OtoGenome Test for Hearing Loss (110 Genes) - Clinical Genetic Test - GTR

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OtoGenome Test for Hearing Loss (110 Genes)

Clinical Genetic Test

offered by

Laboratory for Molecular Medicine

View lab's test page

GTR Test Accession: GTR000509148.13

INHERITED DISEASESYNDROMIC DISEASEDYSMORPHOLOGY ... View more

Last updated in GTR: 2023-12-01

Last annual review date for the lab: 2023-12-01

At a Glance

Test purpose:

Diagnosis

Conditions (23):

Hereditary hearing loss and deafness; Alport syndrome; Alstrom syndrome more...

Genes (109):

ACTG1 (17q25.3); ADCY1 (7p12.3); ADGRV1 (5q14.3); ALMS1 (2p13.1); ATP6V1B1 (2p13.3) more...

Methods (3):

Molecular Genetics - Deletion/duplication analysis: VisCap analysis; ...

Target population:

Individuals with apparently nonsyndromic hearing loss

Clinical validity:

Not provided

Clinical utility:

Not provided

Ordering Information

Offered by:

Laboratory for Molecular Medicine
View lab's website
View lab's test page

Test short name:

OtoGenome

Specimen Source:

Isolated DNA
Peripheral (whole) blood
View specimen requirements

Who can order:

Genetic Counselor
Health Care Provider
Licensed Physician
Nurse Practitioner
Physician Assistant
Registered Nurse

Test Order Code:

lmOto-pnlBv7_L
View other test codes

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:

Physician must complete test requisition and submit a blood sample (see sample requirements)
Order URL

Test service:

Clinical Testing/Confirmation of Mutations Identified Previously

Test development:

Test developed by laboratory but exempt from FDA oversight (eg. NYS CLEP approved, offered within a hospital or clinic)

Informed consent required:

Yes

Test strategy:

The OtoGenome™ Test is best suited for individuals who have a diagnosed hearing loss for which an underlying etiology has not yet been identified. For an individual with apparently non-syndromic hearing loss, this panel covers both non-syndromic causes of hearing loss as well as those which can present as non-syndromic. … View more

View citations (3)

Shearer AE, Hildebrand MS, Schaefer AM, Smith RJH. Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301607.
Molecular diagnosis of hearing loss. Brown KK, et al. Curr Protoc Hum Genet. 2012;Chapter 9:Unit 9.16. doi:10.1002/0471142905.hg0916s72. PMID: 22241658.
https://www.ncbi.nlm.nih.gov/books/NBK1434

Pre-test genetic counseling required:

Post-test genetic counseling required:

Recommended fields not provided:

Lab contact for this test

Conditions

Total conditions: 23

Condition/Phenotype	Identifier

Test Targets

Genes

Total genes: 109

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

Methodology

Total methods: 3

Method Category

Test method

Instrument

Deletion/duplication analysis

VisCap analysis

Sequence analysis of the entire coding region

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

Illumina NextSeq 550

Targeted variant analysis

PCR

Clinical Information

Test purpose:

Diagnosis

Target population:

Individuals with apparently nonsyndromic hearing loss

View citations (2)

Shearer AE, Hildebrand MS, Schaefer AM, Smith RJH. Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301607.
Molecular diagnosis of hearing loss. Brown KK, et al. Curr Protoc Hum Genet. 2012;Chapter 9:Unit 9.16. doi:10.1002/0471142905.hg0916s72. PMID: 22241658.

Variant Interpretation:

What is the protocol for interpreting a variation as a VUS?
All VUS's are reported

Are family members with defined clinical status recruited to assess significance of VUS without charge?
Yes. *Please call. Offered on a case-by-case basis.

Will the lab re-contact the ordering physician if variant interpretation changes?
No. Ordering provider is encouraged to periodically contact the lab to see if there is any new information available. However, if the ordering physician has GeneInsight Clinic, they may receive automatic updates on classification through that program.

Research:

Is research allowed on the sample after clinical testing is complete?
No

Recommended fields not provided:

Clinical validity, Clinical utility, Sample negative report, Sample positive report

Technical Information

Test Procedure:

