Establishing a diagnosis of a syndromic or nonsyndromic hereditary hearing loss disorder
Identifying variants within genes known to be associated with hereditary hearing loss, allowing for predictive testing of at-risk family members
Hereditary hearing loss is a genetically heterogeneous condition that can be either syndromic or nonsyndromic in origin.
This panel evaluates 160 genes related to both syndromic and nonsyndromic hereditary hearing loss.
The following genes are investigated in this panel test: ABHD12, ACTG1, ADCY1, ADGRV1, AIFM1, ALMS1, ATP6V1B1, BCS1L, BDP1, BSND, BTD, CABP2, CACNA1D, CATSPER2, CCDC50, CD164, CDC14A, CDH23, CEACAM16, CEP78, CHD7, CIB2, CISD2, CLDN14, CLIC5, CLPP, CLRN1, COCH, COL2A1, COL4A3, COL4A4, COL4A5, COL4A6, COL9A1, COL9A2, COL9A3, COL11A1, COL11A2, CRYM, DCDC2, DFNA5 (GSDME), DIABLO, DIAPH1, DIAPH3, DNMT1, DSPP, EDN3, EDNRB, ELMOD3, EPS8, EPS8L2, ESPN, ESRRB, EYA1, EYA4, FGF3, FGFR2, FLNA, FOXC1, FOXI1, GATA3, GIPC3, GJB2, GJB6, GPSM2, GRHL2, GRXCR1, GRXCR2, HARS2, HGF, HOMER2, HOXA2, HSD17B4, ILDR1, JAG1, KARS, KCNE1, KCNJ10, KCNQ1, KCNQ4, KITLG, LARS2, LHFPL5, LOXHD1, LRTOMT, MARVELD2, MCM2, MET, MIR96, MITF, MSRB3, MT-RNR1, MT-TS1, MYH14, MYH9, MYO3A, MYO6, MYO7A, MYO15A, NARS2, NF2, NLRP3, OPA1, OSBPL2, OTOA, OTOF, OTOG, OTOGL, P2RX2, PAX3, PCDH15, PDZD7, PEX1, PEX6, PHYH, PJVK, PNPT1, POLR1C, POLR1D, POU3F4, POU4F3, PRPS1, PTPN11, PTPRQ, RDX, RIPOR2, S1PR2, SERPINB6, SIX1, SLC17A8, SLC22A4, SLC26A4, SLC26A5, SLC52A2, SLC52A3, SLITRK6, SMPX, SNAI2, SOX10, STRC, SYNE4, TBC1D24, TCOF1, TECTA, TIMM8A, TJP2, TMC1, TMEM132E, TMIE, TMPRSS3, TNC, TPRN, TRIOBP, TWNK, USH1C, USH1G, USH2A, WBP2, WFS1, and WHRN
Test Id | Reporting Name | Available Separately | Always Performed |
---|---|---|---|
FIBR | Fibroblast Culture | Yes | No |
CRYOB | Cryopreserve for Biochem Studies | No | No |
If skin biopsy is received, fibroblast culture and cryopreservation for biochemical studies will be added at an additional charge.
