Hearing loss is the most common sensory deficit in humans, arising from disruptions in the highly complex auditory system. The transduction of sound requires the precise coordination of inner ear development, cochlear hair cell mechanics, ion homeostasis, synaptic transmission, and auditory nerve integrity.
Germline variants in these pathways are responsible for approximately 50-60% of congenital hearing loss and a significant proportion of early-onset or progressive hearing loss in adults. These genetic etiologies range from isolated (non-syndromic) sensorineural hearing loss to complex syndromic conditions where hearing impairment coexists with visual, renal, cardiac, or metabolic disorders.
PreCheck Health Services Comprehensive Hereditary Hearing Loss Panel (137 genes) is a germline, targeted exome assay focused on genes with established roles in cochlear physiology, hair cell bundle morphogenesis, synaptic fidelity, and connective tissue integrity. The assay is intended for use on constitutional DNA (e.g., peripheral blood or saliva). By interrogating these loci, the panel supports molecular diagnosis across sensorineural, conductive, and mixed hearing loss, auditory neuropathy spectrum disorder (ANSD), and syndromic presentations, identifying etiologies that directly inform prognosis and management.
❖ Congenital or Early-Onset Hearing Loss: Infants failing newborn hearing screening or children presenting with pre-lingual hearing loss, where establishing a molecular diagnosis (e.g., GJB2, OTOF) guides immediate intervention strategies.
❖ Suspected Auditory Neuropathy Spectrum Disorder (ANSD): Individuals with evidence of normal outer hair cell function (OAEs) but abnormal auditory brainstem responses (ABR), where distinguishing between presynaptic (e.g., OTOF) and postsynaptic/neural causes helps predict cochlear implant success.
❖ Progressive or Late-Onset Hearing Loss: Adults or adolescents with unexplained decline in hearing thresholds, particularly those with a family history suggesting autosomal dominant (DFNA) or mitochondrial inheritance patterns.
❖ Suspected Syndromic Etiologies: Patients with hearing loss accompanied by other clinical features, such as:
* Visual impairment (Retinitis Pigmentosa in Usher syndrome; USH2A, MYO7A).
* Renal pathology (Alport syndrome; COL4A series).
* Thyroid enlargement (Pendred syndrome; SLC26A4).
* Pigmentary abnormalities (Waardenburg syndrome; PAX3, MITF, SOX10).
* Cardiac arrhythmias (Jervell and Lange-Nielsen syndrome; KCNQ1, KCNE1).
❖ Cochlear Implant Candidates: Individuals undergoing evaluation for cochlear implantation, where genetic findings can help predict neural integrity and post-implantation outcomes.
This panel targets germline variants in genes that regulate cochlear development, mechanotransduction, ion recycling, and structural integrity. Genes are organized into biologic and clinical pathways relevant to non-syndromic and syndromic deafness.
1. Gap Junctions and Ion Homeostasis (Connexins & Channels)
Genes that maintain the high potassium concentration in the endolymph, which is essential for hair cell depolarization. Disruption here is the most common cause of non-syndromic hearing loss.
❖ BSND, CLDN14, GJB2, GJB3, GJB6, KCNQ1, KCNQ4, KCNE1, SLC26A4, SLC26A5
2. Stereocilia Structure and Mechanotransduction
Genes encoding the cytoskeletal proteins, motors, and linkers that form the hair cell bundle. Defects in these genes prevent the conversion of sound waves into electrical signals.
❖ ADGRV1, CDH23, CIB2, ESPN, GPSM2, MYO6, MYO7A, MYO15A, PCDH15, STRC, TECTA, TMC1, TRIOBP, USH1C, USH1G, USH2A, WHRN
3. Synaptic Transmission and Auditory Neuropathy
Genes involved in the release of neurotransmitters at the ribbon synapse or the maintenance of spiral ganglion neurons.
❖ CABP2, OTOF, PJVK, SLC17A8
4. Transcription Factors and Ear Development
Genes that regulate the embryological development of the inner ear, neural crest cells, and melanocytes (stria vascularis).
❖ EYA1, EYA4, GATA3, GRHL2, HGF, MITF, PAX3, POU3F4, POU4F3, SIX1, SOX10, TBC1D24
5. Extracellular Matrix and Connective Tissue
Genes encoding collagens and tectorial membrane components.
❖ COL2A1, COL4A3, COL4A4, COL4A5, COL4A6, COL9A1, COL11A1, COL11A2, TECTA
Genes Analyzed 137 Hearing Loss & Otologic Health genes.
