Fanconi Anemia

FA is an inherited disorder that is characterized by congenital abnormalities, bone marrow failure, and predisposition to hematologic malignancies. It is rare, with an incidence of less than ten per million live births.^1, FA is usually transmitted by the autosomal recessive route (>99%) and by the X-linked route in a very small number of cases. The carrier frequency in the U. S. is approximately 1 in 300 for the general population, and as high as 1 in 100 for certain populations such as Ashkenazi Jews and South Africans of Afrikaner descent.

The clinical expression of FA is variable, but it is associated with early mortality and a high degree of morbidity. Approximately 60% to 70% have at least 1 congenital abnormality, most common being disorders of the thumb and radial bones, short stature, skin hyperpigmentation, hypogonadism, and cafe-au-lait spots.^2, A variety of other abnormalities of internal organs such as the heart, lungs, kidneys, and gastrointestinal tract can occur in up to 20% to 25% of patients.^3, The most serious clinical problems are bone marrow abnormalities and malignancies. Hematologic abnormalities and bone marrow failure present in the first decade of life, although they can present much later.^4, There is an increased predisposition to malignancies, especially myelodysplastic syndrome, acute myeloid leukemia, and squamous cell cancers of the head and neck.^5,

Diagnosis

For patients with suspected FA after clinical and hematologic examination, the diagnosis can be confirmed by chromosome breakage analysis. A positive chromosome breakage test after exposure to alkylating agents such as diepoxybutane or mitomycin C confirms the diagnosis of FA and a negative test rules out FA. However, results may sometimes be inconclusive, leaving uncertainty as to the diagnosis of FA.^6, In these cases, the detection of a genetic variant that is known to be pathogenic for FA can confirm the diagnosis.

Other inherited bone marrow failure disorders can mimic FA. They include dyskeratosis congenita, Shwachman-Diamond syndrome, and congenital amegakaryocytic thrombocytopenia.^7, These disorders will not typically have a positive chromosomal breakage test, but if the breakage test is not definitive, then it may be difficult to distinguish between the syndromes on clinical parameters. Genetic testing for these other disorders is also available, targeting variants that are distinct from those seen in FA.

Treatment

Treatment recommendations based on expert consensus were published in 2014, sponsored by the Fanconi Anemia Research Fund.^8, For bone marrow failure, this document recommends monitoring for mild bone marrow failure and hematopoietic cell transplantation (HCT) for moderate-to-severe bone marrow failure. Androgen therapy and/or hematopoietic growth factors are treatment options if HCT is unavailable or if the patient declines transplantation. FA patients have increased sensitivity to the conditioning regimens used for HCT and, as a result, reduced intensity regimens are used. Because of this different treatment approach, it is crucial to confirm or exclude a diagnosis of FA before HCT.

Genetics of FA

Molecular genetic testing is complicated by the presence of at least 15 genes. For all the known genes associated with FA sequence, the analysis is complicated by the number of genes to be analyzed, a large number of possible variants in each gene, the presence of large insertions or deletions in some genes, and the size of many of the FA-related genes. If the complementation group has been established, the responsible variant can be determined by sequencing of the corresponding gene (see Table 1).^9,

Table 1. Genes Associated with Fanconi Anemia

Gene	Proportion of Individuals With Fanconi Anemia, %	Variant Type(s)
FANCA	60-70	Sequence variants; deletions/duplications
FANCB	2	Sequence variants; deletions/duplications
FANCC	14	Sequence variants; deletions/duplications
BRCA2	3	Sequence variants
FANCD2	3	Sequence variants
FANCE	3	Sequence variants
FANCF	2	Sequence variants
FANCG	10	Sequence variants
FANCI	1	Sequence variants
BRIP1	2	Sequence variants
FANCL	0.2	Sequence variants
FANCM	0.2	Sequence variants
PALB2	0.7	Deletions/duplications
RAD51C	0.2	Sequence variants
SLX4	0.2	Sequence variants

Adapted from Mehta and Tolar (2013).^9,

Regulatory Status

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

Related Policies

• None

• Clinical signs and symptoms of Fanconi anemia are present; AND
• A definitive diagnosis of Fanconi anemia cannot be made after standard workup, ie, nondiagnostic results on chromosome breakage analysis
  

• Previous offspring with a diagnosis of Fanconi anemia; OR
• One or both parents are known carriers of a Fanconi anemia pathogenic variant; OR
• One or both parents have a first or second-degree relative with a diagnosis of Fanconi anemia; OR
• One or both parents are members of an ethnic group with a baseline carrier frequency of 1 in 100 or greater:
  • Ashkenazi Jews
  • South Africans of Afrikaner descent

• Both parents are known carriers of a pathogenic Fanconi anemia pathogenic variant; OR
• One parent has a diagnosis of Fanconi anemia and the other parent is a known carrier of a pathogenic variant.