Custom Sequence Capture and Targeted Next-Generation Sequencing (NGS)/Polymerase Chain Reaction (PCR)/Digital Droplet PCR (ddPCR)/ qPCR/Sanger Sequencing/Gene Dosage Analysis by Multiplex Ligation- Dependent Probe Amplification (MLPA)
ADCADN
ARTS
AUNA1
Auditory neuropathy, autosomal dominant, 1
BOS2
BOS3
BVVLS
C10orf2
Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant
Charcot-Marie-Tooth disease X-linked recessive 5
CMTX5
CRDHL
Deafness, autosomal dominant 1
Deafness, autosomal dominant 2A
Deafness, autosomal dominant 2B
Deafness, autosomal dominant 3A
Deafness, autosomal dominant 3B
Deafness, autosomal dominant 4A
Deafness, autosomal dominant 4B
Deafness, autosomal dominant 5
Deafness, autosomal dominant 6/14/38
Deafness, autosomal dominant 8/12
Deafness, autosomal dominant 9
Deafness, autosomal dominant 10
Deafness, autosomal dominant 11
Deafness, autosomal dominant 13
Deafness, autosomal dominant 15
Deafness, autosomal dominant 17
Deafness, autosomal dominant 20/26
Deafness, autosomal dominant 22
Deafness, autosomal dominant 23
Deafness, autosomal dominant 25
Deafness, autosomal dominant 28
Deafness, autosomal dominant 36
Deafness, autosomal dominant 39
Deafness, autosomal dominant 41
Deafness, autosomal dominant 40
Deafness, autosomal dominant 44
Deafness, autosomal dominant 50
Deafness, autosomal dominant 51
Deafness, autosomal dominant 56
Deafness, autosomal dominant 64
Deafness, autosomal dominant 66
Deafness, autosomal dominant 67
Deafness, autosomal dominant 68
Deafness, autosomal dominant 69
Deafness, autosomal dominant 70
Deafness, autosomal dominant 73
Deafness, autosomal recessive 1A
Deafness, autosomal recessive 1B
Deafness, autosomal recessive 2
Deafness, autosomal recessive 3
Deafness, autosomal recessive 4
Deafness, autosomal recessive 4 with enlarged vestibular aqueduct
Deafness, autosomal recessive 6
Deafness, autosomal recessive 7
Deafness, autosomal recessive 8/10
Deafness, autosomal recessive 9
Deafness, autosomal recessive 15
Deafness, autosomal recessive 16
Deafness, autosomal recessive 18
Deafness, autosomal recessive 18A
Deafness, autosomal recessive 21
Deafness, autosomal recessive 22
Deafness, autosomal recessive 23
Deafness, autosomal recessive 24
Deafness, autosomal recessive 25
Deafness, autosomal recessive 28
Deafness, autosomal recessive 29
Deafness, autosomal recessive 30
Deafness, autosomal recessive 31
Deafness, autosomal recessive 35
Deafness, autosomal recessive 36
Deafness, autosomal recessive 37
Deafness, autosomal recessive 39
Deafness, autosomal recessive 42
Deafness, autosomal recessive 44
Deafness, autosomal recessive 48
Deafness, autosomal recessive 49
Deafness, autosomal recessive 53
Deafness, autosomal recessive 59
Deafness, autosomal recessive 60
Deafness, autosomal recessive 61
Deafness, autosomal recessive 63
Deafness, autosomal recessive 66
Deafness, autosomal recessive 66/67
Deafness, autosomal recessive 68
Deafness, autosomal recessive 70
Deafness, autosomal recessive 74
Deafness, autosomal recessive 76
Deafness, autosomal recessive 77
Deafness, autosomal recessive 79
Deafness, autosomal recessive 82
Deafness, autosomal recessive 84
Deafness, autosomal recessive 84A
Deafness, autosomal recessive 86
Deafness, autosomal recessive 88
Deafness, autosomal recessive 89
Deafness, autosomal recessive 91
Deafness, autosomal recessive 93
Deafness, autosomal recessive 94
Deafness, autosomal recessive 97
Deafness, autosomal recessive 98
Deafness, autosomal recessive 99
Deafness, autosomal recessive 101
Deafness, autosomal recessive 102
Deafness, autosomal recessive 103
Deafness, autosomal recessive 104
Deafness, autosomal recessive 105
Deafness, autosomal recessive 106
Deafness, autosomal recessive 107
Deafness, X-linked 1
Deafness, X-linked 2
Deafness, X-linked 4
Deafness, X-linked 5
Deafness, X-linked 6
DFNA1
DFNA2A
DFNA3A
DFNA3B
DFNA4A
DFNA4B
DFNA6/14/38
DFNA8/12
DFNA9
DFNA10
DFNA11
DFNA13
DFNA15
DFNA17
DFNA20/26
DFNA22
DFNA23
DFNA25
DFNA28
DFNA36
DFNA39
DFNA40
DFNA41
DFNA44
DFNA50
DFNA51
DFNA56
DFNA64
DFNA66
DFNA67
DFNA68
DFNA69
DFNA70
DFNA73
DFNB1A
DFNB1B
DFNB2
DFNB3
DFNB4
DFNB6
DFNB7
DFNB8
DFNB9
DFNB12
DFNB15/72/95
DFNB16
DFNB18
DFNB18A
DFNB21
DFNB22
DFNB23
DFNB24
DFNB25
DFNB28
DFNB29
DFNB30
DFNB31
DFNB35
DFNB36
DFNB37
DFNB39
DFNB42
DFNB44
DFNB48
DFNB49
DFNB53
DFNB60
DFNB61
DFNB63
DFNB66
DFNB66/67
DFNB68
DFNB70
DFNB74
DFNB76
DFNB77
DFNB79
DFNB82
DFNB84
DFNB84A
DFNB86
DFNB88
DFNB89
DFNB91
DFNB93
DFNB94
DFNB97
DFNB98
DFNB99
DFNB101
DFNB102
DFNB103
DFNB104
DFNB105
DFNB106
DFNB107
DFNX1
DFNX2
DFNX4
DFNX5
DFNX6
FAM65B
GPR98
HDR
Hypoparathyroidism, sensorineural deafness, and renal dysplasia
JLNS
Next Gen Sequencing Test
OPD
PHARC
POU4F3
RTA with deafness
SANDD
USH1B
USH1D
USH1D/F
USH1F
USH1J
USH2C
USH2D
USH3A
If skin biopsy is received, fibroblast culture and cryopreservation for biochemical studies will be added at an additional charge.
