Diagnosis: Genetic Diseases/Other/ Hypogonadotropic Hypogonadism Treatment: Lab Work/Blood Tests The health plan denied the requested Genome sequence analysis testing as experimental/investigational. The health plan's determination is overturned. The patient is a male with multiple health issues and congenital anomalies including hypogonadotropic hypogonadism, muscle weakness, obesity, history of cleft lip status post repair and left post axial polydactyly status post removal. This patient had extensive previous genetic workup including metabolic labs, chromosomal microarray, fluorescence in situ hybridization (FISH)/22q11 and fragile X genetic testing and all of these tests did not find a cause for clinical presentation. There is family history of consanguinity which increases risk for autosomal recessive conditions. There is no current treatment plan documented in the medical records. At issue is whether the proposed health service or treatment of Genome sequence analysis testing is likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease. The health plan's determination is overturned, in whole. The patient already had extensive genetic workup done which did not reveal a cause for his overall clinical presentation. Further testing including whole exome/genome sequencing has a higher diagnostic yield when previous testing failed to give a diagnosis. Also, the patient has multiple health issues and more than one congenital anomaly, raising the possibility of having a genetic condition and this is another indication for sending whole exome/genome sequencing. Finding a clinical diagnosis would help determine further specific management and treatment based on diagnosis such as hormone replacement, and screening for other health issues such as cardiomyopathy. Whole exome/genome sequencing is not investigational based on recent clinical studies and publications and based on this patient's medical records and previous inconclusive genetic testing.

Diagnosis: Genetic Diseases/Other/ Hypogonadotropic Hypogonadism Treatment: Lab Work/Blood Tests The health plan denied the requested Genome sequence analysis testing as experimental/investigational. The health plan's determination is overturned. The patient is a man with attention deficit hyperactivity disorder (ADHD), tall stature, muscle weakness and hypotonia, cleft lip and palate, and micropenis and delayed puberty due to hypogonadotropic hypogonadism. Despite extensive genetic evaluations and multiple tests, a definitive diagnosis has not been established. At issue is whether the proposed health service or treatment of Genome sequence analysis testing is likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease. The health plan's determination is overturned, in whole. Yes, this patient had standard genetic evaluations and tests, but a definitive diagnosis has not been established. The result of the requested whole exome sequencing (WES) test will allow a definitive diagnosis to be established and will provide information about the optimal treatment and management regimens and the anticipated future medical problems for this patient. Furthermore, the results of the requested test will allow accurate genetic counseling of the family, an estimate of the recurrence risks, and identification of other family members at risk of having the disease. The WES test analyzes the protein coding portion of the human genome and is offered by a number of certified diagnostic laboratories. WES does not need Food and Drug Administration (FDA) approval, as it is a genetic test based on routine molecular techniques, such as deoxyribonucleic acid (DNA) isolation, enrichment, polymerase chain reaction (PCR), and DNA sequencing. The results of the tests will likely identify the underlying genetic causes of this patient's disorder and may offer an opportunity for targeted treatment. Furthermore, WES is in a wide use by clinical geneticists and is current standard of care for patients with similar complex genetic syndromes of unknown causes. Despite extensive genetic clinical and molecular evaluations, no definitive diagnosis was established for this patient. The disease is presumed to have genetic etiology based on the clinical symptoms. The WES has the potential to identify a mutation a gene responsible for this patient's disease.

Diagnosis: Genetic Diseases/Other/ Hypogonadotropic Hypogonadism Treatment: Lab Work/Blood Tests The health plan denied the requested Genome sequence analysis testing as experimental/investigational. The health plan's determination is overturned. The patient is a male with hypogonadotropic hypogonadism, prediabetes, hypotonia, muscle weakness, attention deficit hyperactivity disorder (ADHD), unilateral cleft lip, vesicoureteral reflux, micropenis and small testicles. At issue is whether the proposed health service or treatment of Genome sequence analysis testing is likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease. The health plan's determination is overturned, in whole. The requested health service/treatment of Whole Exome Sequencing (WES) would be medically necessary for this patient as well as evidence-based and cost effective. Etiology of the patient's multiple medical problems has not been established. Due to complexity of his history, genetic etiology is likely. Finding a genetic mutation that could explain his hypogonadotropic hypogonadism, prediabetes, hypotonia, muscle weakness, ADHD, unilateral cleft lip, vesicoureteral reflux, micropenis and small testicles would be crucial for the patient's management, prognosis, and recurrence risks. Furthermore, several areas of possible health concerns may not be addressed if the patient's doctors do not know where to look (in case if other organ systems are involved) and therefore potentially life-threatening complications may not be prevented. WES can be used to identify the underlying molecular basis of a genetic disorder in an affected individual [1]. WES can test the largest number of genes than any other genetic test because it uses next-generation sequencing (NGS) technology that allows all genes to be sequenced simultaneously and therefore saves time and cost [2]. WES tests entire coding deoxyribonucleic acid (DNA) with approximately 20,000 genes and parental samples are tested to help with interpretation of the results. Multiple studies have demonstrated over the past 10 years (since WES was first developed in 2009 and became clinically available in 2012) its vast power to identify disease-associated genetic variants across a diverse spectrum of human diseases which directly affects treatment [3]. WES has been very effective as a clinical tool. Since the patient's presentation is not specific for any disorder, WES would be the most cost-effective method with the highest yield and bypass multiple tests that would have lower yields. WES would indeed be the best option.

1) https://pubmed.ncbi.nlm.nih.gov/32194879/. 2) https://pubmed.ncbi.nlm.nih.gov/34211152/.

1) Exome Sequencing: Dual Role as a Discovery and Diagnostic Tool. Ku CS, Cooper DN, Polychronakos C, Naidoo N, Wu M, Soong R. Ann Neurol. 2012 Jan;71(1):5-14. doi: 10.1002/ana.22647. Review. 2) Next Generation Sequencing in the Clinical Domain: Clinical Advantages, Practical, and Ethical Challenges. Thompson R, Drew CJ, Thomas RH. Adv Protein Chem Struct Biol. 2012;89:27-63. 3) Exome Sequencing: an Efficient Diagnostic Tool for Complex Neurodegenerative Disorders. Hammer MB, Eleuch-Fayache G, Gibbs JR, Arepalli SK, Chong SB, Sassi C, Bouhlal Y, Hentati F, Amouri R, Singleton AB. Eur J Neurol. 2012 Oct 9. 4) Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability. de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, Del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE. N Engl J Med. 2012 Oct 3.

1) Schwarze K. et al. Are Whole-exome and Whole-genome Sequencing Approaches Cost-effective? A Systematic Review of the Literature. Genet Med 2018 Oct;20(10):1122-1130. 2) Brenner SE et al. Application of Full-genome Analysis to Diagnose Rare Monogenic Disorders. NPJ Genom Med. 2021 Sep 23;6(1):77. 3) Shickh S, Mighton C, Uleryk E, Pechlivanoglou P, Bombard Y. The Clinical Utility of Exome and Genome Sequencing Across Clinical Indications: A Systematic Review. Hum Genet. 2021 Oct;140(10):1403-1416.