OtoSCOPE v9 - Clinical Genetic Test - GTR

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OtoSCOPE v9

Clinical Genetic Test

offered by

Molecular Otolaryngology and Renal Research Laboratories

View lab's test page

GTR Test Accession: GTR000593050.3

INHERITED DISEASENERVOUS SYSTEMPSYCHIATRIC ... View more

Last updated in GTR: 2024-01-10

Last annual review date for the lab: 2024-01-11

At a Glance

Test purpose:

Diagnosis; Mutation Confirmation; Prognostic

Conditions (288):

Deafness; 3MC syndrome 1; Alpha mannosidosis type II; ...

Genes (218):

ABHD12 (20p11.21), ACTB (7p22.1), ACTG1 (17q25.3), ADCY1 (7p12.3), ADGRV1 (5q14.3), ...

Methods (2):

Molecular Genetics - Deletion/duplication analysis: Next-Generation (NGS)/Massively parallel sequencing (MPS); ...

Target population:

OtoSCOPE ® (version 9) simultaneously screens 224 genes and microRNAs …

Clinical validity:

Not provided

Clinical utility:

Establish or confirm diagnosis

Ordering Information

Offered by:

Molecular Otolaryngology and Renal Research Laboratories
View lab's website
View lab's test page

Specimen Source:

Buccal swab
Isolated DNA
Peripheral (whole) blood
Saliva
View specimen requirements

Who can order:

Genetic Counselor
Health Care Provider
Licensed Physician
Nurse Practitioner
Physician Assistant

Test Order Code:

OtoSCOPE® panel, OTOSC09
View other test codes

CPT codes:

81430
81431

**AMA CPT codes notice

Lab contact:

Jori Hendon, BA, Administrator
jori-hendon@uiowa.edu
319-335-6653
Amy Weaver, Administrator
amy-weaver@uiowa.edu
319-335-6623

Contact Policy:

Laboratory can only accept contact from health care providers. Patients/families are encouraged to discuss genetic testing options with their health care provider.

How to Order:

Sample types accepted include: 3-5 cc EDTA whole blood; 5 μg DNA, resuspended in at least 50 ul of DNA Elution Buffer; Saliva (DNA Genotek, ORAGene Discover, OGR-500); or Buccal Swabs, at least 4 (DNA Genotek, OraCollect, OCD-100). Samples can be received Monday - Friday (no weekend or holiday deliveries), …

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Order URL

Test service:

Clinical Testing/Confirmation of Mutations Identified Previously
Comment: Includes next-generation sequencing and copy number variation studies (deletion/duplication studies).

Test additional service:

Custom mutation-specific/Carrier testing

Test development:

Test developed by laboratory (no manufacturer test name)

Informed consent required:

Based on applicable state law

Test strategy:

OtoSCOPE® uses custom-targeted sequence capture for DNA enrichment followed by massively parallel DNA sequencing. In this way, all genes known to cause NSHL, Usher syndrome, Pendred syndrome and other syndromes are sequenced at the same time. Data analysis to examine possible causative variants using our custom variant pipeline is followed … View more

View citations (5)

Shearer AE, DeLuca AP, Hildebrand MS, Taylor KR, Gurrola J, Scherer S, Scheetz TE, Smith RJ. Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing. Proc Natl Acad Sci U S A. 2010;107(49):21104-9. doi:10.1073/pnas.1012989107. Epub 2010 Nov 15. PMID: 21078986.
Shearer AE, Kolbe DL, Azaiez H, Sloan CM, Frees KL, Weaver AE, Clark ET, Nishimura CJ, Black-Ziegelbein EA, Smith RJ. Copy number variants are a common cause of non-syndromic hearing loss. Genome Med. 2014;6(5):37. doi:10.1186/gm554. Epub 2014 May 22. PMID: 24963352.
Shearer AE, Smith RJ. Massively Parallel Sequencing for Genetic Diagnosis of Hearing Loss: The New Standard of Care. Otolaryngol Head Neck Surg. 2015;153(2):175-82. doi:10.1177/0194599815591156. Epub 2015 Jun 17. PMID: 26084827.
Sloan-Heggen CM, Bierer AO, Shearer AE, Kolbe DL, Nishimura CJ, Frees KL, Ephraim SS, Shibata SB, Booth KT, Campbell CA, Ranum PT, Weaver AE, Black-Ziegelbein EA, Wang D, Azaiez H, Smith RJH. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet. 2016;135(4):441-450. doi:10.1007/s00439-016-1648-8. Epub 2016 Mar 11. PMID: 26969326.
Azaiez H, Booth KT, Ephraim SS, Crone B, Black-Ziegelbein EA, Marini RJ, Shearer AE, Sloan-Heggen CM, Kolbe D, Casavant T, Schnieders MJ, Nishimura C, Braun T, Smith RJH. Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. Am J Hum Genet. 2018;103(4):484-497. doi:10.1016/j.ajhg.2018.08.006. Epub 2018 Sep 20. PMID: 30245029.

