Physician’s Header
[DATE]
LETTER OF MEDICAL NECESSITY FOR CLINICAL EXOME SEQUENICNG
Patient: [PATIENT_FIRST_NAME] [PATIENT_LAST_NAME], DOB, ID#
ICD-10 Codes
To: Insurance Company: [INSURANCE_COMPANY_NAME], Address, City, State
Subscriber Name: [POLICY_HOLDER_NAME]
Policy #: [POLICY_NUMBER]
Dear Claims Specialist,
I am writing this letter of medical necessity on behalf of the patient [PATIENT_FIRST_NAME] [PATIENT_LAST_NAME] to request coverage for genetic testing for Whole Exome Sequencing (also known as WES) to be performed at the University of Arizona Genetic Core for Clinical Services (UAGC-CS), a high complexity CLIA-certified, CAP-accredited laboratory located in Tucson, Arizona.
The purpose of this test is to identify the underlying molecular basis of a genetic disorder in an affected individual by performing a comprehensive analysis of the patient’s entire protein-coding regions, also known as Whole Exome, where around 85% genetic disease-causing changes occur1.
The clinical applications of Whole Exome Sequencing (WES) have now been well supported by the following lines of evidence:
1- The Policy Statement by The American College of Medical Genetics and Genomics published in 2012 on the clinical application of genomic sequencing recommends exome sequencing for the following clinical scenarios (adapted from original publication)2:
a. The patient’s clinical presentation (phenotype) and family history strongly indicate a genetic etiology, however, no specific disorder can be inferred by the phenotype and therefore no specific clinical targeted genetic test is available for the phenotype
b. The patient’s clinical presentation (including fetal, with limitations) suggests a likely genetic disorder, however, specific genetic tests (including targeted sequencing tests) for phenotype have not been successful in establishing e a diagnosis
c. The patient’s clinical presentation suggests a defined genetic disorder that has a high degree of genetic heterogeneity, making whole exome or genome sequencing of multiple genes simultaneously a more practical approach
2- The clinical utility of exome sequencing has been well established. In a series of 250 patients without prior diagnosis3, exome sequencing achieved an overall molecular diagnostic rate of 25% that was higher than several other comparable genetic tests, including chromosome analysis (5-10%)4, and chromosomal microarray analysis (15-20%)5. More intriguing was the fact that a small percentage of patients (4/250 (1.6%)) were diagnosed with two different Mendelian disorders. In a later study that included 2000 patients with four different types of genetic disorders; A- neurological disorder, B- neurological plus other organ systems, C- specific neurological group that included more defined neurological signs and symptoms such as ataxia, movement disorder, spastic paraplegia, and D- a non-neurological group that had findings from organ systems other than neurological, a diagnostic yield of 27.2%, 24.6%, 36.1%, and 20.1% was achieved for these groups, respectively6. Moreover, 4.6% of patients who received molecular diagnosis had a blend of phenotypes resulting from 2 single gene defects. Another 4.6% of patients had medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management6. These findings clearly demonstrate the clinical utility of exome sequencing for a spectrum of genetic disorders as opposed to individual gene testing.
Reasons for requesting Whole Exome Sequencing ON MY PATIENT
Information on Patient’s Condition:
[PATIENT_FIRST_NAME] is a [PATIENT_AGE] year-old [PATIENT_GENDER] who is [PHENOTYPE]. [HIS_HER] family history is [NOT] notable for having other individuals similarly affected, therefore strongly suggesting a genetic basis as the underlying cause for the condition. Based on the evaluations, the following syndromes/genetic diseases are on the differential
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The patient has undergone the following tests, however, all were uninformative.
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Or (if no previous testing was performed)
However, at the present time we cannot recognize a specific clinical diagnosis. Due to the heterogeneous nature of rare genetic disorders, the most efficient and cost effective way to confirm a genetic diagnosis in this patient is to perform whole exome sequencing genetic testing as recommended by the American College of Medical Genetics and Genomics.
Rather than sequencing the many potential candidate individual genes, WES is the fastest and most cost-effective way to look for a mutation amongst the large number of potential genes that could be causing this condition. Comparing this individual’s exome sequence to additional family member’s exomic data will significantly increase the utility of the test results and increase the likelihood of identifying a disease-causing gene while decreasing the chance of obtaining variants of unknown clinical significance7. This method of evaluation is especially important for individuals with apparently sporadic disease, when no one else in the family is similarly affected. By analyzing parents and unaffected sibs in cases of sporadic disease, it is frequently possible to identify de novo or new mutations in the child not present in either parent or to identify recessive diseases with one mutation inherited from each parent. Knowledge of this genetic information will allow the physician to accurately make diagnosis, assess the prognosis and make recommendations for patient care. In addition, the results of exome sequencing in the index patient will help assess the risk for family members who may also have the same condition or may be under a risk of developing the condition based on their relationship to the index patient.
Due to these benefits, exome sequencing is medically warranted in my patient. As such, I am ordering this medically necessary test and affirm that my patient has provided informed consent for genetic testing.
The whole exome sequencing test offered by the University of Arizona Genetic Core for Clinical Services (UAGC-CS), the only CLIA-certified, CAP accredited lab in Arizona to perform such high complexity testing, thoroughly analyzes the exome, with extensive results analysis and interpretation.
I recommend that you support this request for coverage of clinical exome sequencing in my patient. Exome sequencing testing can take up to several months to complete and the laboratory will not bill until testing is concluded. Therefore, we are requesting that the authorization be valid for 12 months.
Thank you for your review and consideration.
Sincerely,
Ordering Clinician Name (Signature Provided on Test Requisition Form)
(MD/DO, Clinical Nurse Specialist, Nurse-Midwives, Nurse Practitioner, Physician Assistant, Genetic Counselor*)
*Authorized clinician requirements vary by state
References:
1. Pussegoda KA. Exome sequencing: locating causative genes in rare disorders. Clin Genet. 2010 Jul;78(1):32-3.
2. ACMG Board of Directors. ACMG Policy Statement: Points to consider in the clinical application of genomic sequencing. Genet Med. 2012;14(8):759-76.
3. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Engl J Med. 2013;369(16): 1502-1511.
4. Shaffer LG; American College of Medical Genetics Professional Practice and Guidelines Committee. American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation. Genet Med. 2005;7(9):650-654.
5. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749-764.
6. Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014 Nov 12;312(18):1870-9.
7. Singleton AB. Exome sequencing: a transformative technology. Lancet Neurol. 2011 Oct;10(10):942-6.