This OtoGenome Panel includes 110 genes: ACTG1, ADCY1 (excludes exon 1 in NM_021116.2), ADGRV1, ALMS1 (excludes exon 1 in NM_015120.4), ATP6V1B1, BCS1L, BSND, CABP2, CACNA1D, CATSPER2 (deletion analysis only), CCDC50, CD164 (excludes exon 7 in NM_001142403.1), CDC14A, CDH23, CEACAM16, CEP78 (excludes exon 12 in NM_001098802.1), CHD7, CIB2, CLDN14, CLIC5, CLPP, … This OtoGenome Panel includes 110 genes: ACTG1, ADCY1 (excludes exon 1 in NM_021116.2), ADGRV1, ALMS1 (excludes exon 1 in NM_015120.4), ATP6V1B1, BCS1L, BSND, CABP2, CACNA1D, CATSPER2 (deletion analysis only), CCDC50, CD164 (excludes exon 7 in NM_001142403.1), CDC14A, CDH23, CEACAM16, CEP78 (excludes exon 12 in NM_001098802.1), CHD7, CIB2, CLDN14, CLIC5, CLPP, CLRN1 (excludes exon 1B in NM_174880.1)*, COCH, COL11A2, COL4A3 (excludes exons 36 and 51 in NM_000091.4), COL4A4 (excludes exon 31 in NM_000092.4), COL4A5, DIABLO, DIAPH1 (excludes exon 16 and intron 23 in NM_005219.4), EDN3, EDNRB, EPS8 (excludes exons 3, 10, 16 and 18in NM_004447.5), ESPN (excludes exons 1, 3, 4, 7 and 8 in NM_031475.2), ESRRB, EYA1, EYA4, GIPC3, GJB2, GJB6, GPSM2, GRHL2, GRXCR1, GSDME, HARS1, HARS2, HGF (excludes exon 12 in NM_000601.4), HSD17B4, ILDR1, KARS1, KCNE1, KCNQ1, KCNQ4 (excludes exon 1 in NM_004700.3), KITLG, LARS2, LHFPL5, LOXHD1, LRTOMT (excludes e xons 3B and 6B in NM_001145307.1* and exon 6A in NM_145309.2)*, MARVELD2, MIR96, MITF, MSRB3, MTRNR1 (excludes m.648-m.950), MTTS1,MYH14 (excludes exon 28 in NM_001145809.1), MYH9, MYO15A (excludes exon 2 in NM_016239.3), MYO3A, MYO6, MYO7A, NLRP3, OSBPL2, OTOA (excludes exons 2 and 21-27 in NM_144672.3), OTOF, OTOG (excludes exon 32 in NM_001277269.1), OTOGL, P2RX2 (excludes exon 1 in NM_174873.1), PAX3, PCDH15, PDZD7, PJVK, POU3F4, POU4F3, PRPS1, RDX, RIPOR2, S1PR2, SERPINB6, SIX1, SLC26A4, SLC52A2, SLC52A3, SLITRK6, SMPX, SNAI2, SOX10, STRC (NM_153700.2), SYNE4, TBC1D24, TECTA, TIMM8A, TMC1, TMIE, TMPRSS3, TPRN, TRIOBP, USH1C, USH1G, USH2A (includes deep intronic c.7595-2144A>G variant), WFS1, WHRN. *Exon from an alternate transcript. For additional information on reference sequences and exon coverage, please visit our website (www.partners.org/personalizedmedicine/lmm). Genome sequence is generated from genomic DNA that is fragmented and barcoded followed by sequencing on the Illumina NovaSeq instrument with a minimum coverage of at least 20X for 95%. Reads are aligned to the NCBI reference sequence (GRCh38), using the Burrows-Wheeler Aligner (BWA), and variant calls are made using the Genomic Analysis Tool Kit (GATK). Technical sensitivity of this assay is 99.10% (95% CI: 99.04-99.16%) and positive predictive value is 99.39% (95% CI: 99.37-99.41%). Sequence analysis of the STRC gene is performed by amplifying exons 1-29 using long range polymerase chain reaction. Primers proven to discriminate between STRC and its known pseudogene locus are used. The PCR products are then subjected to next generation sequencing library preparation using seqWell’s plexWell™ kit. Samples are pooled and sequenced on the Illumina NextSeq 550 Mid Output Kit (150 bp paired end reads). Reads are aligned to the GRCh38 reference sequence limited to the STRC gene loci only using the Burrows-Wheeler Aligner (BWA 0.7.17), and variant calls are made using the Genomic Analysis Tool Kit – HaplotypeCaller (GATK v4.0.3.0). Sanger sequencing is used to fill in when bases have less than 200x coverage. All clinically significant variants are confirmed by Sanger sequencing or droplet digital PCR; variants classified as likely benign or benign are not confirmed. Droplet digital PCR (ddPCR) is performed using a probe at GRCh38 chr13:21003868-21003954 to test for the presence or absence of the previously reported deletions in the DFNB1 (GJB6 gene) region, including the GJB6 D13S1854 309kb deletion, the GJB6-D13S1854 232kb deletion, and the deletions reported by Wilch 2010 (PMID: 20236118) and Feldman 2009 (PMID: 19101659). Any deletions that are identified are further clarified using the ddPCR probes at the following locations: GrCh38 chr13:21089281- 21089358, chr13:21055271-21055336, chr13:20794699-20794765, chr13:20805056-20805133. Droplet digital PCR (ddPCR) is performed to screen for common large deletions in STRC and CATSPER2 genes. It is performed using a probe at STRC intron 25 (GrCh38chr15:43892948-43893040) to test for the presence of a deletion in STRC. Any deletions that are identified are further clarified using ddPCR probes at the following locations: STRC exon 23 (GrCh38 chr15:43895449-43895542) and CATSPER2 exon 7 (GrCh38chr15:43931196- 43931260). Deletions that do not affect the STRC intron 25 (GrCh38 chr15:43892948 43893040) region will not be identified. Copy number variants that do not affect the GJB6 GrCh38 chr13:21003868-21003954 or the STRC intron 25 (GrCh38 chr15:43892948-43893040) probed regions will not be detected by this assay. CATSPER2 deletions will only be reported if an STRC deletion was also identified. Duplications in STRC and/or CATSPER2 will not be reported because exact breakpoints cannot be determined by this testing methodology and duplications in these genes are not known to be associated with hearing loss and/or male infertility. This test does not include sequencing of the GJB6 or CATSPER2 genes. It will not detect variants in non-coding regions, aside the canonical splice sites STRC. There is reduced sensitivity for larger indels and variants in low complexity regions. It will not detect triplet repeat expansions, translocations, inversions, gene -pseudogene conversions, or other complex rearrangements. Low level mosaic variants may not be identified. Certain exons are excluded due to homology or other technical limitations (see above for excluded regions). Variant classifications are based on ACMG/AMP criteria (Richards et al. 2015) with ClinGen rule specifications (https://www.clinicalgenome.org/working-groups/sequence-variant-interpretation/). Variants are reported according to HGVS nomenclature (www.hgvs.org/mutnomen). Likely benign and benign variants are not included in this report but are available upon request. This test does not routinely detect variants in non-coding regions (aside from the canonical splice sites), triplet repeat expansions, translocations, inversions, and copy number variants encompassing less than 2 consecutive exons. There is reduced detection for large r indels, variants in low complexity regions, and variants in regions with high homology. This test was developed, and its performance characteristics determined by the Laboratory for Molecular Medicine at Partners HealthCare Personalized Medicine (LMM, 65 Landsdowne St, Cambridge, MA 02139; 617-768-8500; CLIA#22D1005307). It has not been cleared or approved by the U.S. Food and Drug Administration (FDA). The FDA has determined that such clearance or approval is not necessary. View more

