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:

Use 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/R8

82OTN.pdf

None Use Health Net Policy

Instructions

Medicare NCDs and National Coverage Manuals apply to ALL Medicare members

in ALL regions.

Medicare LCDs and Articles apply to members in specific regions. To access your

specific region, select the link provided under “Reference/Website” and follow the

search instructions. Enter the topic and your specific state to find the coverage

determinations for your region

If more than one source is checked, you need to access all sources as, on

occasion, an LCD or article contains additional coverage information than

contained in the NCD or National Coverage Manual.

https://www.cms.gov/transmittals/downloads/R882OTN.pdf

https://www.cms.gov/transmittals/downloads/R882OTN.pdf


If there is no NCD, National Coverage Manual or region specific LCD/Article,

follow the Health Net Hierarchy of Medical Resources for guidance.

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

http://www.nlm.nih.gov/medlineplus/ency/article/002053.htm

http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetest.shtml

http://www.mwsearch.com/creatingbaby.html

http://www.cdc.gov/genomics/

http://www.nlm.nih.gov/medlineplus/spanish/ency/article/002053.htm

http://www.cdc.gov/genomics/spanish/aboutsp.htm

http://www.nacersano.org/

http://www.mlo-online.com/ce/pdfs/oct02.pdf

http://www.mlo-online.com/ce/pdfs/oct02.pdf

http://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/preimplantationgeneticdiagnos

is-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.



http://www.newhealth.govt.nz/necahr/guidelines/preimplantationgeneticdiagnosis-consultation0904.pdf

http://www.newhealth.govt.nz/necahr/guidelines/preimplantationgeneticdiagnosis-consultation0904.pdf

http://humrep.oxfordjournals.org/cgi/content/full/20/1/35#SEC4

http://216.242.209.125/11m.shtml

http://www.hygeia.org/pgd.htm




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.


Movement Disorders. June 15, 2010.


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


http://www.hfea.gov.uk/docs/SCAG_ELC_June05.pdf

http://www.uptodate.com/contents/principles-of-molecular-genetics?source=see_link

http://www.uptodate.com/contents/principles-of-molecular-genetics?source=see_link

http://www.uptodate.com/contents/preimplantation-genetic-screening-pgs-for-aneuploidy?view=print

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.

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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:


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

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preimplantation genetic diagnosis_oct_11

Documents

national coverage manuals

coverage guidelines

coverage determinations

genetic test

genetic problem

medicare members

ivf services

fertilization ivf