Technology Platform Illumina NGS (Hybrid-Capture Target Enrichment).
Coverage Metrics >98% bases at ≥20× read depth.
Variant Types Detected SNVs and small indels (≤20 bp) within coding exons ±10 bp intronic boundaries.
Reference Genome GRCh38/hg38.
Bioinformatics Pipeline SeqOne™, ACMG/AMP compliant.
Confirmatory Testing Sanger sequencing or orthogonal method as indicated.
Turnaround Time ~10 calendar days.
Quality Metrics Read quality ≥Q30; allelic balance ≥0.3; minimum coverage 20×.
1. Diagnostic Clarity and Prognosis
❖ Provides a molecular explanation for "idiopathic" hearing loss, ending the diagnostic odyssey for families.
❖ Distinguishes between stable, congenital hearing loss (e.g., GJB2) and progressive conditions (e.g., MYO7A, TMC1), allowing for better long-term educational and audiological planning.
2. Therapy Selection and Cochlear Implantation
❖ Genetic diagnosis helps predict the site of lesion. Patients with intracochlear defects (e.g., OTOF, GJB2) generally have better cochlear implant performance compared to those with auditory nerve hypoplasia or central pathway defects.
❖ Identification of variants in specific genes can warn against the use of aminoglycoside antibiotics (e.g., gentamicin) which may precipitate profound deafness in susceptible individuals.
3. Reproductive Planning and Cascade Testing
❖ Defines inheritance patterns (autosomal recessive, dominant, X-linked, or mitochondrial), providing accurate recurrence risk counseling (e.g., 25% for recessive, 50% for dominant) for future pregnancies.
❖ Facilitates targeted testing for family members and reproductive partners.
Risk Stratification and Diagnostic Clarification
Identify pathogenic or likely pathogenic variants underlying sensorineural, conductive, or mixed hearing loss, distinguishing hereditary causes from environmental factors (e.g., CMV, meningitis, ototoxicity). Refine differential diagnoses generated by audiograms and temporal bone imaging, enabling the transition from a "suspected" isolated hearing loss to a definitive syndromic diagnosis (e.g., Usher, Pendred, or Alport syndromes) that requires broader systemic surveillance
Family Risk Assessment, Cascade Testing, and Reproductive Counseling
Clarify recurrence risk for families and identify at-risk relatives once a pathogenic variant is identified—particularly for recessive conditions (e.g., GJB2, SLC26A4), dominant progressive types (e.g., WFS1, MYO7A), or X-linked forms (e.g., POU3F4). Support partner testing when appropriate (e.g., GJB2 carrier screening) to assess couple-level reproductive risk and provide anticipatory guidance for gene-positive relatives who may be at risk for late-onset or progressive hearing loss, allowing for early audiological monitoring.
Habilitation Selection and Auditory Management
Use molecular findings to guide personalized management, including predicting the success of cochlear implantation (CI). For example, individuals with intra-cochlear defects (e.g., OTOF, GJB2) typically respond better to CI than those with neural or central auditory pathway defects and avoid ineffective interventions or potentially harmful exposures (e.g., aminoglycosides in susceptible individuals or contact sports in SLC26A4-associated Enlarged Vestibular Aqueduct syndrome).
Pharmacogenetics Testing (for drug metabolism and gene-drug interactions)
Match treatments to the patient’s metabolic phenotype (e.g., CYP2D6, CYP2C19, CYP3A5, CYP2C9), reducing the risk of adverse drug reactions and improving efficacy.
Together, these tools enable precision medicine teams to offer a fully customized, data-driven treatment plan for each patient.
Germline testing for hearing loss has become an essential tool in precision medicine, enabling clinicians to identify the molecular causes of congenital deafness, auditory neuropathy, progressive hearing loss, and syndromic otologic disorders. When combined with audiological evaluation and imaging, a targeted gene panel provides diagnostic clarity that surpasses clinical assessment alone.
With high analytic performance and curated gene–disease evidence, PreCheck Health Services delivers genomic insights that refine diagnosis, guide habilitation strategies (such as cochlear implants or hearing aids), and support decisions around educational planning and reproductive risk management. Molecular findings also enable targeted cascade testing and appropriate partner evaluation.
This integrated approach enhances long-term audiological and general health care by enabling earlier, more accurate, and individualized management, ultimately improving outcomes and supporting informed planning for patients and families.