Varies
Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. See FMTT / Familial Mutation, Targeted Testing, Varies.
Specimen preferred to arrive within 96 hours of collection.
Specimen Type: Whole blood
Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.
Container/Tube:
Preferred: Lavender top (EDTA) or yellow top (ACD)
Acceptable: Any anticoagulant
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 14 days
Additional Information: To ensure minimum volume and concentration of DNA is met, the preferred volume of blood must be submitted. Testing may be canceled if DNA requirements are inadequate.
Specimen Type: Skin biopsy
Supplies: Fibroblast Biopsy Transport Media (T115)
Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin.
Specimen Volume: 4-mm punch
Specimen Stability Information: Refrigerated (preferred)/Ambient
Additional Information: A separate culture charge will be assessed under FIBR / Fibroblast Culture, Tissue. An additional 4 weeks is required to culture fibroblasts before genetic testing can occur.
Specimen Type: Cultured fibroblast
Container/Tube: T-25 flask
Specimen Volume: 2 Flasks
Collection Instructions: Submit confluent cultured fibroblast cells from a skin biopsy from another laboratory. Cultured cells from a prenatal specimen will not be accepted.
Specimen Stability Information: Ambient (preferred)/Refrigerated (<24 hours)
Additional Information: A separate culture charge will be assessed under FIBR / Fibroblast Culture, Tissue. An additional 4 weeks is required to culture fibroblasts before genetic testing can occur.
1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing (Spanish) (T826)
3. Targeted Genes and Methodology Details for the Hereditary Hearing Loss Panel in Special Instructions.
4. If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen.
3 mL
Specimen Type | Temperature | Time | Special Container |
---|---|---|---|
Varies | Varies (preferred) |
Establishing a diagnosis of a syndromic or nonsyndromic hereditary hearing loss disorder
Identifying variants within genes known to be associated with hereditary hearing loss, allowing for predictive testing of at-risk family members
Hereditary hearing loss is a genetically heterogeneous condition that can be either syndromic or nonsyndromic in origin.
This panel evaluates 160 genes related to both syndromic and nonsyndromic hereditary hearing loss.
The following genes are investigated in this panel test: ABHD12, ACTG1, ADCY1, ADGRV1, AIFM1, ALMS1, ATP6V1B1, BCS1L, BDP1, BSND, BTD, CABP2, CACNA1D, CATSPER2, CCDC50, CD164, CDC14A, CDH23, CEACAM16, CEP78, CHD7, CIB2, CISD2, CLDN14, CLIC5, CLPP, CLRN1, COCH, COL2A1, COL4A3, COL4A4, COL4A5, COL4A6, COL9A1, COL9A2, COL9A3, COL11A1, COL11A2, CRYM, DCDC2, DFNA5 (GSDME), DIABLO, DIAPH1, DIAPH3, DNMT1, DSPP, EDN3, EDNRB, ELMOD3, EPS8, EPS8L2, ESPN, ESRRB, EYA1, EYA4, FGF3, FGFR2, FLNA, FOXC1, FOXI1, GATA3, GIPC3, GJB2, GJB6, GPSM2, GRHL2, GRXCR1, GRXCR2, HARS2, HGF, HOMER2, HOXA2, HSD17B4, ILDR1, JAG1, KARS, KCNE1, KCNJ10, KCNQ1, KCNQ4, KITLG, LARS2, LHFPL5, LOXHD1, LRTOMT, MARVELD2, MCM2, MET, MIR96, MITF, MSRB3, MT-RNR1, MT-TS1, MYH14, MYH9, MYO3A, MYO6, MYO7A, MYO15A, NARS2, NF2, NLRP3, OPA1, OSBPL2, OTOA, OTOF, OTOG, OTOGL, P2RX2, PAX3, PCDH15, PDZD7, PEX1, PEX6, PHYH, PJVK, PNPT1, POLR1C, POLR1D, POU3F4, POU4F3, PRPS1, PTPN11, PTPRQ, RDX, RIPOR2, S1PR2, SERPINB6, SIX1, SLC17A8, SLC22A4, SLC26A4, SLC26A5, SLC52A2, SLC52A3, SLITRK6, SMPX, SNAI2, SOX10, STRC, SYNE4, TBC1D24, TCOF1, TECTA, TIMM8A, TJP2, TMC1, TMEM132E, TMIE, TMPRSS3, TNC, TPRN, TRIOBP, TWNK, USH1C, USH1G, USH2A, WBP2, WFS1, and WHRN
If skin biopsy is received, fibroblast culture and cryopreservation for biochemical studies will be added at an additional charge.
