Massively Parallel Sequencing for Genetic Diagnosis of Hearing Loss
The New Standard of Care
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
To evaluate the use of new genetic sequencing techniques for comprehensive genetic testing for hearing loss.
Articles were identified from PubMed and Google Scholar databases using pertinent search terms.
Literature search identified 30 studies as candidates that met search criteria. Three studies were excluded, and 8 studies were found to be case reports. Twenty studies were included for review analysis, including 7 studies that evaluated controls and 16 studies that evaluated patients with unknown causes of hearing loss; 3 studies evaluated both controls and patients.
In the 20 studies included in the review analysis, 426 control samples and 603 patients with unknown causes of hearing loss underwent comprehensive genetic diagnosis for hearing loss using massively parallel sequencing. Control analysis showed a sensitivity and specificity >99%, sufficient for clinical use of these tests. The overall diagnostic rate was 41% (range, 10%-83%) and varied based on several factors, including inheritance and prescreening prior to comprehensive testing. There were significant differences in platforms available with regard to the number and type of genes included and whether copy number variations were examined. Based on these results, comprehensive genetic testing should form the cornerstone of a tiered approach to clinical evaluation of patients with hearing loss along with history, physical examination, and audiometry and can determine further testing that may be required, if any.
Implications for Practice
Comprehensive genetic testing has become the new standard of care for genetic testing for patients with sensorineural hearing loss.
- 1, , . DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA. 1977; 74: 5463–5467.
- 2, , , . Deafness in the genomics era. Hear Res. 2011; 282: 1–9.
- 3, . Next-generation DNA sequencing. Nat Biotechnol. 2008; 26: 1135–1145.
- 4. Next-generation DNA sequencing methods. Annu Rev Genom Human Genet. 2008; 9: 387–402.
- 5, , , et al. Genome sequencing in microfabricated high-density picolitre reactors. Nature. 2005; 437: 376–380.
- 6. Disease-targeted sequencing: a cornerstone in the clinic. Nat Rev Genet. 2013; 14: 295–300.
- 7, , , et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci USA. 2010; 107: 12629–12633.
- 8, , , et al. Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing. Proc Natl Acad Sci USA. 2010; 107: 21104–21109.
- 9, , , et al. Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families. Genome Biol. 2011; 12: R89.
- 10, , , et al. Targeted massive parallel sequencing: the effective detection of novel causative mutations associated with hearing loss in small families. Orphanet J Rare Dis. 2012; 7: 60.
- 11, , , et al. Molecular diagnostics for congenital hearing loss including 15 deafness genes using a next generation sequencing platform. BMC Med Genomics. 2012; 5: 17.
- 12, , , et al. Whole-exome sequencing efficiently detects rare mutations in autosomal recessive nonsyndromic hearing loss. PLoS ONE. 2012; 7: e50628.
- 13, , , et al. Prediction of cochlear implant performance by genetic mutation: the spiral ganglion hypothesis. Hear Res. 2012: 1–8.
- 14, , , et al. A low-cost exon capture method suitable for large-scale screening of genetic deafness by the massively-parallel sequencing approach. Genet Test Mol Biomarkers. 2012; 16: 536–542.
- 15, , , et al. Next-generation sequencing identifies a novel compound heterozygous mutation in MYO7A in a Chinese patient with Usher Syndrome 1B. Clin Chim Acta. 2012; 413: 1866–1871.
- 16, , , et al. Diagnostic application of targeted resequencing for familial nonsyndromic hearing loss. PLoS ONE. 2013; 8: e68692.
- 17, , , et al. Novel compound heterozygous TMC1 mutations associated with autosomal recessive hearing loss in a Chinese family. PLoS ONE. 2013; 8: e63026.
- 18, , , , . Massively Parallel DNA Sequencing Successfully Identifies New Causative Mutations in Deafness Genes in Patients with Cochlear Implantation and EAS. A Kimura, ed. PLoS ONE. 2013; 8: e75793.
- 19, , , et al. Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study. Orphanet J Rare Dis. 2013; 8: 172.
- 20, , , et al. Genetic analysis through OtoSeq of Pakistani families segregating prelingual hearing loss. Otolaryngol Head Neck Surg. 2013; 149: 478–487.