Pre-test genetic counseling required:

Decline to answer

Post-test genetic counseling required:

Decline to answer

Conditions

Total conditions: 288

Condition/Phenotype	Identifier

Test Targets

Genes

Total genes: 218

Gene	Associated Condition	Germline or Somatic	Allele (Lab-provided)	Variant in NCBI

Methodology

Total methods: 2

Method Category

Test method

Instrument

Deletion/duplication analysis

Next-Generation (NGS)/Massively parallel sequencing (MPS)

Agilent SureSelect

Sequence analysis of the entire coding region

Next-Generation (NGS)/Massively parallel sequencing (MPS)

Agilent SureSelect

Clinical Information

Test purpose:

Diagnosis; Mutation Confirmation; Prognostic

Clinical utility:

Establish or confirm diagnosis

View citations (1)

Li MM, Tayoun AA, DiStefano M, Pandya A, Rehm HL, Robin NH, Schaefer AM, Yoshinaga-Itano C, . Clinical evaluation and etiologic diagnosis of hearing loss: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2022;24(7):1392-1406. doi:10.1016/j.gim.2022.03.018. Epub 2022 May 10. PMID: 35802133.

Target population:

OtoSCOPE ® (version 9) simultaneously screens 224 genes and microRNAs known to cause non-syndromic sensorineural hearing loss, Alström, BOR, Brown-Vialetto-Van Laere, CHARGE, Jervell and Lange Nielsen, Pendred, Perrault, Usher and Wolfram syndromes, or other hearing loss-related phenotypes by using custom-targeted sequence capture for DNA enrichment followed by massively parallel DNA … View more

View citations (5)

Shearer AE, DeLuca AP, Hildebrand MS, Taylor KR, Gurrola J, Scherer S, Scheetz TE, Smith RJ. Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing. Proc Natl Acad Sci U S A. 2010;107(49):21104-9. doi:10.1073/pnas.1012989107. Epub 2010 Nov 15. PMID: 21078986.
Shearer AE, Kolbe DL, Azaiez H, Sloan CM, Frees KL, Weaver AE, Clark ET, Nishimura CJ, Black-Ziegelbein EA, Smith RJ. Copy number variants are a common cause of non-syndromic hearing loss. Genome Med. 2014;6(5):37. doi:10.1186/gm554. Epub 2014 May 22. PMID: 24963352.
Shearer AE, Smith RJ. Massively Parallel Sequencing for Genetic Diagnosis of Hearing Loss: The New Standard of Care. Otolaryngol Head Neck Surg. 2015;153(2):175-82. doi:10.1177/0194599815591156. Epub 2015 Jun 17. PMID: 26084827.
Sloan-Heggen CM, Bierer AO, Shearer AE, Kolbe DL, Nishimura CJ, Frees KL, Ephraim SS, Shibata SB, Booth KT, Campbell CA, Ranum PT, Weaver AE, Black-Ziegelbein EA, Wang D, Azaiez H, Smith RJH. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet. 2016;135(4):441-450. doi:10.1007/s00439-016-1648-8. Epub 2016 Mar 11. PMID: 26969326.
Azaiez H, Booth KT, Ephraim SS, Crone B, Black-Ziegelbein EA, Marini RJ, Shearer AE, Sloan-Heggen CM, Kolbe D, Casavant T, Schnieders MJ, Nishimura C, Braun T, Smith RJH. Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. Am J Hum Genet. 2018;103(4):484-497. doi:10.1016/j.ajhg.2018.08.006. Epub 2018 Sep 20. PMID: 30245029.

