of establishing a pregnancy is with the help of IVF.
PGD is used to identify single gene defects such as cystic fibrosis, Tay-Sachs disease, sickle cell anemia, and Huntington disease. In such diseases, the molecular abnormality is detectable with molecular techniques using PCR amplification of DNA from a single cell. Although progress has been made, some single gene defects have a wide variety of rare mutations (e.g., cystic fibrosis has approximately 1000 known mutations). Only 25 of these mutations are currently routinely tested. Because most of these rare mutations are not routinely tested, a parent without any clinical manifestations of cystic fibrosis could be a carrier. This allows the possibility for a parent carrying a rare mutation gene to be tested as negative but still have the ability to pass on the mutant cystic fibrosis gene. The last group includes chromosomal disorders in which a variety of chromosomal rearrangements, including translocations, inversions, and deletions, can be detected using FISH. Some parents may have never achieved a viable pregnancy without using PGD because previous conceptions resulted in chromosomally unbalanced embryos and were spontaneously miscarried.
The risk of aneuploidy in children increases as women age. The chromosomes in the egg are less likely to divide properly, leading to an extra or missing chromosome in the embryo. The rate of aneuploidy in embryos is greater than 20% in mothers aged 35-39 years and is nearly 40% in mothers aged 40 years or older. The rate of aneuploidy in children is 0.6-1.4% in mothers aged 35-39 years and is 1.6-10% in mothers older than 40 years. The difference in percentages between affected embryos and live births is due to the fact that an embryo with aneuploidy is less likely to be carried to term and will most likely be miscarried, some even before pregnancy is suspected or confirmed. Therefore, using PGD to determine the chromosomal makeup of embryos increases the chance of a healthy pregnancy and reduces the number of pregnancy losses and affected offspring with so-called serious inherited disorders such as Tay Sachs; Trisomies 13, 18, and 21; cystic fibrosis; muscular dystrophy; Huntington disease; Lesch-Nyhan; and neurofibromatosis.
PDG is also presently has much wider indications than prenatal diagnosis, including common diseases with genetic predisposition and preimplantation human leukocyte antigen typing, with the purpose of establishing potential donor progeny for stem cell treatment of siblings. Many hundreds of apparently healthy, unaffected children have been born after preimplantation genetic diagnosis, presenting evidence of its accuracy, reliability and safety. Preimplantation genetic diagnosis appears to be of special value for avoiding age-related aneuploidies in patients of advanced reproductive age, improving reproductive outcome, particularly obvious from their reproductive history, and is presently an extremely attractive option for carriers of balanced translocations to have unaffected children of their own. Many people fear that PGD will be used to select a child of a preferred sex. PGD could also be used in attempts to select a future child's cosmetic, behavioral, and other non-disease traits. However, the genetic laws of independent assortment make it difficult for PGD to be used for any traits that depend on two or more genes. Thus, PGD provides an

alternative to germline modification as a way to prevent the births of children with serious genetic diseases, most of which are single-gene disorders, but does not open the door to escalating and species-altering applications.
Research continues in the area of PGD. There is now a rapidly growing list of disorders for which PGD has been applied successfully, including cystic fibrosis, Tay- Sachs disease, hemophilia A and B, retinitis pigmentosa, numerous inborn errors of metabolism, fragile X syndrome, Duchenne muscular dystrophy, and chromosomal abnormalities, to name a few. The risks of PGD are similar to risks for IVF, namely multiple-fetal pregnancies and the twofold increased risk for major birth defects and low birth weight. Preliminary studies show no increased risk for spontaneous abortions. The data from long-term follow-up of children conceived after PGD, however, have yet to be collected.
Review History
October 2005 Medical Advisory Council initial approval
November 2006 Medical Advisory Council - no changes
November 2007 Update – no revisions
February 2011 Update. Added Medicare Table. No revisions.
