Exome Sequencing: Experimental / Investigational? A neurologist vs the "Flat Earthers"

Exome Sequencing: Experimental / Investigational? A neurologist vs the "Flat Earthers"

I have a patient with chronic developmental ataxia who has had an extensive work-up. An exome array was ordered (via Baylor) but the insurance company and its "reviewer" called the test experimental.

While the test is EXpensive I do not think its EXperimental. Obviously, to save money, insurance companies label new technologies as "exprerimental" even after they have cpt codes and are widley recommended (MR spectroscopy and actigraphy).

I am not surprised by the insurance company's tactics, I am shocked that an independent reviewer would agree.

Not only is the test available at academic and commercial labs, its widely published and recommended in challenging cases by textbooks.

Does anyone else have information in this against  insurance "flat earthers"?

JR

Daroff: Bradley's Neurology in Clinical Practice, 6th ed. - Neurogenetics Chapter

Utilize new technology in challenging cases

Whole genome and/or exome sequencing, when clinically available, could potentially be an appropriate consideration for patients with suspected genetic disease and complete negative genetic and non-genetic evaluations.

Clinical application of exome sequencing in undiagnosed genetic conditions. - Need AC - J Med Genet - 01-JUN-2012; 49(6): 353-61 (MEDLINE® is the source for the citation and abstract of this record )

Abstract:

BACKGROUND: There is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenotypic presentations.

METHODS: The authors present a pilot programme of whole-exome sequencing on 12 patients with unexplained and apparent genetic conditions, along with their unaffected parents. Unlike many previous studies, the authors did not seek patients with similar phenotypes, but rather enrolled any undiagnosed proband with an apparent genetic condition when predetermined criteria were met.

RESULTS: This undertaking resulted in a likely genetic diagnosis in 6 of the 12 probands, including the identification of apparently causal mutations in four genes known to cause Mendelian disease (TCF4, EFTUD2, SCN2A and SMAD4) and one gene related to known Mendelian disease genes (NGLY1). Of particular interest is that at the time of this study, EFTUD2 was not yet known as a Mendelian disease gene but was nominated as a likely cause based on the observation of de novo mutations in two unrelated probands. In a seventh case with multiple disparate clinical features, the authors were able to identify homozygous mutations in EFEMP1 as a likely cause for macular degeneration (though likely not for other features).

CONCLUSIONS: This study provides evidence that next-generation sequencing can have high success rates in a clinical setting, but also highlights key challenges. It further suggests that the presentation of known Mendelian conditions may be considerably broader than currently recognised.

Citation:

Clinical application of exome sequencing in undiagnosed genetic conditions.

Need AC - J Med Genet - 01-JUN-2012; 49(6): 353-61

MEDLINE® is the source for the citation and abstract of this record 

NLM Citation ID:

22581936 (PubMed ID)

Full Source Title:

Journal of medical genetics

Publication Type:

Journal Article; Research Support, American Recovery and Reinvestment Act; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't

Language:

English

Author Affiliation:

Center for Human Genome Variation, Duke University School of Medicine, Box 91009, Durham, NC 27708, USA. d.goldstein@duke.edu

Authors:

Need AC; Shashi V; Hitomi Y; Schoch K; Shianna KV; McDonald MT; Meisler MH; Goldstein DB

Major Subjects:

• Exome
• Genetic Diseases, Inborn / * diagnosis / genetics
• Molecular Diagnostic Techniques / * methods
• Sequence Analysis, DNA / * methods

Additional Subjects:

• Adolescent
• Adult
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
• Child
• Child, Preschool
• Female
• Humans
• Infant
• Male
• Models, Genetic
• Mutation
• NAV1.2 Voltage-Gated Sodium Channel / genetics
• Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / genetics
• Smad4 Protein / genetics
• Transcription Factors / genetics

Diagnostic exome sequencing in persons with severe intellectual disability. - de Ligt J - N Engl J Med - 15-NOV-2012; 367(20): 1921-9 (MEDLINE® is the source for the citation and abstract of this record )

Abstract:

BACKGROUND: The causes of intellectual disability remain largely unknown because of extensive clinical and genetic heterogeneity.