The Comprehensive Hereditary Hearing Loss Panel is designed to detect single-nucleotide variants (SNVs) and small insertions and deletions in 137 genes associated with inherited hearing loss. Targeted regions for this panel include the coding exons and 10 bp intronic sequences immediately to the exon-intron boundary of each coding exon in each of these genes. Extracted patient DNA is prepared using targeted hybrid capture, assignment of a unique index, and sequencing via Illumina sequencing by synthesis (SBS) technology. Data is aligned using the human genome build GRCh38. Variant interpretation is performed according to current American College of Medical Genetics and Genomics (ACMG) professional guidelines for the interpretation of germline sequence variants using SeqOne Pipeline.
ABHD12, ACTG1, ADGRV1, AIFM1, ALMS1, AMMECR1, ATP2B2, ATP6V1B1, BCS1L, BSND, BTD, CABP2, CACNA1D, CCDC50, CDC14A, CDH23, CEACAM16, CEP78, CHD7, CHSY1, CIB2, CISD2, CLDN14, CLIC5, CLPP, CLRN1, COCH, COL11A1, COL11A2, COL2A1, COL4A3, COL4A4, COL4A5, COL4A6, COL9A1, COL9A2, COL9A3, CRYM, DIABLO, DIAPH1, DIAPH3, DNMT1, DSPP, EDN3, EDNRB, EPS8, ESPN, ESRRB, EYA1, EYA4, FGF3, GATA3, GIPC3, GJB2, GJB3, GJB6, GPSM2, GRHL2, GRXCR1, GRXCR2, GSDME, HARS2, HGF, HOMER2, HOXB1, HSD17B4, ILDR1, KCNE1, KCNQ1, KCNQ4, KITLG, LARS2, LHFPL5, LHX3, LOXHD1, LRP2, LRTOMT, MARVELD2, MIR96, MITF, MSRB3, MYH14, MYH9, MYO15A, MYO3A, MYO6, MYO7A, NARS2, NDP, OSBPL2, OTOA, OTOF, OTOG, OTOGL, P2RX2, PAX3, PCDH15, PDZD7, PJVK, PNPT1, POU3F4, POU4F3, PRPS1, PTPRQ, RDX, RIPOR2, SERPINB6, SIX1, SLC17A8, SLC19A2, SLC26A4, SLC26A5, SLC4A11, SLC52A2, SLC52A3, SLITRK6, SMAD4, SMPX, SNAI2, SOX10, STRC, SYNE4, TBC1D24, TCOF1, TECTA, TIMM8A, TMC1, TMIE, TMPRSS3, TPRN, TRIOBP, TWNK, USH1C, USH1G, USH2A, WFS1, WHRN
This test aims to detect all clinically relevant variants within the coding regions of the genes evaluated. Pathogenic and likely pathogenic variants detected in these genes should be confirmed by orthogonal methods. Detected genetic variants classified as benign, likely benign, or of uncertain significance are not included in this report. Homopolymer regions and regions outside of the coding regions cannot be captured by the standard NGS target enrichment protocols. Currently, the assay does not detect large deletions and duplications. This analysis also cannot detect pathogenic variants within regions that were not analyzed (e.g., introns, promoter and enhancer regions, long repeat regions, and mitochondrial sequence). This assay is not designed to detect mosaicism and is not designed to detect complex gene rearrangements or genomic aneuploidy events. It is important to understand that there may be variants in these genes undetectable using current technology. Additionally, there may be genes associated with hearing loss whose clinical association has not yet been definitively established. The test may therefore not detect all variants associated with hearing loss. The interpretation of variants is based on our current understanding of the genes in this panel and is based on current ACMG professional guidelines for the interpretation of germline sequence variants. Interpretations may change over time as more information about the genes in this panel becomes available. Qualified health care providers should be aware that future reclassifications of genetic variants can occur as ACMG guidelines are updated. Factors influencing the quantity and quality of extracted DNA include, but are not limited to, collection technique, the amount of buccal epithelial cells obtained, the patient’s oral hygiene, and the presence of dietary or microbial sources of nucleic acids and nucleases, as well as other interfering substances and matrix-dependent influences. PCR inhibitors, extraneous DNA, and nucleic acid-degrading enzymes may adversely affect assay results.
This laboratory-developed test (LDT) was developed, and its performance characteristics were determined by PreCheck Health Services, Inc. This test was performed at PreCheck Health Services, Inc. (CLIA ID: 10D2210020 and CAP ID: 9101993), which is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) as qualified to perform high complexity testing.
This assay has not been cleared or approved by the U.S. Food and Drug Administration (FDA). Clearance or approval by the FDA is not required for the clinical use of this analytically and clinically validated laboratory-developed test. This assay has been developed for clinical purposes, and it should not be regarded as investigational or for research.
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