Hereditary hearing loss encompasses a heterogeneous group of syndromic and nonsyndromic conditions. A comprehensive diagnostic genetic test is useful to help determine a molecular etiology for hearing loss and, therefore, identify other organ systems that may be involved, establish long-term prognosis, and ascertain the inheritance pattern and recurrence risk within a family.
Individuals with syndromic hearing loss typically have involvement of other organs or organ systems and may have malformations of the external ear. Individuals with nonsyndromic hearing loss may have abnormalities of the middle ear and/or inner ear but typically do not have visible abnormalities of the external ear and often do not have additional organ system involvement or other related medical problems.
Approximately 50% of individuals with hearing loss have a genetic etiology that can be identified. Of those, approximately 70% of individuals have a nonsyndromic condition, and the remaining 30% have 1 of over 400 syndromes involving hearing loss. Of the individuals with nonsyndromic hearing loss, at least three-quarters have an autosomal recessive condition, approximately 25% of whom have variants in the GJB2 or GJB6 genes.
An interpretive report will be provided.
Variant curation is performed using published American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations as a guideline.(1) Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity, and reported with interpretive comments detailing their potential or known significance.
Clinical Correlations:
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.
If testing was performed because of a clinically significant family history, it is often useful to first test an affected family member. Detection of at least one reportable variant in an affected family member would allow for more informative testing of at-risk individuals.
To discuss the availability of additional testing options or for assistance in the interpretation of these results, contact the Mayo Clinic Laboratory genetic counselors at 800-533-1710.
Technical Limitations:
Next-generation sequencing may not detect all types of genomic variants. In rare cases, false-negative or false- positive results may occur. The depth of coverage may be variable for some target regions, but assay performance below the minimum acceptable criteria or for failed regions will be noted. Given these limitations, negative results do not rule out the diagnosis of a genetic disorder. Additionally, low level mosaic variants may not be detected. If a specific clinical disorder is suspected, evaluation by alternative methods can be considered.
If the patient has had an allogeneic hematopoietic stem cell transplant or a recent heterologous blood transfusion, these results may be inaccurate due to the presence of donor DNA.
There may be regions of genes that cannot be effectively amplified for sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. Confirmation of select reportable variants will be performed by alternate methodologies based on internal laboratory criteria.
Of note, absence of the mitochondrial variants MT-RNR1 m.1494C>T, MT-RNR1 m.1555A>G, or MT-TS1 m.7445A>G on the report does not rule out the presence of these variants below the limits of detection of this assay (<5% heteroplasmy).
This test is not designed to differentiate between somatic and germline variants. If there is a possibility that any detected variant is somatic, additional testing may be necessary to clarify the significance of results.
Reclassification of Variants Policy:
At this time, it is not standard practice for the laboratory to systematically review previously classified variants on a regular basis. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.
Variant Evaluation:
Evaluation and categorization of variants is performed using published American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) recommendations as a guideline.(1) Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Variants classified as benign or likely benign are not reported.
Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and periodic updates to these tools may cause predictions to change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.