• Both parents are known carriers of a pathogenic Fanconi anemia variant: OR
• One parent has a diagnosis of Fanconi anemia and the other parent is a known carrier of a Fanconi anemia pathogenic variant.

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

Genetic testing for Fanconi anemia is a complex process that involves multiple steps and a number of different potential approaches. Most testing procedures described in the literature involve a combination of polymerase chain reaction, direct sequencing, and next-generation sequencing to identify a full complement of variants associated with Fanconi anemia.

However, in clinical care, a more directed approach can be taken. In many cases, testing complementation groups will have been performed prior to genetic testing, and this will direct genetic testing to one of the 15 known genes associated with Fanconi anemia. Direct sequencing and/or deletion/duplication analysis of these few genes may be the most accurate and efficient approach in many cases.

In the absence of complementation testing, the greatest yield will be in testing for the FANCA gene, followed by the FANCC and FANCG genes. If a patient with Fanconi anemia is negative for variants in these genes, then testing for many low-frequency variants may be necessary. Next-generation sequencing offers considerable advantages in testing multiple genes simultaneously for patients in this situation.

Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical policy updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Previous	Updated	Definition
Mutation	Disease-associated variant	Disease-associated change in the DNA sequence
	Variant	Change in the DNA sequence
	Familial variant	Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

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

Variant Classification	Definition
Pathogenic	Disease-causing change in the DNA sequence
Likely pathogenic	Likely disease-causing change in the DNA sequence
Variant of uncertain significance	Change in DNA sequence with uncertain effects on disease
Likely benign	Likely benign change in the DNA sequence
Benign	Benign change in the DNA sequence

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

Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.


[RATIONALE: This policy was created in 2015 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through October 14, 2019.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Genetic Testing for Fanconi Anemia

Clinical Context and Test Purpose

The purpose of genetic testing for FA in patients who are symptomatic for FA, have a close relative with a confirmed diagnosis, or are at risk and are planning to start a family is to diagnose FA and direct care, including direct early monitoring and treatment of bone marrow failure or inform reproductive planning decisions.

The question addressed in this policy is: Does genetic testing for FA improve the net health outcome compared with standard clinical workup without testing or no testing at all in those who are symptomatic or at risk for FA?

The following PICOs were used to select literature to inform this review.

Patients

The relevant populations of interest are individuals who are symptomatic for FA, those who have a close relative with a confirmed diagnosis, and those at risk who are planning a family.

Interventions

The relevant intervention of interest is testing for FA.

Symptomatic and asymptomatic patients may be evaluated in a medical, genetics clinic for suspected FA.

Comparators

The following tests and practices are currently being used to manage FA: standard clinical workup without genetic testing or no testing.

Outcomes

The primary outcomes of interest are bone marrow abnormalities (eg, bone marrow failure and malignancies) and early mortality.

The development of bone marrow failure occurs over many years or decades with patients typically manifesting bone marrow failure by age 40.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

There is limited published data on the clinical validity of genetic testing for FA. The evidence reviewed derives from some of the larger cohorts of FA patients described in the literature, with emphasis on more recent publications, because earlier publications may not reflect the current spectrum of variants currently known.

The International Fanconi Anemia Registry is a registry of FA patients that has been maintained since 1982 at Rockefeller University. Several publications from this registry provide information on clinical validity.^10,11,12, However, these publications tend to be variant-specific, thereby providing information on clinical validity for a specific variant. For example, Levran et al (2005) published an analysis of the spectrum of FANCAvariants in patients enrolled in the International Fanconi Anemia Registry.¹¹ They reported the detection rate for FANCA variants (clinical sensitivity) in 181 patients in the registry was 55%. A similar study (2003) analyzing the FANCG gene reported that pathogenic variants were identified in 9%.^10,

De Rocco et al (2014) published the results of variant analysis of 100 unrelated patients with FA, most of whom were of Italian ancestry.^13, All patients had a clinical diagnosis of FA and approximately half (48/100) had complementation group analysis to direct candidate gene selection, an algorithm of genetic testing that used a combination of direct sequencing, multiplex ligation-dependent probe amplification, and next-generation sequencing.

