Medical Necessity Justification

When completed, this form will contain Protected Health Information. Follow your institutional HIPAA guidelines when usingthis form.

Patient Name: DOB:

Payor: Plan:

Subscriber Name:DOBSubscriber Number:

Ordering Provider:

Contact Person:Phone:Fax:

Name of test:Whole Exome Sequencing

Test Code:

CPT code(s):

ICD10 code(s):

List price:

Do you have a preferred clinical laboratory for genetic testing?

X NO(or not applicable)

__ YES, (provide preferred lab name):

Please state the reason why testing should/must be performed at this laboratory:

@FNAME@ is a @AGE@ @SEX@ with a history of ***.

-What laboratory and/or clinical testing have been performed to date (genetic and other testing)?

-Why is genetic testing necessary at this time? @FNAME@ has a complex medical history suggestive of an underlying genetic etiology and has had normal/negative testing thus far. The majority of genetic changes that cause known diseases occur within the exome – the set of protein-coding regions that make up approximately 1% of the entire human genome.1Whole Exome Sequencing (WES) has been shown to be a useful diagnostic test for individuals with previously unidentified genetic conditions.2

The American College of Medical Genetics and Genomics published a 2012 Policy Statement on the clinical application of genomic sequencing.3The statement recommends exome sequencing for the following clinical scenarios (adapted from original publication):

1. The clinical presentation (phenotype) or family history strongly implicate a genetic etiology, but the phenotype does not correspond with a specific disorder for which a targeted clinical genetic test is available.
2. The clinical presentation suggests a likely genetic disorder, but specific genetic tests (including targeted sequencing tests) for phenotype have failed to provide a diagnosis.
3. A defined genetic disorder with a high degree of genetic heterogeneity is suspected, making whole exome or genome sequencing of multiple genes simultaneously a more practical approach.

@FNAME@’s history of *** suggests that @HE@ has a genetic disorder for which conventional single-gene or biochemical testing has not been able to diagnose. Per ACMG guidelines (points ***1,2,3 which ones?), clinical exome sequencing is warranted in@FNAME@.3

-How will the results of the genetic test, whether negative or positive, impact the future management of the member being tested? (explainall that apply):

Stop the need for further diagnostic testing:Additional genetic testing would not be pursued if WES identified a clinically significant result consistent with the patient’s phenotype.

Inform on prognosis:A clinically significant result will allow us to analyze precedent and provide information on other individuals with changes in the same gene regarding natural history and prognosis (if available).

Change treatment plan (e.g. medical or surgical decision-making or treatment):Clinical exome sequencing has the potential to lead to a specific treatment or management strategy that changes clinical outcome.2,4,5,6. A recent study showed that WES results affected medical management in 44% of probands with intellectual developmental disorder and unexplained metabolic abnormalities.7

Change surveillance (e.g. annual echocardiograms, either begin or stop):Clinical exome sequencing has the potential to lead to a specific treatment or management strategy that changes clinical outcome.A diagnosis can also help identify necessary medical referrals and screening for associated complications.2,4,5,6 A recent study showed that WES results affected medical management in 44% of probands with intellectual developmental disorder and unexplained metabolic abnormalities.7

Provide information for family members:Identification of a clinically significant finding on WES would allow for a refined risk of recurrence for the parents and targeted, informative testing in other at-risk family members. Also, it would allow for @FNAME@ to better understand the risk to @HIS@ future children.

-What is the probability that this test will be positive? If this is not known, then please indicate which clinical features increase the probability that this test will provide a diagnosis. The detection rate using WES varies depending on the clinical indication. Among individuals with intellectual disability or developmental delay, WES has identified an etiology in approximately 32% of patients. This number increases to approximately 36% among those with multiple congenital anomalies or seizures.8 A more recent study reported a 68% WES detection rate among individuals with intellectual developmental disorder and unexplained metabolic abnormalities.7

-If this is a request is for a gene panel, then please describe why a single gene test is not as useful.NA

-Please list specific guidelines and/or references in support of your request:

1.Pussegoda KA. Exome sequencing: locating causative genes in rare disorders. Clin Genet. 2010;78(1):32-3.

2. Biesecker LG and Green RC. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014;370:2418-25.

3. ACMG Board of Directors. ACMG Policy Statement: Points to consider in the clinical application of genomic sequencing. Genet Med. 2012;14(8):759-76.

4. Worthey EA et al. Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med. 2011;13(3):255-62.

5. Cannon A et al. Advanced genetic testing comes to the pain clinic to make a diagonosis of paroxysmal extreme pain disorder. Case Rep Neurol Med. 2016;2016:9212369

6. Lee S et al. Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4. J Allergy ClinImmunol. 2015;137(1):327-30.

7. Tarailo-Graovac et al. Exome sequencing and the management of neurometabolic disorders. N Engl J Med. 2016;374(23):2246-55.

8. Farwell KD. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based anlaysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med. 2014; Nov 6. doi: 10.1038/gim.2014.154. [Epub ahead of print].