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 female child with medical history significant for premature birth at 35 weeks' gestation, myelomeningocele status post fetal repair, hydrocephalus, microcephaly, hypoplastic cerebellum, neurogenic bowel and bladder, strabismus, short stature (length less than 1st percentile), and hearing loss.  She was referred to Genetics Clinic for evaluation and was noted to have the following dysmorphic features: wide nasal bridge, bulbous nasal tip, anteverted nares, long philtrum, micrognathia, sparse eyebrows, epicanthic folds, and fisted hands with adducted thumbs.  The family history was non-contributory. 

With completion of chromosome analysis and chromosomal microarray, both normal, several complex conditions were under consideration in addition to the possibility of a novel disease.  The defined conditions under consideration included Smith-Lemli-Opitz syndrome type 1 (mutations in the delta-7 sterol-reductase gene on chromosome 11q13), Menke-Hennekam syndrome 1 (mutation in exon 30 or 31 of the gene on chromosome 16p13), and oculo-cerebro-facial syndrome Kaufman type (loss of E3 ubiquitin-protein ligase on chromosome 12p24).  

Whole exome gene sequencing has been recommended to potentially identify clear genetic etiology.

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

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

Whole exome sequencing is a means of investigating the human genome using next generation sequencing, "consisting of a massively parallel sequencing strategy enabling rapid genome-scale sequencing of DNA [deoxyribose nucleic acid] at a significantly reduced cost relative to the Sanger method [the most common method used for single-gene and multi-gene sequencing currently], yet capable of detecting all the same types of mutations (e.g., point mutations, small insertions/deletions, and splice site mutations).  Because of the associated reduction in cost and time, next-generation sequencing allows for sequencing of the entire exome, i.e., the 1%-2% of the human genome representing all protein-coding regions." (1)  Clinical exome sequencing "is rapidly becoming the new standard for sequencing in genetic diagnostics, as all 21,000 genes in the human genome can be evaluated in an essentially unbiased manner." (1)

When determining the appropriateness of genetic testing, the first essential step is clinical evaluation.  In instances where phenotypic presentation does not yield a diagnosis, rather than embarking on a series of expensive diagnostic tests, "exome
sequencing could abbreviate or stop the diagnostic testing cascade by establishing the specific rare diagnosis genetically.  A Pediatric Genomic Medicine group found that next-generation sequencing has the potential to truncate the diagnostic odyssey by 5 years." (1)  Further, "exome sequencing results can alleviate family member concerns regarding potential risk of transmission or identify individuals in need of more specialized care or surveillance to reduce future disease complications." (1) 

Clinical exome sequencing is not a screening test.  However, if the differential diagnosis is broad, "exome sequencing may be the most high-yield and cost effective evaluation strategy to pursue." (1)  Currently, exome sequencing is generally indicated for undiagnosed neurologic disorders with nonspecific or clinically heterogeneous phenotype, following expert evaluation with detailed history and examination, and negative initial genetic testing when deemed appropriate.

In this patient's case, she has a number of clinical conditions as a result of and in
addition to her myelomeningocele, as well as a number of dysmorphic features.  Both chromosomal analysis and chromosomal microarray have failed to identify a genetic etiology.  Using current genetic "catalogues" representing clinical features and recognizable syndromes, several conditions have come under consideration as detailed above, none of which completely explains her situation.  Each of these conditions, as well as any potential novel conditions, has a unique pathway of comprehensive care and anticipatory guidance for future complications.  Whole exome sequencing, as described above, is indicated in this type of situation, with an undiagnosed neurologic disorder and complex phenotype despite detailed history/physical and negative initial genetic testing. Exome sequencing would be more beneficial for evaluation of this situation than any other available testing.