A total of 108 variants were identified that were potentially pathogenic, with all patients having at least 1 variant identified and some patients having more than 1 variant. The most common involved genes were FANCA (79%), FANCG (8%), FANCC (3%), FANCD2 (2%), and FANCB (1%). Of the 108 variants, 62 had been previously identified as associated with FA, and the remaining 46 were novel variants. For the novel variants, large deletions or duplications were considered to be pathogenic, but point mutations could not always be determined as definitely pathogenic. For example, of the 85 variants in the FANCA gene, 22% were point mutations that were classified as variants of uncertain significance.

In a cohort of 80 patients from the Netherlands who were referred for genetic testing after a confirmed diagnosis of FA, Ameziane et al (2008) identified a variant in 73 (91%) patients.^14, All patients had a comprehensive variant analysis that consisted of polymerase chain reaction, multiplex ligation-dependent probe amplification, and next-generation sequencing. Ninety-two distinct variants were detected in 73 patients, 56 of which were novel. Variants were most common in the FANCA (63%), FANCC (10%), and FANCG (7%) genes.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

No studies were identified that directly evaluated the clinical usefulness of the test.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Testing in Individuals with Signs and Systems of Fanconi Anemia

The diagnosis of FA can usually be made by clinical presentation and chromosome breakage analysis. In these cases, genetic testing is not required to confirm the diagnosis. In a minority of cases, the chromosome breakage analysis is not conclusive, and the diagnosis cannot be made with certainty. In those situations, genetic testing can confirm the diagnosis of FA if a known pathologic variant is found. Genetic testing can also distinguish FA from related causes of bone marrow failure, in which variants distinct from those associated with FA are found.

Testing in Individuals with a Close Relative with Fanconi Anemia

Early identification of asymptomatic patients may improve outcomes by instituting treatment of early bone marrow failure that may delay or prevent the progression to complete failure. Outcomes of hematopoietic cell transplantation are likely to be optimal when patients have bone marrow failure, but do not have severe, debilitating disease and have not yet developed complications of the severe disease (eg, opportunistic infections). Therefore, testing of asymptomatic individuals who have a first-degree relative with a diagnosis of FA is likely to result in improved outcomes.

Testing in Individuals at Risk for Fanconi Anemia Considering Offspring

The goal of reproductive testing is to reduce the likelihood of having an affected offspring. According to the principles outlined in the following evidence reviews, genetic testing for FA has potential clinical utility in the reproductive setting under the conditions listed.

Carrier Screening for Genetic Diseases (Policy #095 in the Pathology Section)

FA meets the general characteristics of a disease that warrants genetic testing. It is a disorder in which the natural history is well understood, and that has a reduced life expectancy and high morbidity. There are no other ways to diagnose the carrier state besides genetic testing. Genetic testing has adequate sensitivity and specificity for FA, and there is a known association between the genetic variants and clinical disease. As a result, genetic testing for FA meets has potential clinical utility if the following conditions are also met:

• Previous offspring with a diagnosis of FA; OR
• One or both parents are known carriers of an FA variant; OR
• One or both parents have a first- or second-degree relative with a diagnosis of FA; OR
• One or both parents are members of an ethnic group with a baseline carrier frequency of 1 in 100 or greater:
  • Ashkenazi Jews
  • South Africans of Afrikaner descent.

Similar to the case of carrier testing, FA meets the characteristics of a disease that warrants genetic testing. As a result, fetal testing has potential clinical utility if the following conditions are also met:

• Both parents are known carriers of a pathogenic FA variant; OR
• One parent has a diagnosis of FA, and the other parent is a known carrier of a pathogenic variant.

Similar to the case of carrier testing, FA meets the characteristics of a disease that warrants genetic testing. As a result, fetal testing meets has potential clinical utility if the following conditions are also met:

• Both parents are known carriers of a pathogenic FA variant; OR
• One parent has a diagnosis of FA, and the other parent is a known carrier of a pathogenic variant.

