Appeal type: Experimental/Investigational
Decision: Overturned

Diagnosis:  Myelomeningocele, hydrocephalus, microcephaly.
Treatment:  Genetic testing Exome Sequence Analysis (Pre-Service).

The insurer denied the Genetic testing Exome Sequence Analysis (Pre-Service).  The denial is overturned.

The patient is a girl with a history of myelomeningocele status post fetal repair,
hydrocephalus, microcephaly, dysmorphic craniofacial features and neurogenic bowel and bladder.  She has hypoplastic cerebellum on MRI (magnetic resonance imaging), strabismus, bilateral hearing loss, and profound developmental delay and intellectual disability.  Her combination of clinical features does not identify a specific genetic disorder or syndrome.  Her AP (attending physician) geneticist has requested whole exome sequencing to better define her diagnosis, refine her prognosis, direct her future medical, surgical, developmental cares, hopefully improve her outcomes, and provide recurrence risk information to her parents.

Yes, the health plan should cover the Exome Sequence Analysis.

Yes, the Exome Sequence Analysis is likely to be more beneficial.

Whole exome sequencing has a 30 to 40% diagnostic yield in this young girl's clinical context, and leads to disease and/or syndrome specific interventions and treatment changes that will hopefully improve her outcomes.  There is no other standard treatment or treatments that are more likely than whole exome sequencing to provide a specific diagnosis in this young girl's clinical context.  For further discussion, see rationale below.

Evidence-based medicine and published, peer-reviewed, authoritative medical
literature render this testing medically and clinically appropriate in this one-year-old
girl with repaired myelomeningocele, microcephaly, and multiple congenital anomalies.  Whole Exome Sequencing (WES) to identify novel or unusual genetic disorders is now viewed as medically and clinically appropriate, is consistent with the generally accepted "best practices" in medical genetics, meets the generally accepted standards of medical genetics practice and is consistent with the views of the major professional medical genetic organizations in the United States.  It is clinically appropriate for individuals with unusual combinations of medical problems that are not explained by any known genetic or nongenetic syndrome, neurogenetic disorders, unusual combinations of birth defects and congenital anomalies, unexplained intellectual disability, autism spectrum disorders, dysmorphic features and developmental delays.  The available published, peer-reviewed scientific evidence clearly demonstrates the utility and efficacy of Whole Exome Sequencing for identification of specific gene mutations underlying developmental anomalies, anatomic birth defects, unusual clinical syndromes, mental retardation, developmental, and autistic syndromes to be effective in improving health
outcomes.  It is clinically appropriate in its type, frequency, extent and delivery
settings.  It is appropriate to the adverse health condition for which is provided and
used and is expected to produce the desired outcome of a specific clinical and
genetic diagnosis.  It is the most conservative alternative that effectively addresses
and treats this medical problem.

WES (whole exome sequencing) provides essential, unique, and appropriate information when used for diagnostic purposes.  Its use is clearly not for the convenience of the patient, physician, or other health care practitioner.  In addition, this testing is lawfully marketed for the proposed use and is performed in CLIA (Clinical Laboratory Improvement Amendments)-approved laboratories.  It is not the subject of review or approval by an IRB (institutional review board) for the proposed use.  Its use in the context of this and related clinical cases is not the subject of a clinical trial.

This patient displays clinical features consistent with a genetic disorder, and the clinical condition is clearly associated with a significant disability, and, after history, physical examination, pedigree analysis and completion of conventional studies, a definitive diagnosis remains uncertain.  The results of the requested test, whole exome sequencing, will be used specifically for diagnosis of the underlying condition and may provide treatment options for the patient's disorder and influence current and future treatment, as well as provide recurrence risk information to the family.  This testing is well supported by authoritative, peer-reviewed, published medical literature and does not require FDA (Food and Drug Administration) approval for its performance.

