Appeal type: Experimental/Investigational
Decision: Overturned

Diagnosis: Central Nervous System/Neuromuscular Disorder. 
Treatment: Genetic Testing. 
The insurer denied: Genetic Testing: Exome Sequence Analysis/WES-Whole Exome Sequencing. 
The denial is overturned in whole. 

The patient is a male who has been evaluated in the Neurogenetics Clinic. Reports  and a letter were reviewed. The patient has developmental delay and abnormal movements. His mother first noticed the movements when he was starting to walk. He was evaluated by a child neurologist and was thought to have epilepsy. He was started on Trileptal, which did not help his movements. The movements are described as intermittent and choreiform, and do not correlate with fatigue. They are troublesome to him, who may grab an affected limb. The frequency of the episode movements is increasing, and now involve his face and limbs during sleep, awakening him. He may also have drooping of his left eyelid on days when the limb movements are prevalent. He usually has episodes of movements 3-4 times daily, lasting several minutes. He has had a trial of Gabapentin, which was of some benefit for the movements during sleep. Tetrabenazine did not help.

The proposed health service, Genetic Testing: Exam Sequence Analysis/WES - Whole Exome Sequencing is likely to be more beneficial than any standard treatment (in this case, testing) for the insured' life threatening or disabling condition. The patient has developmental delay and an unusual hyperkinetic movement disorder. His treating physicians are highly suspicious that the underlying etiology is a neurogenetic disorder. The reviewer concurs with their opinion.
Newer genetic diagnostic techniques available, including whole exome sequencing, frequently obviate a lengthy, expensive and frustrating diagnostic odyssey for the patient and their family [1].
In 2012 American College of Medical Genetics (ACMG) released a policy statement identifying the circumstances in which Whole Exome Sequencing can and should contribute to clinical care [2].
These circumstances included:
A.	A phenotype or family history strongly implicating an underlying genetic cause, but the phenotype does not correspond with a specific disorder for which a genetic test targeting a specific gene is available.
B.	A patient presents with defined genetic disorder that demonstrates a high degree of genetic heterogeneity, making Whole Exome Sequencing 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.
Vissers et al. [3] studied 150 patients (and their parents) presenting with complex neurological disorders of suspected genetic origin. In a parallel study, all patients received both the standard diagnostic workup (e.g., cerebral imaging, muscle biopsies or lumbar punctures, and sequential gene-by-gene-based testing) and WES simultaneously. The authors found that WES identified significantly more conclusive diagnoses (29.3%) than the standard care pathway (7.3%) without incurring higher costs. The authors concluded that "exploratory analysis of WES as a first-tier diagnostic test indicates that WES may even be cost-saving, depending on the extent of other tests being omitted."
In a case series of 53 patients with developmental delay seen in the pediatric neurology clinic at the University of Michigan between 2011 and 2015, Nolan and Carlson [4] reported that 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. The authors concluded that compared to current second tier testing, whole exome sequencing can result in lower long-term charges and more timely diagnosis.
Wise et al. [5] recently discussed how whole exome sequencing is being used to obtain molecular diagnoses for pediatric patients with previously undiagnosed diseases, with the potential for change in clinical management.
Kuperberg et al. [6] described a retrospective cohort study performed whole exome sequencing on 57 patients in neurogenetic clinics, with unknown diagnoses despite previous workup. A causative gene was identified in 49.1% of patients, of which 17 had an autosomal dominant mutation, 9 autosomal recessive, and 2 X-linked. The highest rate of positive diagnosis was found for patients with developmental delay, ataxia, or suspected neuromuscular disease. Whole exome sequencing warranted a definitive change of treatment for 5 patients. The authors concluded that use of the technique could affect diagnosis, treatment, and prognostics for both patients and relatives.
Cordeiro et al. [7] reviewed 51 patients in the Pediatric Genetic Movement Disorder Clinic at the Hospital for Sick Children in Toronto. Twenty-five patients had dystonia, 27 patients had ataxia, 7 patients had chorea-athetosis, 8 patients had tremor, and 7 patients had hyperkinetic movements. A genetic diagnosis was confirmed in 26 patients, including in 20 patients with ataxia and 6 patients with dystonia. Targeted next-generation sequencing panels confirmed a genetic diagnosis in 9 patients, and whole exome sequencing identified a genetic diagnosis in 14 patients. The authors concluded that they obtained a genetic diagnosis in 26 (51%) patients. A genetic diagnosis provided either disease-specific treatment or affected management in 10 patients with a genetic diagnosis, highlighting the importance of early and specific diagnosis.
Whole exam sequencing for this patient has a significantly higher probability of providing a diagnosis and guiding treatment of his developmental delay and movement disorder of apparent neurogenetic etiology than any other standard testing.