For individuals who have signs and/or symptoms of FA who receive genetic testing for FA, the evidence includes small cohort studies and case series. The relevant outcomes are test validity, other test performance measures, change in disease status, and morbid events. Due to the rarity of clinical FA, there is limited published evidence to determine whether genetic testing for FA improves outcomes. The available evidence demonstrates that most patients with a clinical diagnosis of FA have identified pathogenic variants. This supports the use of genetic testing for the diagnosis when standard testing, including chromosomal breakage analysis, is inconclusive. Therefore, when signs and/or symptoms of FA are present, but the diagnosis cannot be made by standard testing, genetic testing will improve the ability to make a definitive diagnosis and direct care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have a close relative with the diagnosis of FA who receive genetic testing for FA to determine future risk of the disease, the evidence consists of small cohort studies and case series. The relevant outcomes are test validity, other test performance measures, and changes in reproductive decision making. Genetic testing has clinical utility if there is a close relative with FA primarily first-degree relatives. This will primarily apply to young siblings of an affected individual and may help to direct early monitoring and treatment of bone marrow failure that may prevent or delay progression. Treatment of bone marrow failure with hematopoietic cell transplantation is considered more likely to be successful if initiated earlier in the course of the disease. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are at risk for FA and considering offspring who receive carrier testing for FA, the evidence consists of small cohort studies and case series. The relevant outcomes are test validity, other test performance measures, and changes in reproductive decision making. Genetic testing is likely to have clinical utility in the reproductive setting. FA is a severe disorder with limited life expectancy, thus warranting consideration for carrier testing, fetal testing, and preimplantation genetic testing. In these situations, testing of selected individuals is likely to impact reproductive decisions and reduce the likelihood of having an affected offspring; therefore, health outcomes are improved. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

Fanconi Anemia Research Foundation

The Fanconi Anemia Research Foundation (2014) issued guidelines on diagnosis and management of the disease.^15, The guidelines provided the following information on genetic testing:

“In the last few years, the development of next-generation sequencing (NGS) methodology, also referred to as massively parallel sequencing, has transformed the field of genetic testing because it enables detailed analysis of thousands of genes simultaneously (i.e., in parallel). Such analyses would be too time-consuming and costly to attempt using classic DNA sequencing methodologies, such as Sanger sequencing, that analyze a single gene at a time. Many laboratories have developed targeted panels of genes to be assessed by NGS to search for mutations among a group of genes that have been previously documented or have been suggested to be important in a particular disease. Such panels may include anywhere from a few genes to greater than 500. The number of genes examined varies from laboratory to laboratory depending on the testing platform and algorithm being used.”

American College of Obstetricians and Gynecologists

The American College of Obstetricians and Gynecologists (2017) updated committee Opinion on carrier screening for genetic diseases in individuals of Eastern European and Jewish descent.^16, The opinion made the following seven recommendations:

1. The family history of individuals considering pregnancy, or who are already pregnant, should determine whether either member of the couple is of Eastern European (Ashkenazi) Jewish ancestry or has a relative with one or more of the genetic conditions listed in Table 1.
2. Carrier screening for Tay-Sachs disease, Canavan disease, cystic fibrosis, and familial dysautonomia should be offered to Ashkenazi Jewish individuals before conception or during early pregnancy so that a couple has an opportunity to consider prenatal diagnostic testing options. If the woman is already pregnant, it may be necessary to screen both partners simultaneously so that the results are obtained in a timely fashion to ensure that prenatal diagnostic testing is an option.
3. Individuals of Ashkenazi Jewish descent may inquire about the availability of carrier screening for other disorders. Carrier screening is available for mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia group C, Bloom syndrome, and Gaucher disease. Patient education materials can be made available so that interested patients can make an informed decision about having additional screening tests. Some patients may benefit from genetic counseling.
4. “When only one partner is of Ashkenazi Jewish descent, that individual should be screened first. If it is determined that this individual is a carrier, the other partner should be offered screening. However, the couple should be informed that the carrier frequency and the detection rate in non-Jewish individuals are unknown for most of these disorders, except for Tay-Sachs disease and cystic fibrosis. Therefore, it is difficult to accurately predict the couple's risk of having a child with the disorder.”
5. Individuals with a positive family history of one of these disorders should be offered carrier screening for the specific disorder and may benefit from genetic counseling.
6. When both partners are carriers of one of these disorders, they should be referred for genetic counseling and offered a prenatal diagnosis. Carrier couples should be informed of the disease manifestations, the range of severity, and available treatment options. Prenatal diagnosis by DNA-based testing can be performed on cells obtained by chorionic villus sampling and amniocentesis.
7. When an individual is found to be a carrier, his or her relatives are at risk for carrying the same mutation. The patient should be encouraged to inform his or her relatives of the risk and the availability of carrier screening. The provider does not need to contact these relatives because there is no provider-patient relationship with the relatives, and confidentiality must be maintained.

