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Test Catalog

Test ID: HHLP    
AudioloGene Hereditary Hearing Loss Panel, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

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

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

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

 

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

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.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

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.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

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 a reportable variant in an affected family member would allow for more informative testing of at risk individuals.

 

To discuss the availability of further testing options, or for assistance in the interpretation of these results, Mayo Clinic Laboratory genetic counselors can be contacted 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.

Clinical Reference Recommendations for in-depth reading of a clinical nature

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;17:405-423

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;16:347-355

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;135(4):441-450

Special Instructions Library of PDFs including pertinent information and forms related to the test