METHODS: We evaluated patients with intellectual disability to exclude known causes of the disorder. We then sequenced the coding regions of more than 21,000 genes obtained from 100 patients with an IQ below 50 and their unaffected parents. A data-analysis procedure was developed to identify and classify de novo, autosomal recessive, and X-linked mutations. In addition, we used high-throughput resequencing to confirm new candidate genes in 765 persons with intellectual disability (a confirmation series). All mutations were evaluated by molecular geneticists and clinicians in the context of the patients' clinical presentation.

RESULTS: We identified 79 de novo mutations in 53 of 100 patients. A total of 10 de novo mutations and 3 X-linked (maternally inherited) mutations that had been previously predicted to compromise the function of known intellectual-disability genes were found in 13 patients. Potentially causative de novo mutations in novel candidate genes were detected in 22 patients. Additional de novo mutations in 3 of these candidate genes were identified in patients with similar phenotypes in the confirmation series, providing support for mutations in these genes as the cause of intellectual disability. We detected no causative autosomal recessive inherited mutations in the discovery series. Thus, the total diagnostic yield was 16%, mostly involving de novo mutations.

CONCLUSIONS: De novo mutations represent an important cause of intellectual disability; exome sequencing was used as an effective diagnostic strategy for their detection. (Funded by the European Union and others.).

Citation:

Diagnostic exome sequencing in persons with severe intellectual disability.

de Ligt J - N Engl J Med - 15-NOV-2012; 367(20): 1921-9

MEDLINE® is the source for the citation and abstract of this record 

NLM Citation ID:

23033978 (PubMed ID)

Full Source Title:

The New England Journal of Medicine

Publication Type:

Journal Article; Research Support, Non-U.S. Gov't

Prenatal Whole Genome Sequencing: Just Because We Can, Should We?

Prenatal Whole Genome Sequencing: Just Because We Can, Should We?

ScienceDaily (Aug. 10, 2012) — With whole genome sequencing quickly becoming more affordable and accessible, we need to pay more attention to the massive amount of information it will deliver to parents -- and the fact that we don't yet understand what most of it means, concludes an article in the Hastings Center Report. The authors are current or former scholars at the National Institutes of Health's Department of Bioethics.

Most analyses of the ethical issues raised by whole genome sequencing have been "futuristic forecasting," but the authors conclude that "this is problematic given the speed with which whole genome sequencing is likely to be incorporated into clinical care," as its price falls to under $1,000.

Prenatal whole genome sequencing differs from current prenatal genetic testing practice in ethically relevant ways. Most notably, whole genome sequencing would radically increase the volume and scope of available prenatal genetic data. In contrast with current tests, which identify serious genetic conditions in fetuses at high risk of them, the new tests would likely be used by many more expectant parents and reveal a wide spectrum of genetic traits, including disease susceptibility.

Some of the ethical challenges posed by prenatal whole genome sequencing arise from the uncertainty of what the information means. The function of more than 90 percent of genes in the human genome is unknown and as a result, the article says, "much of the data generated from whole genome sequencing over the next few years (or even decades) will be of questionable utility."

After analyzing the kind of information that whole genome prenatal testing will yield, the authors conclude that most of it would probably not be as helpful as information uncovered by the current categories of prenatal tests. They cited specific areas of concern.

First of all, the quality and quantity of information may augment parents' anxiety. "To the extent that parents now think of their child as a 'clean slate' during pregnancy, the prenatal image of a normal, healthy baby will be dramatically altered by this technology," the authors write. The anxiety over the results and changing views of what is "normal" could lead to an increase in pregnancy terminations.
Apart from reproductive decisions, the authors also foresee whole genome prenatal testing having a negative impact on child rearing. For example, if parents were able to get genetic information suggesting that their child's predicted IQ may be low, they might not strongly encourage and support the child's efforts in school.

Finally, the new technology could increase the tension between the interests of parents and children. Although parents have a strong interest in getting information that informs their reproductive choices, children have a competing interest in not knowing certain kinds of information about themselves -- information that could limit their autonomy as they grow into adulthood.

Given the potential harms from prenatal whole genome sequencing, the authors make four preliminary recommendations......

Web address:      HERE