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 upheld. The patient is an female toddler. She has been diagnosed with multiple congenital anomalies that include spina bifida, hydrocephalus, neurogenic bladder, microcephaly, and dysmorphic features. Genetic test was initiated with microarray, which failed to identify any abnormalities. The provider has subsequently requested whole exome sequencing (WES). The request has been denied due to the testing being considered experimental/investigational. Submitted medical records include a very detailed discussion regarding the patient's clinical presentation, which does describe the multiple organ abnormalities, benign family history, and goals of genetic exome sequencing. The discussion does include a review of specific syndromes of which many of this child's findings are consistent with a specific syndrome (Smith-Lemli-Opitz). Other syndromes also have findings that are partially met in this patient. The provider maintains that clinical utility of the requested testing has been established and offers a single example of how such testing benefited a particular patient. No, the health plan should not cover the Exome Sequence Analysis. Denial of the proposed treatment is appropriate based on the testing being experimental/investigational and unproven to benefit health outcome. No, the Exome Sequence Analysis is not likely to be more beneficial. Benefit to patient management and health outcome is not established to result from WES (whole exome sequencing) testing. The testing is best considered an academic activity with little likelihood of patient having clinical benefit. Current published peer-reviewed medical literature does not demonstrate that a patient with these findings (spina bifida, hydrocephalus, neurogenic bladder, microcephaly, and dysmorphic features) is likely to see improved clinical condition as accruing from WES (whole exome sequencing) testing. While testing may identify genetic errors, benefit to health outcome does not necessarily follow. Submitted medical records include a very detailed discussion regarding the patient's clinical presentation which does describe the multiple organ abnormalities, benign family history, and goals of genetic exome sequencing. The discussion does include a review of specific syndromes of which many of this child's findings are consistent with a specific syndrome (Smith-Lemli-Opitz). Other syndromes also have findings that are partially met in this patient. The provider maintains that clinical utility of the requested testing has been established and offers a single example of how such testing benefited a particular patient. However, in this scenario, there is no known cure for microcephaly, and associated neurodevelopmental deficits. Benefit to this patient's disabilities resulting from spina bifida also would not benefit from requested testing.
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.
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.
1) NPJ Genom Med. 2018; 3: 16. Published online 2018 Jul 9. doi: 10.1038/s41525- 018-0053-8 PMCID: PMC6037748 PMID: 30002876. Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. Michelle M. Clark,1 Zornitza Stark,2 Lauge Farnaes,1,3 Tiong Y. Tan,2,4 Susan M. White,2,4 David Dimmock,1 and Stephen F. Kingsmore corresponding author1 "Additional randomized controlled studies are needed, particularly studies that examine the diagnostic determinants of optimal outcomes for children with rare genetic diseases." 2) Genet Med. 2017 Sep; 19(9): 1055-1063. Published online 2017 Mar 23. doi: 10.1038/gim.2017.1 PMCID: PMC5589982 PMID: 28333917. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Lisenka E.L.M. Vissers, PhD,1,* Kirsten J.M. van Nimwegen, MSc,2, Jolanda H. Schieving, MD,3 Erik-Jan Kamsteeg, PhD,1 Tjitske Kleefstra, MD, PhD,1 Helger G. Yntema, PhD,1 Rolph Pfundt, PhD,1 Gert Jan van der Wilt, PhD,2 Lotte Krabbenborg, PhD,4,5 Han G. Brunner, MD, PhD,1,6 Simone van der Burg, PhD,4 Janneke Grutters, PhD,2, Joris A. Veltman, PhD,1,6 and Michèl A.A.P. Willemsen, MD, PhD3. 3) Genetics in Medicine Genet Med advance online publication 3 December 2015. Clinical application of whole-exome sequencing across clinical indications. "Although the numbers are still modest for some indications, our series demonstrates a diagnostic yield of at least 25% for indications of deafness, blindness, muscular dystrophies/myopathies, skeletal dysplasias, dermatologic conditions, multiple congenital anomalies, intellectual disabilities/developmental delay/hypotonia, cardiac diseases, metabolic disorders, hematologic conditions and seizures."
1) Molecular findings among patients referred for clinical whole-exome sequencing. Yang Y et al. JAMA. (2014). 2) Whole Exome Sequencing in Pediatric Neurology Patients: Clinical Implications and Estimated Cost Analysis. Nolan D et al. J Child Neurol. (2016). 3) Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract. van der Ven AT et al. J Am Soc Nephrol. (2018). 4) Genetic Diagnostic Evaluation of Trio-Based Whole Exome Sequencing Among Children With Diagnosed or Suspected Autism Spectrum Disorder. Du X, Gao X, Liu X, Shen L, Wang K, Fan Y, Sun Y, Luo X, Liu H, Wang L, Wang Y, Gong Z, Wang J, Yu Y, Li F. Front Genet. 2018 Nov 30;9:594. doi: 10.3389/fgene.2018.00594. eCollection 2018. 5) GPR126: A novel candidate gene implicated in autosomal recessive intellectual disability. Hosseini M, Fattahi Z, Abedini SS, Hu H, Ropers HH, Kalscheuer VM, Najmabadi H, Kahrizi K. Am J Med Genet A. 2018 Dec 14. doi: 10.1002/ajmg.a.40531.
1) BL Fogel, S Satya-Murti, BH Cohen. Clinical exome sequencing in neurologic disease. Neurol Clin Practice 2016; 6:164-176. 2) EA Worthey. Analysis and annotation of whole-genome or whole-exome sequencing derived variants for clinical diagnosis. Currently Protoc Hum Genet 2017; 95:9.24.1-9.24.28. 3) S Nambot, J Thevenon, et al. Clinical whole-exome sequencing for the diagnosis of rare disorders with congenital anomalies and/or intellectual disability: Substantial interest of prospective annual reanalysis. Genet Med 2018; 20(6):645-654.