Test Confirmation:

All clinically significant variants are confirmed by Sanger sequencing or an alternate assay.

Availability:

Tests performed
Entire test performed in-house

Analytical Validity:

This test is 99.93% sensitive (95% CI =99.92-99.94%) to detect variants changing a single base and 96.75% sensitive to detect insertion/deletions (95% CI =96.28-97.22%) within covered regions. Technical positive predictive value for single nucleotide variant changes is 99.42% (95% CI = 99.37-99.48%) and 94.16% (95% CI = 93.34-94.97%) for insertion/deletion … View more

View citations (1)

http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medicine/Tests/Hearing-Loss/OtoGenome.aspx

Assay limitations:

This test does not detect variants in non-coding regions, aside from the splice junctions, that could affect gene expression and a few exons have been excluded due to technical difficulties. CNV analysis is only performed when data meets necessary quality standards and may not be available for all cases.

Proficiency testing (PT):

Is proficiency testing performed for this test?
Yes

Method used for proficiency testing:
Intra-Laboratory

VUS:

Software used to interpret novel variations
Alamut, UCSC Genome Browser, gnomAd, ExAC, ESP, 1000 Genomes, PolyPhen, SIFT, AlignGVGD, and more.

Laboratory's policy on reporting novel variations
All novel VUS's are reported

Recommended fields not provided:

Citations to support assay limitations, Description of internal test validation method, PT Provider, Description of PT method, Major CAP category, CAP category, CAP test list

Regulatory Approval

FDA Review:

Category: FDA exercises enforcement discretion

Additional Information

Reviews:

Genereviews

PubMed Clinical Queries

Clinical resources:

Molecular resources:

View MT-CO1 variations in ClinVar

View MT-RNR1 variations in ClinVar

View MT-TS1 variations in ClinVar

View POU3F4 variations in ClinVar

View PRPS1 variations in ClinVar

View SMPX variations in ClinVar

Practice guidelines:

Consumer resources:

MedlinePlusGenetics (GHR)

MedlinePlus

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.