October 2011 Update. No revisions
Patient Education Websites
English
1. MedlinePlus. Genetic counseling and prenatal diagnosis. Available at:http://www.nlm.nih.gov/medlineplus/ency/article/002053.htm
2. Human Genome Program. Gene Testing. Available at: http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetest.shtml
3. Medical World Search. Preimplantation Genetics Diagnosis for Preventing Birth Defect, Making Designer Babies or Creating Babies To Help Sick Siblings -- Why? What? How? Right or Wrong? Available at: http://www.mwsearch.com/creatingbaby.html
4. Office of Genomics & Disease Prevention, Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/genomics/
Spanish
1. MedlinePlus. Asesoramiento genético y diagnóstico prenatal. Available at: http://www.nlm.nih.gov/medlineplus/spanish/ency/article/002053.htm
2. Información sobre la Oficina de Genómica y Prevención de Enfermedades de los CDC. Available at: http://www.cdc.gov/genomics/spanish/aboutsp.htm
3. March of Dimes Birth Defects. Available at: http://www.nacersano.org/
This policy is based on the following evidence-based guidelines:
1. American College of Obstetricians and Gynecologists, American College of Medical Genetics: Preconception and Prenatal Carrier Screening for Cystic Fibrosis: Clinical and Laboratory Guidelines. Washington, DC; American College of Obstetrics and Gynecology; October, 2001. Available at: http://www.mlo- online.com/ce/pdfs/oct02.pdf
2. American Society for Reproductive Medicine, Society for Assisted Reproductive Technology: A practice committee report: Preimplantation genetic diagnosis. Birmingham, Ala. June 2001. Available at: www.asrm.org/Media/Practice/practice.html

3. National Ethics Committee on Assisted Human Reproduction. Guidelines for Preimplantation Genetic Diagnosis in New Zealand. Consultation Document. September 2004. Available at: http://www.newhealth.govt.nz/necahr/guidelines/preimplantationgeneticdiagnosis-consultation0904.pdf
4. Thornhill AR, deDie-Smulders CE, Geraedts JP, et al. European Society of Human Reproduction and Embryology (ESHRE) PGD Consortium. Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS). 2005. Available at: http://humrep.oxfordjournals.org/cgi/content/full/20/1/35#SEC4
5. Developments in infertility therapy. Diagnosis of genetic disease in embryos. Australian Family Physician Vol. 34, No. 3, March 2005. Available at: www.asrm.org/Media/Practice/practice.html
6. International Working Group on Preimplantation Genetics, International Congress of Human Genetics: Preimplantation Genetic Diagnosis: Experience of Three Thousand Cycles. Report of the 11th Annual Meeting of International Working Group on Preimplantation Genetics, in association with 10th International Congress of Human Genetics. Vienna, Austria; May, 2001. Available at: http://216.242.209.125/11m.shtml
7. American Society For Reproductive Medicine. Preimplantation Genetic Diagnosis Fact Sheet. 12/96. Available at: http://www.hygeia.org/pgd.htm
8. Preimplantation genetic testing: a Practice Committee opinion. Practice Committee of the Society for Assisted Reproductive Technology; Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2007;88:1497–504.
9. Hayes. Medical Technology Directory. Genetic Testing for Tay-Sachs Disease. Updated March 6, 2008.
10. Hayes. Genetic Test Overview. Fragile X Syndrome (FMR1) for Mental Retardation. August 7, 2008
11. Hayes. Genetic Test Overview. Y Chromosome Microdeletion Analysis for Male Infertility. November 14, 2008.
12. American Congress of Obstetricians and Gynecologists (ACOG). ACOG Committee Opinion. Number 430 • March 2009. Preimplantation Genetic Screening for Aneuploidy. Available at: http://www.acog.org/publications/committee_opinions/co430.cfm
13. Hayes. Genetic Test Overview. Spinal Muscular Atrophy (SMA) for Progressive Muscle Weakness. January 23, 2009.
14. Hayes. Genetic Test Evaluation Overview. Ashkenazi Jewish Genetic Screening Panel for Risk Assessment. February 18, 2009
15. Hayes. Genetic Test Overview. COL1A1 and COL1A2 Testing for Osteogenesis Imperfecta Types I to IV. February 20, 2009.
16. Hayes. Genetic Test Overview. GTE Report: Charcot-Marie-Tooth Type 1A (PMP22). Published: August 5, 2008. Latest Update Search: Aug 23, 2010
17. Hayes. Genetic Test Overview. Spinocerebellar Ataxia Type 1 (SCA1) for Movement Disorders. March 3, 2010.
18. Hayes. Genetic Test Overview. GTE Report: Myotonic Dystrophy Types 1 and 2 Published: March 9, 2009. Latest Update Search: Mar 31, 2010
20. Hayes. Genetic Test Overview. Spinocerebellar Ataxia Type 3 (SCA3; Machado- Joseph Disease) for Movement Disorders. March 3, 2010.