Whole exome sequencing (WES) meets medical genetics standard of care criteria for diagnostic genetic testing; genetic counseling will be provided before the actual diagnostic genetic testing; this testing is medically necessary, clinically appropriate,
and is supported as a standard of diagnostic care in the published, peer-reviewed
medical literature.  This conclusion is further strengthened and supported by an article published in the New England Journal of Medicine online: "Clinical Whole Exome Sequencing for the Diagnosis of Mendelian Disorders Online First; Y. Yang et al."  It was noted, "In conclusion, the use of whole-exome sequencing to analyze 250 consecutive clinical cases yielded a diagnosis in 25% of these cases, which supports the use of whole-exome sequencing as a diagnostic test for patients with nonspecific or unusual disease presentations of possible genetic cause and for patients with clinical diagnoses of heterogeneous genetic conditions."

A more recent clinically based study of whole exome sequencing has yielded virtually identical data and conclusions: "Enhanced Utility of Family Centered Diagnostic Exome Sequencing with Inheritance Model-based Analysis: Results from 500 Unselected Families with Undiagnosed Genetic Conditions, Farwell et al.  Genetics in Medicine, "This study concluded that: "Overall, we present results from the largest clinical cohort of diagnostic exome sequencing cases to date.  These data demonstrate the utility of family-based exome sequencing and analysis toobtain the highest reported detection rate in an unselected clinical cohort, illustrating the utility of diagnostic exome sequencing as a transformative technology for the molecular diagnosis of genetic disease." This conclusion is further supported by a more recent publication: "Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental
disorders, Sarah E. Soden, et al."

Whole exome sequencing is not experimental, investigational, or unproven.  This testing is performed in CLIA (Clinical Laboratory Improvement Amendments)-approved laboratories by American Board of Medical Genetics Board-Certified Clinical Molecular Geneticists and is supported by peer-reviewed, published medical literature.  It is now a standard of care in diagnosis of individuals with undefined and unexplained genetic and/or neurologic syndromes, developmental delay, skeletal dysplasias, malformations, birth defects, dysmorphic features, mental retardation, and autism spectrum disorders.  The clinical and medical utility of this testing in delineating and identifying a specific gene mutations that would not be detectable by conventional microarray, targeted gene sequencing, karyotypic, cytogenetic and chromosomal studies, both prenatally and postnatally, is well proven and documented (see References below).

There are many examples of genetic disorders which are exceptionally difficult to diagnose by conventional means and whose clinical outcome can be modified by accurate genetic diagnosis using whole exome sequencing; a partial list follows with
disease specific treatments indicated in parentheses.  These include disorders of riboflavin metabolism and transport (Riboflavin, FAD [flavin adenine dinucleotide],
FMN [flavin mononucleotide]), variants of urea cycle disorders (ammonia
scavengers, amino acid supplements, special diets), unusual Hyperinsulinemia/Hyperammonemia syndromes (ammonia scavengers, diazoxide,
glucagon), Smith-Lemli-Opitz syndrome (crystalline cholesterol), certain variants of
the Carbohydrate Deficient Glycoprotein Syndromes (mannose), rare neurotransmitter metabolism disorders (Kuvan, 5-hydroxytryptophan, L-dopamine), creatine synthetic disorders (creatine), MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome-like mitochondrial disorders (arginine, citrulline), lysosomal storage diseases (enzyme replacement therapies, substrate reduction therapies, Miglustat), familial/genetic seizure syndromes (choice of preferred antiepileptic drugs), and unusual disorders of amino acid metabolism (special diets, amino acid supplements).  It should also be noted that sequential or simultaneous enzymatic, biochemical, metabolic, and/or genetic/molecular testing for these individual disorders or groups of disorders, when taken together, will be more burdensome than whole exome sequencing.

It may well impact further medical management depending on the specific defect
underpinning the cause of the malformations.  Many genetic disorders predispose to
unforeseen risks, tumor development, cardiomyopathy or cardiac conduction
defects, seizures and many other clinical entities, which are not directly linked to a
physical trait.  The medical management team for this patient has a broad
differential of possible diagnoses and considered WES (whole exome sequencing)
as an effective manner in which to screen multiple genes at once.