**Indications and Limitations of Coverage**  
Based upon currently available information, HLA-DQB1*06:02 typing (81383) for
the diagnosis or management of narcolepsy is considered
experimental/investigational/unproven for all populations. Although research
suggests a strong association between HLA-DQB1*06:02 and narcolepsy risk, HLA-
DQB1*06:02 typing is insufficient to confirm a diagnosis of narcolepsy, rule
out a diagnosis of narcolepsy or quantify risk for narcolepsy. Therefore, at
this time there is no clinical utility for genetic testing or HLA-DQB1*06:02
typing in the diagnosis or treatment of narcolepsy.  
  
 **Background**  
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness,
cataplexy (sudden loss of voluntary muscle tone), and uncontrollable sleep
episodes. Most cases of narcolepsy are sporadic, with symptoms beginning
around the time of adolescence.  
  
According to the International Classification of Sleep Disorders, Third
Edition (ICSD-3) and the Diagnostic and Statistical Manual of Mental Disorder,
Fifth Edition (DSM-5), narcolepsy is diagnosed by a combination of physical
exam, medical history, polysomnogram, multiple sleep latency testing (MSLT),
and low CSF hypocretin-1 levels. Current recommended treatment options include
stimulants and antidepressants. At this time, treatment is aimed towards the
control of symptoms and is not curative.12  
  
Narcolepsy has a multifactorial etiology, likely caused by the interaction
between genetic risk factors and environmental exposures. Research efforts to
identify the genetic contributors to narcolepsy have focused on an association
between certain human leukocyte antigen (HLA) haplotypes and narcolepsy risk.
The HLA complex encodes greater than 200 genes responsible for the recognition
of foreign antigens. These genes are highly polymorphic, and certain alleles
have long been known to confer risk for autoimmune disorders.  
  
A variation of the HLA-DQB1 gene called HLA-DQB1*06:02 has been strongly
associated with narcolepsy, particularly in individuals who also have
cataplexy and a loss of hypocretins. Several genetic association studies in
ethnically diverse populations have found a robust association between
narcolepsy and the HLA-DQB1*06:02 allele. However, 15 to 25% of unaffected
individuals in the general population also carry this risk haplotype,
suggesting that it is necessary but not sufficient for the development of
narcolepsy.6 Additionally, persons with narcolepsy and cataplexy have been
identified without the HLA-DQB1*06:02 marker.4 More recent studies further
suggest that predisposition to narcolepsy may be the result of complex genetic
associations between multiple risk alleles.11  
  
Despite multiple studies replicating the association between HLA-DQB1*06:02
and narcolepsy in different ethnic groups, the overall contribution of HLA
variation to disease risk is low. Monozygotic twin studies have shown only
partial concordance (25-31%), indicating that environmental factors play a
large role in the etiology of narcolepsy.8 Recent studies have suggested that
exposure to streptococcus, H1N1, and the H1N1 vaccine may also increase the
risk for narcolepsy, specifically among individuals with the HLA-DQB1*06:02
allele.3,14,4  
  
Although research suggests a strong association between HLA-DQB1*06:02 and
narcolepsy risk, at this time there is no evidence for any diagnostic utility
of HLA typing.5