Appeal type: Experimental/Investigational
Decision: Overturned

Diagnosis: Genetic Diseases-Other
Treatment: Genetic Testing-WES
The health plan denied the WES test as experimental/Investigational. The reviewer has overturned the HP determination in whole.

This patient has  clinical symptoms of chronic abdominal pain, acute pancreatitis, and persistently elevated sweat chloride levels. These symptoms are strongly suggestive of underlying genetic syndrome or disorder. She has been evaluated multiple times by medical geneticist and a number of genetic tests (including CFTR gene analysis for cystic fibrosis) have been performed with normal results. The AP ordered whole-exome sequencing.

The proposed genetic testing is likely to be beneficial. Despite extensive genetic evaluations and tests a definitive diagnosis has not been established for this member. The WES test is the most appropriate test in such clinical circumstances. The alternative is to perform targeted tests of a selected gene or a group of genes that may cause disorders with similar symptoms (such as genetic forms of chronic pancreatitis). However, this alternative approach is more cost- and time-demanding and are less likely to uncover the genetic cause of this patient's disorder. Based on these considerations the WES test can be justified as medically necessary for this member. Furthermore, the WES test meets the recommended guidelines and is the current standard of care for patients with suspected genetic disorders where diagnosis has not been established after proper genetic evaluations and tests.
The whole exome sequencing (WES) test analyzes the protein coding portion of the human genome and is offered by a number of CLIA-certified diagnostic laboratories. WES does not need Food and Drug Administration (FDA) approval as it is a genetic test based on routine molecular techniques, such as deoxyribonucleic acid (DNA) isolation, enrichment, polymerase chain reaction (PCR), and DNA sequencing. The results of the tests will likely identify the underlying genetic causes of this patient's disorder and may offer an opportunity for targeted treatment. Furthermore, WES is in a wide use by clinical geneticists and is current standard of care for patients with similar complex genetic syndromes of unknown causes. Despite extensive genetic clinical and molecular evaluations no definitive diagnosis was established for this patient. The disease is presumed to have genetic etiology based on the clinical symptoms. The WES has the potential to identify a mutation a gene responsible for this member's disease.
The current recommendations by the American College of Medical Genetics determines the indications for exome sequencing that are listed below: Indications for Diagnostic Testing:
1. WGS/WES should be considered in the clinical diagnostic assessment of a phenotypically affected individual when:
a.	The phenotype or family history data strongly implicate a genetic etiology, but the phenotype does not correspond with a specific disorder for which a genetic test targeting a specific gene is available on a clinical basis (THIS IS THE CASE OF THIS MEMBER).
b.	A patient presents with a defined genetic disorder that demonstrates a high degree of genetic heterogeneity, making WES or WGS analysis of multiple genes simultaneously a more practical approach.
c.	A patient presents with a likely genetic disorder but specific genetic tests available for that phenotype have failed to arrive at a diagnosis (THIS IS ALSO THE CASE OF THIS MEMBER).
d.	A fetus with a likely genetic disorder in which specific genetic tests , including targeted sequencing tests, available for that phenotype have failed to arrive at a diagnosis.
Recent developments in high-throughput sequence capture methods and next-generation sequencing technologies have now made WES a viable approach that has become a standard of care in order to elucidate the genetic basis of Mendelian disorders with hitherto unknown etiology. The current status of exome sequencing is summarized in a recent review papers by Ku et al (2012) and Thompson et al (2012). Hammer et al (2012) provided compelling evidence that exome sequencing is an efficient and direct diagnostic tool for identifying the causes of complex and genetically heterogeneous neurodegenerative diseases, early-stage disease, or cases with limited clinical data. The total diagnostic yield of exome sequencing was 16% in a large cohort of patients with severe intellectual disability, as recently demonstrated by de Liqt et al (2012). The diagnostic yield for finding a causative deleterious gene mutation using WES ranges from around 20% to 30% in patients with the clinical manifestations listed below in whom biochemical, chromosomal, microarray, metabolic, and targeted gene sequencing studies have yielded normal or equivocal results.
In a study by Nolan and Carlson (2016) whole exome sequencing was recommended obtained in 53 patients with various symptoms of genetic disorders. The most common indication for whole exome sequencing was neurodevelopmental disorders. Whole exome sequencing improved the presumptive diagnostic rate in the patient cohort from 25% to 48%. Clinical implications included family planning, medication selection, and systemic investigation. Importantly, compared to current second tier testing, whole exome sequencing can result in lower long-term charges and more timely diagnosis. The actors concluded that overcoming barriers related to whole exome sequencing insurance authorization could allow for more efficient and fruitful diagnostic neurological evaluations.
Cordoba M et al. also stated that WES for neurogenetic disorders has been proven to be an effective, cost- and time-saving approach for the molecular diagnosis of this heterogeneous and complex group of patients.
In concurrence with the currently accepted standard of care, Lazaridis KN et al concluded that the significant diagnostic yield, moderate cost, and notable health marketplace acceptance for WES compared with conventional genetic testing make the former method a rational diagnostic approach for patients on a diagnostic odyssey.
There are a number of genetic syndromes and disorders that are successfully treated when a definitive diagnosis is established. Without a specific diagnosis it is not possible to predict what the best treatment options for this member are, which is why the WES test is medically necessary and appropriate. Once a specific genetic diagnosis is established the next step in the management of this member would be to determine the best treatment options for her condition.