22. Hayes. Genetic Test Overview. Spinocerebellar Ataxia Type 7 (SCA7) for Movement Disorder. April 29, 2010.
23. Hayes. Genetic Test Overview. GTE Report: Huntington Chorea/Disease (HD) for Diagnostic, Predictive, and Prenatal or Preimplantation Genetic Diagnosis Purposes. Published: April 29, 2008. Updated May 6, 2010
24. Hayes. Genetic Test Overview. Comparative Genomic Hybridization (CGH) Microarray for Chromosomal Imbalance. April 12, 2010.
25. Hayes. Genetic Test Overview. Marfan Syndrome. May 7, 2010.
26. Hayes. Genetic Test Overview. Spinocerebellar Ataxia Type 12 (SCA12) for Movement Disorders. June 15, 2010.
27. Hayes. Genetic Test Overview. Spinocerebellar Ataxia Type 17 (SCA17) for Movement Disorders. June 17, 2010.
28. Hayes. Genetic Test Overview. GTE Report: Neurofibromatosis Type 1 (NF1). Published: November 17, 2010
29. Hayes. Genetic Test Overview. GTE Synopsis: Hemophilia A (Factor VIII Deficiency). Published: January 24, 2011
30. American College of Obstetricians and Gynecologists (ACOG). Committee Opinion. Family History as a Risk Assessment Tool. Number 478. March 2011. Available at: http://www.acog.org/publications/committee_opinions/co478.cfm
References Update – October 2011
1. Colls P, Silver L, Olivera G, et al. Preimplantation genetic diagnosis for gender selection in the USA. Reprod Biomed Online. 2009;19 Suppl 2:16-22.
2. Cooper AR, Jungheim ES. Preimplantation Genetic Testing: Indications and Controversies. Clinics in Laboratory Medicine. Volume 30, Issue 3, September 2010.
3. Debrock S, Melotte C, Spiessens C, et al. Preimplantation genetic screening for aneuploidy of embryos after in vitro fertilization in women aged at least 35 years: a prospective randomized trial. Fertil Steril 2010; 93:364.
4. El-Toukhy T, Bickerstaff H, Meller S. Preimplantation genetic diagnosis for haematologic conditions. Current Opinion in Pediatrics. 2010 Feb;22(1):28-34.
5. Fischer J, Colls P, Escudero T, Munné S, et al. Preimplantation genetic diagnosis (PGD) improves pregnancy outcome for translocation carriers with a history of recurrent losses. Fertil Steril. 2010;94(1):283.
6. Harper JC, Harton G. The use of arrays in preimplantation genetic diagnosis and screening. Fertil Steril 2010; 94:1173.
7. Human Fertilisation and Embryology Authority. Authority decision on the use of PGD for lower penetrance, later onset inherited conditions. London (UK): HFEA; 2006. Available at: http://www.hfea.gov.uk/docs/SCAG_ELC_June05.pdf
8. Liebaers I, Desmyttere S, Verpoest W, et al. Report on a consecutive series of 581 children born after blastomere biopsy for preimplantation genetic diagnosis. Hum Reprod 2010; 25:275.
9. Musters AM, Twisk M, Leschot NJ, et al. Perspectives of couples with high risk of transmitting genetic disorders. Fertil Steril 2010; 94:1239.
10. Raby BA. Principles of molecular genetics. May 31, 2011. Available at: http://www.uptodate.com/contents/principles-of-molecular- genetics?source=see_link
11. Schattman GL. Preimplantation genetic screening (PGS) for aneuploidy. March 15, 2011. Available at: http://www.uptodate.com/contents/preimplantation- genetic-screening-pgs-for-aneuploidy?view=print

12. Schattman GL. Preimplantation genetic diagnosis. May 31, 2011. Available at: http://www.uptodate.com/contents/preimplantation-genetic- diagnosis?view=print
References Update – February 2011
1. Laurie AD, Hill AM, Harraway JR, et al. Preimplantation genetic diagnosis for hemophilia A using indirect linkage analysis and direct genotyping approaches. Journal of Thrombosis and Haemostasis. 8 (4) (pp 783-789), 2010.
2. Debrock S, Melotte C, Spiessens C, et al. Preimplantation genetic screening for aneuploidy of embryos after in vitro fertilization in women aged at least 35 years: a prospective randomized trial. Fertil Steril. 2010 Feb;93(2):364-73. Epub 2009 Feb 26.
3. Vanneste E, Melotte C, Debrock S, et al. Preimplantation genetic diagnosis using fluorescent in situ hybridization for cancer predisposition syndromes caused by microdeletions. Hum Reprod. 2009;24(6):1522-1528.
