Appeal type: Experimental/Investigational
Decision: Overturned

Diagnosis: Developmental delay
Issue under review: Genetic testing

Determination: 
The health plan denied Genetic testing. The health plan's denial is upheld.

The patient is a teen-aged male diagnosed with autism spectrum disorder (ASD). No evaluation for ASD by a qualified diagnostician using the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) with review of the DSM-5 criteria was submitted for review. He carries numerous other diagnoses (e.g., anxiety disorder, childhood apraxia of speech) for which no diagnostic evaluations were provided. There is no documentation of his performance on standardized testing of intelligence or language function. 

An electroencephalogram showed an abnormally slow background rhythm with no epileptiform discharges; this pattern is common in children who have severe/profound developmental disabilities. He has constitutional short stature, as evidenced by delayed bone age. Previous diagnostic genetic testing for Angelman syndrome and Prader-Willi syndrome was normal. Physical examination revealed short stature, normocephaly (74th percentile), body mass index of 15.5 kg/m2 (third percentile), widow's peak, and metopic depression. He had no documented dysmorphic findings. The clinician noted "subjectively long palms," but failed to measure the palms against standard measures. Chromosomal microarray analysis was normal. The request is for whole exome sequencing (WES).

NGS (next generation sequencing) has been studied with regard to the evaluation and management of numerous conditions, including cancer, chronic disease, and developmental disabilities [Wright 2015, Tarailo-Graovac 2016, Kalia 2017, Splinter 2018].

In 2016, Tarailo-Graovac and colleagues published a prospective study of 41 consecutive subjects with intellectual disability and unexplained metabolic abnormalities who underwent WES, with a diagnostic yield of 68%. Sequencing results impacted clinical treatment in 44% of patients. In a similar study from 2015, Wright and colleagues "achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings."

The use of NGS, specifically WES, is indicated for a patient who meets one or more of the following criteria [Wright 2015, Tarailo-Graovac 2016, Kalia 2017, Splinter 2018]:
1) The phenotype or family history data strongly implicate a genetic etiology, but the phenotype does not correspond with a specific disorder [Not met] for which sequencing of a single gene is either: unavailable on a clinical basis, OR unlikely to provide a diagnosis 2) The patient presents with a defined genetic disorder that demonstrates a high degree of genetic heterogeneity, making WES analysis of multiple genes simultaneously more practical, more efficient, and less costly than sequencing multiple genes individually [Not met] 3) The patient presents with a likely genetic disorder but specific genetic tests available for that phenotype failed to arrive at a diagnosis [Not met] 4) The patient has severe global developmental delay (i.e., a patient aged zero to four years with cognitive standard score or cognitive developmental quotient < 40) or severe intellectual disability (i.e., a patient aged five years or older with IQ < 40) or believed to have a genetic etiology and had a negative initial evaluation with chromosomal microarray analysis (CMA) [Not met. There is no documentation of an IQ < 40 or cognitive standard score or DQ < 40]

This patient meets none of the above criteria for WES.  Thus, it is not medically appropriate, or standard of care.