Reducing the Cost of the Diagnostic Odyssey in Early Onset Epileptic Encephalopathies

Abstract

Whole exome sequencing (WES) has revolutionized the way we think about and diagnose epileptic encephalopathies. Multiple recent review articles discuss the benefits of WES and suggest various algorithms to follow for determining the etiology of epileptic encephalopathies. Incorporation of WES in these algorithms is leading to the discovery of new genetic diagnoses of early onset epileptic encephalopathies (EOEEs) at a rapid rate; however, WES is not yet a universally utilized diagnostic tool. Clinical WES may be underutilized due to provider discomfort in ordering the test or perceived costliness. At our hospital WES is not routinely performed for patients with EOEE due to limited insurance reimbursement. In fact for any patient with noncommercial insurance (Medicaid) the institution does not allow sending out WES as this is not "established"/"proven to be highly useful and cost effective"/"approved test" in patients with epilepsy. Recently, we performed WES on four patients from three families and identified novel mutations in known epilepsy genes in all four cases. These patients had State Medicaid as their insurance carrier and were followed up for several years for EOEE while being worked up using the traditional/approved testing methods. Following a recently proposed diagnostic pathway, we analyzed the cost savings (US dollars) that could be accrued if WES was performed earlier in the diagnostic odyssey. This is the first publication that addresses the dollar cost of traditional testing in EOEE as performed in these four cases versus WES and the potential cost savings.

Figure 1

A timeline indicating the 8-year diagnostic odyssey for patients C1 and C2.

Figure 2

KARS has two isoforms, one retained in the cytoplasm and one transported to the mitochondria. A mitochondrial targeting sequence spans exons 2 and 3; the cytoplasmic isoform skips exon 2 and is not transported. Case 3 has two inherited mutations that disrupt the gene. An Ala29Pro missense mutation alters the end of the mitochondrial targeting sequence; we predict that it is not transported, but the cytoplasmic isoform is still functional. The other allele has an approximately 8 kb deletion spanning exons 2–4, resulting in a frameshift and early termination.