4. Meyer LR, Klipstein S, Hazlett WD, et al. A prospective randomized controlled trial of preimplantation genetic screening in the “good prognosis” patient. Fertil Steril. 2009 May;91(5):1731-8. Epub 2008 Sep 18.
5. Van de Velde H, De Rycke M, De Man C, et al. The experience of two European preimplantation genetic diagnosis centres on human leukocyte antigen typing. Hum Reprod. 2009 Mar;24(3):732-40. Epub 2008 Dec 5.
6. Checa MA, Alonso-Coello P, Sola I, et al. IVF/ICSI with or without preimplantation genetic screening for aneuploidy in couples without genetic disorders: a systematic review and meta-analysis. J Assist Reprod Genet. 2009 May;26(5):273-83. Epub 2009 Jul 24.
7. Shaw SW. Cheng PJ. Chang SD, et al. Rapid prenatal diagnosis of spinal muscular atrophy by denaturing high-performance liquid chromatography system. Acta Obstetricia et Gynecologica Scandinavica. 87(9):960-8, 2008.
8. Girardet A. Fernandez C. Claustres M. Efficient strategies for preimplantation genetic diagnosis of spinal muscular atrophy. Fertility & Sterility. 90(2):443.e7- 12, 2008 Aug.
9. Kakourou G, Dhanjal S, Mamas T, et al. (2008). Preimplantation genetic diagnosis for myotonic dystrophy type 1 in the UK. Neuromuscul Disord. 2008;18(2):131-136.
10. Fares F. Badarneh K. Abosaleh M, et al. Carrier frequency of autosomal-recessive disorders in the Ashkenazi Jewish population: should the rationale for mutation choice for screening be reevaluated? Prenatal Diagnosis. 28(3):236-41, 2008 Mar.
11. Fritz MA. Perspective on the efficacy and indications for preimplantation genetic screening: where are we now? Hum Reprod 2008; 23(12):2617-21.
12. Fauser BC. Preimplantation genetic screening: the end of an affair? Hum Reprod 2008; 23 (12): 2622-5.
13. Altarescu G. Brooks B. Margalioth E, et al. Simultaneous preimplantation genetic diagnosis for Tay-Sachs and Gaucher disease. Reproductive Biomedicine Online. 15 (1): 83-8, 2007 Jul.
14. Malcov M, Naiman T, Yosef DB, et al. Preimplantation genetic diagnosis for fragile X syndrome using multiplex nested PCR. Reprod Biomed Online. 2007;14 (4):515-521.
15. Meldrum C, Scott C, Swoboda KJ. Spinal muscular atrophy genetic counseling access and genetic knowledge: parents' perspectives. J Child Neurol. 2007;22(8):1019-1026.

16. ClinicalTrials.gov. Quantitative Analysis of SMN1 and SMN2 Gene Based on DHPLC System. NCT00155168. Updated September 9, 2005. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00155168
17. ClinicalTrials.gov. Establishing Novel Detection Techniques for Various Genetic- Related Diseases by Applying DHPLC Platform. NCT00154960. Updated November 25, 2005. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00154960
References Initial
1. Marik JJ. eMedicine. Preimplantation genetic diagnosis. 2005. Available at: http://www.emedicine.com/med/topic3520.htm
2. Devolder K. Preimplantation HLA typing: having children to save our loved ones. J Med Ethics. 2005 Oct;31(10):582-6.
3. Kuliev A, Rechitsky S, Verlinsky O, et al. Preimplantation diagnosis and HLA typing for haemoglobin disorders. Reprod Biomed Online. 2005 Sep;11(3):362- 70.
4. Harper JC, Boelaert K, Geraedts J, et al. ESHRE PGD Consortium data collection V: Cycles from January to December 2002 with pregnancy follow-up to October 2003. Hum Reprod. 2005 Sep 19.
5. Shenfield F. Preimplantation genetic diagnosis in order to choose a saviour sibling. Gynecol Obstet Fertil. 2005 Oct;33(10):833-4.
6. Sugiura-Ogasawara M, Suzumori K. Can preimplantation genetic diagnosis improve success rates in recurrent aborters with translocations? Hum Reprod. 2005 Aug 25;
7. Rao R. Preimplantation genetic diagnosis and reproductive equality. Gend Med. 2004 Dec;1(2):64-9.
8. Platteau P, Staessen C, Michiels A, et al. Preimplantation genetic diagnosis for aneuploidy screening in women older than 37 years. Fertil Steril. 2005 Aug;84(2):319-24.