Variant Interpretation:

Are family members with defined clinical status recruited to assess significance of VUS without charge?
Yes. Comprehensive genetic testing is fast and accurate but understanding the impact of Variants of Uncertain Significance (VUS) is not always straight forward. The HEAR VUS program offers follow up testing at no additional cost for family members of a patient previously tested with OtoSCOPE. https://morl.lab.uiowa.edu/clinical-diagnostics/hearing-loss-otoscope/hear-vus-program

Will the lab re-contact the ordering physician if variant interpretation changes?
Yes. If new information comes to light about a previously identifed variant that changes the result significantly (ie, the variant was previously reported as damaging and now is considered a benign polymorphism) a revised report will be sent to the ordering physician.

Recommended fields not provided:

Clinical validity, What is the protocol for interpreting a variation as a VUS?, Is research allowed on the sample after clinical testing is complete?, Sample negative report, Sample positive report

Technical Information

Test Procedure:

targeted genomic enrichment and massively parallel sequencing

View citations (3)

Shearer AE, DeLuca AP, Hildebrand MS, Taylor KR, Gurrola J, Scherer S, Scheetz TE, Smith RJ. Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing. Proc Natl Acad Sci U S A. 2010;107(49):21104-9. doi:10.1073/pnas.1012989107. Epub 2010 Nov 15. PMID: 21078986.
Shearer AE, Kolbe DL, Azaiez H, Sloan CM, Frees KL, Weaver AE, Clark ET, Nishimura CJ, Black-Ziegelbein EA, Smith RJ. Copy number variants are a common cause of non-syndromic hearing loss. Genome Med. 2014;6(5):37. doi:10.1186/gm554. Epub 2014 May 22. PMID: 24963352.
Azaiez H, Booth KT, Ephraim SS, Crone B, Black-Ziegelbein EA, Marini RJ, Shearer AE, Sloan-Heggen CM, Kolbe D, Casavant T, Schnieders MJ, Nishimura C, Braun T, Smith RJH. Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. Am J Hum Genet. 2018;103(4):484-497. doi:10.1016/j.ajhg.2018.08.006. Epub 2018 Sep 20. PMID: 30245029.

Test Platform:

targeted genomic enrichment and massively parallel sequencing

Test Confirmation:

We have shown experimentally variants with QD >10 do not require Sanger sequencing validation (PMID: 21078986). In cases where the QD is between 5 and 10 and/or the zygosity status is indeterminate, Sanger confirmation is performed. Quality control testing to detect specimen mislabeling or sample contamination (sample integrity check) is … View more

Test Comments:

Genomic regions within the 224 genes of OtoSCOPE v9, which are not sufficiently covered with high quality sequence reads are not included in the OtoSCOPEv9 report. The following exons are not included in the panel as they are not sufficiently covered: DNMT1 (NM_001130823.3: Exon 3, 5), BTD (NM_001370658.1: Exon 5). … View more

Availability:

Tests performed
Interpretation performed in-house
Report generated in-house
Specimen preparation performed both in-house and at an outside lab
Wet lab work performed in-house

Test performance comments
Sample preparation (DNA isolation of whole blood) can be performed by an outside laboratory (such as the institution of the ordering healthcare provider) with extracted DNA being sent to the MORL for testing.

Analytical Validity:

greater than 99%

View citations (2)

Shearer AE, DeLuca AP, Hildebrand MS, Taylor KR, Gurrola J, Scherer S, Scheetz TE, Smith RJ. Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing. Proc Natl Acad Sci U S A. 2010;107(49):21104-9. doi:10.1073/pnas.1012989107. Epub 2010 Nov 15. PMID: 21078986.
Shearer AE, Kolbe DL, Azaiez H, Sloan CM, Frees KL, Weaver AE, Clark ET, Nishimura CJ, Black-Ziegelbein EA, Smith RJ. Copy number variants are a common cause of non-syndromic hearing loss. Genome Med. 2014;6(5):37. doi:10.1186/gm554. Epub 2014 May 22. PMID: 24963352.

Assay limitations:

OtoSCOPE is designed to evaluate the exonic and flanking intronic sequence of genes involved in non-syndromic hearing loss and select types of syndromic hearing loss. Deep intronic or regulatory variants of the genes included in OtoSCOPE® v9 (224 genes) are not detected by this assay. Absence of a plausible explanation … View more

Proficiency testing (PT):

Is proficiency testing performed for this test?
Yes

Method used for proficiency testing:
Formal PT program

PT Provider:
European Molecular Genetics Quality Network, EMQN

Description of PT method:
In addition to formal proficiency testing through EMQN, the MORL does in-house proficiency testing biannually.

