Appeal type: Experimental/Investigational
Decision: Overturned

The patient is a male who has severe developmental delay, particularly of his gross motor milestones, abnormal tone. abnormal movements, and a history of epilepsy.
Evaluation notes by his pediatric neurologist were reviewed. In her initial note, the provider describes that the patient was born at 32 weeks 4 days gestation, the second naturally conceived child to a mother whose first pregnancy was complicated by pre-eclampsia. Mother took baby aspirin during her pregnancy with the patient. There was no history of alcohol or recreational drug use during pregnancy. Mother had vaginal bleeding for several days prior to delivery, and there was concern for placental abruption. Birth weight was 2090g, Apgar scores were 8 at 1 minute, and 9 at 5 minutes. The patient spent 13 days in the neonatal intensive care unit. He was initially on continuous positive airway pressure (CPAP). A rule out sepsis workup was performed, during which time he was treated with ampicillin and gentamicin. Cultures were negative.
The patient started having seizures when he was 2 months old. These were manifested by jerks of the upper torso, with stiffening of the limbs, lasting 10-15 seconds and occurring in clusters. Video electroencephalogram (EEG) telemetry showed onset of seizures alternating between the left and right centroparietal regions. No further seizures were noted after he was loaded with phenobarbital.
The patient had episodes of rapid breathing and staring when he was an infant, but video EEG telemetry was normal, and the events were thought to be non-epileptic. Keppra was added, but per his family the events for which it was added were later found to be non-epileptic. He has had subsequently normal EEGs, and normal video EEG telemetry. In her later notes, the provider describes weaning down the Keppra, then phenobarbital as he had remained seizure free for two years.
The patient has significant developmental delay, particularly with regard to his gross motor skills. In her note the provider described that he was unable to walk, crawl, pull to stand, or sit without support for more than 2 seconds.
Family history is significant for several family members having muscular dystrophy on father's side of the family. Father is unaffected. A first cousin had febrile seizures, grandmother and an aunt had multiple sclerosis, and maternal grandfather had epilepsy.
The patient lives with his parents and older sister. Examination was significant for decreased axial tone, increased appendicular tone, normal muscle bulk and deep tendon reflexes. Strength was at least 4/5 throughout.
Diagnostic evaluation has included normal plasma amino acids, urine organic acids, lactate, pyruvate, acyl carnitine profile, creatine kinase, and acetyl glycine levels.
Magnetic resonance imaging (MRI) of the brain has shown no structural abnormality on two occasions.
Chromosomal microarray analysis showed a 203 kilobase loss at 4p16.2, felt to be a copy number variant of unknown significance and not responsible for the patient's developmental delay and epilepsy.
The provider recommended Whole Exome Sequencing as the next step in the diagnostic evaluation to try to determine an underlying etiology for his developmental disabilities. Whether Whole Exome Sequencing is likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease is the issue at question in this review.

The health plan's determination is overturned.

The proposed health service or treatment Whole Exome Sequencing is likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease. The patient has had a thorough and appropriate step-wise diagnostic evaluation aimed at determining the etiology of his developmental delay and epilepsy without revealing a definitive diagnosis.
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] 
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.
In a case series of 53 patients with developmental delay seen in the pediatric neurology clinic at the University of Michigan, Nolan and Carlson [3] 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. [4] recently discussed the role of 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.