9. Kuliev A, Verlinsky Y. Preimplantation genetic diagnosis in assisted reproduction.
Expert Rev Mol Diagn. 2005 Jul;5(4):499-505.
10. Crockin SL. Reproduction, genetics and the law. Reprod Biomed Online. 2005 Jun;10(6):692-704.
11. Aittomaki K, Bergh C, Hazekamp J, et al. Genetics and assisted reproduction technology. Acta Obstet Gynecol Scand. 2005 May;84(5):463-73.
12. Kahraman S, Karlikaya G, Sertyel S, et al: Clinical aspects of preimplantation genetic diagnosis for single gene disorders combined with HLA typing. Reprod Biomed Online 2004 Nov; 9(5): 529-32.
13. Zhuang GL, Zhang D. Preimplantation genetic diagnosis. Int J Gynecol Obstet 2003;82:419-23.
14. Baird DD, Weinberg CR, McConnaughey DR, Wilcox AJ: Rescue of the corpus luteum in human pregnancy. Biol Reprod 2003 Feb; 68(2): 448-56.
15. Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 2002;346(10):725-30.
16. Schieve LA, Meikle SF, Ferre C, et al. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346(10):731-7.
17. Munne S, Cohen J, Sable D: Preimplantation genetic diagnosis for advanced maternal age and other indications. Fertil Steril 2002 Aug; 78(2): 234-6.
18. Flinter FA. Preimplantation genetic diagnosis. Br Med J 2001;322:1008-9.
19. Findlay I. Pre-implantation genetic diagnosis. Br Med Bull 2000;56:672-90.

20. Soussis I, Harper JC, Handyside AH, et al. Obstetric outcome of pregnancies resulting from embryos biopsied for pre-implantation diagnosis of inherited disease. Br J Obstet Gynaecol 1996;103:784-8.
21. Kristjansson K, Chong SS, Van den Veyver IB, et al. Preimplantation single cell analyses of dystrophin gene deletions using whole genome amplification. Nat Genet 1994;6:19-23.
22. Snabes MC, Chong SS, Subramanian SB, et al. Preimplantation single-cell analysis of multiple genetic loci by whole-genome amplification. Proc Natl Acad Sci USA 1994;91:6181-5.
23. Handyside AH, Lesko JG, Tarin JJ, et al. Birth of a normal girl after in vitro fertilization and preimplantation diagnostic testing for cystic fibrosis. N Engl J Med 1992;327:905-9.
24. Handyside AH, Pattinson JK, Penketh RJ, et al: Biopsy of human preimplantation embryos and sexing by DNA amplification. Lancet 1989 Feb 18; 1(8634): 347-9.
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The Policies do not constitute authorization or guarantee of coverage of particular procedure, drug, service or supply. Members and providers should refer to the Member contract to determine if exclusions, limitations, and dollar caps apply to a particular procedure, drug, service or supply.
Policy Limitation: Member’s Contract Controls Coverage Determinations.
The determination of coverage for a particular procedure, drug, service or supply is not based upon the Policies, but rather is subject to the facts of the individual clinical case, terms and conditions of the member‟s contract, and requirements of applicable laws and regulations. The contract language contains specific terms and conditions, including pre-existing conditions, limitations, exclusions, benefit maximums, eligibility, and other relevant terms and conditions of coverage. In the event the Member‟s contract (also known as the benefit contract, coverage document, or evidence of coverage) conflicts with the Policies, the Member‟s contract shall govern. Coverage decisions are the result of the terms and conditions of the Member‟s benefit contract. The Policies do not replace or amend the Member‟s contract. If there is a discrepancy between the Policies and the Member‟s contract, the Member‟s contract shall govern.
Policy Limitation: Legal and Regulatory Mandates and Requirements.
The determinations of coverage for a particular procedure, drug, service or supply is subject to applicable legal and regulatory mandates and requirements. If there is a discrepancy between the Policies and legal mandates and regulatory requirements, the requirements of law and regulation shall govern.
Policy Limitations: Medicare and Medicaid.
Policies specifically developed to assist Health Net in administering Medicare or Medicaid plan benefits and determining coverage for a particular procedure, drug, service or supply for Medicare or Medicaid members shall not be construed to apply to any other Health Net plans and members. The Policies shall not be interpreted to limit the benefits afforded Medicare and Medicaid members by law and regulation.

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