Description of internal test validation method: Help
OtoSCOPE Targeted Genomic Enrichment and Sequencing The OtoSCOPE® v9 (224 genes) platform targets genes known to cause non-syndromic hearing loss and several forms of syndromic hearing loss (https://morl. lab.uiowa.edu/genes-included-otoscope). Solution-phase targeted genomic enrichment is performed to isolate and enrich all exons and their flanking intronic sequence and intronic deafness-causing variants … OtoSCOPE Targeted Genomic Enrichment and Sequencing The OtoSCOPE® v9 (224 genes) platform targets genes known to cause non-syndromic hearing loss and several forms of syndromic hearing loss (https://morl. lab.uiowa.edu/genes-included-otoscope). Solution-phase targeted genomic enrichment is performed to isolate and enrich all exons and their flanking intronic sequence and intronic deafness-causing variants of all 224 genes included on the OtoSCOPE v9® platform. Also included are some intronic sequence and some pseudogenes to improve our ability to detect copy number variations. Sequencing by reversible chain-termination is performed using Illumina systems with post-capture barcoded multiplexing and 150 bp paired-end reads. Bioinformatics Analysis Raw reads are converted to FASTQ files on the sequencer. FASTQ files are loaded on to a local installation of Galaxy software running on a secured highperformance computing cluster for bioinformatics analysis. Reads are mapped with the Burrows-Wheeler Aligner (BWA-MEM), duplicates removed with Picard, and local-realignment and variant calling is performed with the Genome Analysis Toolkit (GATK). Mapping and analysis are performed in comparison with the published human genome build (UCSC hg19 reference sequence). Variants are annotated with custom MORL software using hearing loss relevant transcripts. Copy number variants are identified using a read-depth based approach validated with MLPA. Variants are assigned pathogenicity prediction scores when available. Predicted pathogenicity is assessed using six computational methods (SIFT, LRT, Mutation Taster, PolyPhen HDIV, PhyloP and GERP). In general, variants with a score of at least 4 are considered more likely to be deleterious. However, pathogenicity predictions are used only as a guideline to aid interpretation and are not used solely to determine pathogenicity. Pathogenicity predictions are not available for all variants. Variant Filtering Identified variants are assigned quality scores using QD (Phred-like Quality / Depth at variant position) and only variants with a QD>5 are retained. Variants are also filtered by minor allele frequencies present in publicly available genomic databases (Genome Aggregation Database) and the MORL OtoSCOPE database. Variants with MAFs > 1% in public databases and >5% in the OtoSCOPE database are filtered out with exceptions made for previously identified pathogenic variants, which are retained for consideration. All retained variants, termed “Genetic Variants Considered” (outlined in table above) are discussed at the multidisciplinary hearing meeting (Hearing Group) by a panel of experts. Variant Interpretation Variant interpretation is complex and relies on all available clinical, phenotypic and genetic information. There is no single method, tool, or filter that reliably determines pathogenicity and so expert analysis is required. The goal of our multidisciplinary Hearing Group is to integrate clinical information with results from OtoSCOPE to determine the most likely genetic cause of deafness, if any. All variants in the “Genetic Variants Considered” table are discussed. The Hearing Group meeting comprises experts in the genetics and molecular biology of hearing and deafness and includes physicians, geneticists, scientists, genetic counselors, and bioinformaticians who discuss each variant in the context of clinical information provided and provide expert interpretation of genetic variants. Exclusion of variants as causative is a complex process. Possible justifications for exclusion of a variant may include any of the following but are not limited solely to these reasons: 1) Causality of the identified variant is not consistent with the reported family history; 2) Causality of the identified variant is not consistent with the clinical description and/or phenotypic information provided to MORL; 3) Causality of the identified variant is unlikely based on deleteriousness prediction score; 4) Allele frequency is too high. View more

VUS:

Laboratory's policy on reporting novel variations
A routine report is provided if a novel variantion is identified.

Recommended fields not provided:

Citations to support assay limitations, Major CAP category, CAP category, CAP test list

Regulatory Approval

FDA Review:

Category: FDA exercises enforcement discretion

Additional Information

Reviews:

PubMed Clinical Queries

Clinical resources:

Consumer resources:

IMPORTANT NOTE: NIH does not independently verify information submitted to GTR; it relies on submitters to provide information that is accurate and not misleading. NIH makes no endorsements of tests or laboratories listed in GTR. GTR is not a substitute for medical advice. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.