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force recommendations for genetic testing for Fanconi anemia have been identified.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in October 2019 did not identify any ongoing or unpublished trials that would likely influence this review.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Genetic Testing for Fanconi Anemia
Fanconi Anemia

References:
1. Sakaguchi H, Nakanishi K, Kojima S. Inherited bone marrow failure syndromes in 2012. Int J Hematol. Jan 2013;97(1):20-29. PMID 23271412

2. Khincha PP, Savage SA. Genomic characterization of the inherited bone marrow failure syndromes. Semin Hematol. Oct 2013;50(4):333-347. PMID 24246701

3. Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. May 2010;24(3):101-122. PMID 20417588

4. Zhang MY, Keel SB, Walsh T, et al. Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity. Haematologica. Jan 2015;100(1):42-48. PMID 25239263

5. Kutler DI, Singh B, Satagopan J, et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood. Feb 15 2003;101(4):1249-1256. PMID 12393516

6. ARUP Laboratories. Laboratory Test Directory. Chromosome Analysis - Breakage, Fanconi Anemia, Whole Blood. 2017; http://ltd.aruplab.com/Tests/Pub/0097688. Accessed October 14, 2019.

7. Teo JT, Klaassen R, Fernandez CV, et al. Clinical and genetic analysis of unclassifiable inherited bone marrow failure syndromes. Pediatrics. Jul 2008;122(1):e139-148. PMID 18595958

8. Sanborn E, Zierhut H. Chapter 17: Genetic Counseling. In: Frohnmayer D, Frohnmayer L, Guinan E, et al., eds. Fanconi Anemia: Guidelines for Diagnosis and Management, Fourth Edition. Eugene, OR: Fanconi Anemia Research Fund; 2014:307-332.

9. Metha PA, Tolar J. Fanconi Anemia. GeneReviews. Seattle, WA: University of Washington; 2013.

10. Auerbach AD, Greenbaum J, Pujara K, et al. Spectrum of sequence variation in the FANCG gene: an International Fanconi Anemia Registry (IFAR) study. Hum Mutat. Feb 2003;21(2):158-168. PMID 12552564

11. Levran O, Diotti R, Pujara K, et al. Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study. Hum Mutat. Feb 2005;25(2):142-149. PMID 15643609

12. Levran O, Erlich T, Magdalena N, et al. Sequence variation in the Fanconi anemia gene FAA. Proc Natl Acad Sci U S A. Nov 25 1997;94(24):13051-13056. PMID 9371798

13. De Rocco D, Bottega R, Cappelli E, et al. Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology. Haematologica. Jun 2014;99(6):1022-1031. PMID 24584348

14. Ameziane N, Errami A, Leveille F, et al. Genetic subtyping of Fanconi anemia by comprehensive mutation screening. Hum Mutat. Jan 2008;29(1):159-166. PMID 17924555

15. MacMillan M. Chapter 20: Clinical Management Checklist. In: Frohnmayer D, Frohnmayer L, Guinan E, et al., eds. Fanconi Anemia: Guidelines for Diagnosis and Management. Fourth Edition. Eugene, OR: Fanconi Anemia Research Foundation; 2014:367-381.

16. American College of Obstetricians and Gynecologists (ACOG), Committee on Genetics. Committee Opinion No. 691: Carrier screening for genetic conditions. 2017; https://www.acog.org/Resources-And- Publications/Committee-Opinions/Committee-on-Genetics/Carrier-Screening-for-Genetic-Conditions. Accessed October 14, 2019.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

81242
81479