1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424
2. Alford R, Arnos K, Fox M, et al: American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. Genet Med. 2014 Apr;16(4):347-355
3. DiStefano MT, Hemphill SE, Oza AM, et al: ClinGen expert clinical validity curation of 164 hearing loss gene-disease pairs. Genet Med. 2019 Oct;21(10):2239-2247
4. Oza AM, DiStefano MT, Hemphill SE, et al: Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. Hum Mutat. 2018 Nov;39(11):1593-1613
5. Shearer AE, Hildebrand MS, Smith RJH: Hereditary hearing loss and deafness overview. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 1999. Updated July 27, 2017. Accessed September 15, 2020. Available at www.ncbi.nlm.nih.gov/books/NBK1434/
6. Sloan-Heggen CM, Bierer AO, Shearer AE, et al: Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet. 2016 Apr;135(4):441-450
Next-generation sequencing (NGS) and/or Sanger sequencing is performed to test for the presence of a sequence variant in all genes analyzed. Additionally, digital droplet polymerase chain reaction (ddPCR) is performed to test for 3 mitochondrial variants included in this panel.
Finally, NGS or multiplex ligation-dependent probe amplification (MLPA) is used to test for the presence of large deletions and duplications in the majority of genes. There may be regions of genes that cannot be effectively amplified for sequencing or large deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC)-rich content, and repetitive sequences. MLPA, PCR, qPCR, array comparative genomic hybridization (aCGH) or Sanger sequencing may be used to confirm alterations detected by NGS when appropriate.(Unpublished Mayo method)
Genes analyzed: ABHD12, ACTG1, ADCY1, ADGRV1, AIFM1, ALMS1, ATP6V1B1, BCS1L, BDP1, BSND, BTD, CABP2, CACNA1D, CATSPER2, CCDC50, CD164, CDC14A, CDH23, CEACAM16, CEP78, CHD7, CIB2, CISD2, CLDN14, CLIC5, CLPP, CLRN1, COCH, COL2A1, COL4A3, COL4A4, COL4A5, COL4A6, COL9A1, COL9A2, COL9A3, COL11A1, COL11A2, CRYM, DCDC2, DFNA5 (GSDME), DIABLO, DIAPH1, DIAPH3, DNMT1, DSPP, EDN3, EDNRB, ELMOD3, EPS8, EPS8L2, ESPN, ESRRB, EYA1, EYA4, FGF3, FGFR2, FLNA, FOXC1, FOXI1, GATA3, GIPC3, GJB2, GJB6, GPSM2, GRHL2, GRXCR1, GRXCR2, HARS2, HGF, HOMER2, HOXA2, HSD17B4, ILDR1, JAG1, KARS, KCNE1, KCNJ10, KCNQ1, KCNQ4, KITLG, LARS2, LHFPL5, LOXHD1, LRTOMT, MARVELD2, MCM2, MET, MIR96, MITF, MSRB3, MT-RNR1, MT-TS1, MYH14, MYH9, MYO3A, MYO6, MYO7A, MYO15A, NARS2, NF2, NLRP3, OPA1, OSBPL2, OTOA, OTOF, OTOG, OTOGL, P2RX2, PAX3, PCDH15, PDZD7, PEX1, PEX6, PHYH, PJVK, PNPT1, POLR1C, POLR1D, POU3F4, POU4F3, PRPS1, PTPN11, PTPRQ, RDX, RIPOR2, S1PR2, SERPINB6, SIX1, SLC17A8, SLC22A4, SLC26A4, SLC26A5, SLC52A2, SLC52A3, SLITRK6, SMPX, SNAI2, SOX10, STRC, SYNE4, TBC1D24, TCOF1, TECTA, TIMM8A, TJP2, TMC1, TMEM132E, TMIE, TMPRSS3, TNC, TPRN, TRIOBP, TWNK, USH1C, USH1G, USH2A, WBP2, WFS1, and WHRN
Weekly
This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.
81430
81431
Test Id | Test Order Name | Order LOINC Value |
---|---|---|
HHLP | Hereditary Hearing Loss Panel | In Process |
Result Id | Test Result Name |
Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
|
---|---|---|
606159 | Test Description | 62364-5 |
608470 | Specimen | 31208-2 |
608471 | Source | 31208-2 |
608465 | Result Summary | 50397-9 |
608466 | Result | 82939-0 |
608467 | Interpretation | 69047-9 |
606160 | Resources | 99622-3 |
608468 | Additional Information | 48767-8 |
608469 | Method | 85069-3 |
606161 | Genes Analyzed | 48018-6 |
608473 | Disclaimer | 62364-5 |
608472 | Released By | 18771-6 |