- 21, , , et al. A sensitive and specific diagnostic test for hearing loss using a microdroplet PCR-based approach and next generation sequencing. Am J Med Genet A. 2013; 161A: 145–152.
- 22, , , et al. Advancing genetic testing for deafness with genomic technology. J Med Genet. 2013; 50: 627–634.
- 23, , , et al. Performance evaluation of the next-generation sequencing approach for molecular diagnosis of hereditary hearing loss. Otolaryngol Head Neck Surg. 2013; 148: 1007–1016.
- 24, , , et al. Application of massively parallel sequencing to genetic diagnosis in multiplex families with idiopathic sensorineural hearing impairment. PLoS ONE. 2013; 8: e57369.
- 25, , , , . Genetic etiology study of the non-syndromic deafness in Chinese Hans by targeted next-generation sequencing. Orphanet J Rare Dis. 2013; 8: 85.
- 26, , , , , . The many faces of sensorineural hearing loss: one founder and two novel mutations affecting one family of mixed Jewish ancestry. Genet Test Mol Biomarkers. 2014; 18: 123–126.
- 27, , , et al. Exome sequencing identifies a novel frameshift mutation of MYO6 as the cause of autosomal dominant nonsyndromic hearing loss in a Chinese family [published online September 17, 2014]. Ann Hum Genet.
- 28, , , et al. Genetic testing for sporadic hearing loss using targeted massively parallel sequencing identifies 10 novel mutations. Clin Genet. 2015; 87: 588–593.
- 29, , , et al. Exome sequencing and genome-wide copy number variant mapping reveal novel associations with sensorineural hereditary hearing loss. BMC Genomics. 2014; 15: 1155.
- 30, , , , . Combined examination of sequence and copy number variations in human deafness genes improves diagnosis for cases of genetic deafness. BMC Ear Nose Throat Disord. 2014; 14: 9.
- 31, , , et al. Resolving the genetic heterogeneity of prelingual hearing loss within one family: performance comparison and application of two targeted next generation sequencing approaches. J Hum Genet. 2014; 59: 599–607.
- 32, , , et al. Exploration of molecular genetic etiology for Korean cochlear implantees with severe to profound hearing loss and its implication. Orphanet J Rare Dis. 2014; 9: 167.
- 33, , , et al. Whole-exome sequencing to decipher the genetic heterogeneity of hearing loss in a Chinese family with deaf by deaf mating. PLoS ONE. 2014; 9: e109178.
- 34, , , , , . Comprehensive genetic testing can save lives in hereditary hearing loss. Clin Genet. 2015; 87: 190–191.
- 35, , , et al. Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss. J Transl Med. 2014; 12: 311.
- 36, , , et al. Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations. Genet Med. 2014; 16: 945–953.
- 37, , , . Clinical application of a custom AmpliSeq library and ion torrent PGM sequencing to comprehensive mutation screening for deafness genes. Genet Test Mol Biomarkers. 2015; 19: 209–217.
- 38, , , et al. Copy number variants are a common cause of non-syndromic hearing loss. Genome Med. 2014; 6: 37.
- 39, , , , , . Genetic testing for hearing loss in the United States should include deletion/duplication analysis for the deafness/infertility locus at 15q15.3. Mol Cytogenet. 2013; 6: 19.
- 40, , . GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. Genet Med. 2002; 4: 258–274.
- 41, , , et al. Mutations in GJB2, GJB6, and mitochondrial DNA are rare in African American and Caribbean Hispanic individuals with hearing impairment. Am J Med Genet A. 2007; 143A: 830–838.
- 42, , . Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics? Mutat Res. 2009; 681: 189–196.
- 43, , . Taxonomizing, sizing, and overcoming the incidentalome. Genet Med. 2012; 14: 399–404.
- 44, , , et al. Incidental medical information in whole-exome sequencing. Pediatrics. 2012; 129: e1605–e1611.
- 45, , , et al. Panel-based genetic diagnostic testing for inherited eye diseases is highly accurate and reproducible, and more sensitive for variant detection, than exome sequencing. Genet Med. 2015; 17: 253–261.
- 46, , , et al. Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am J Hum Genet. 2014; 95: 445–453.
- 47, , , et al. ACMG clinical laboratory standards for next-generation sequencing. Genet Med. 2013; 15: 733–747.
- 48, , , 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.
- 49, . New treatment options for hearing loss. Nature Rev Drug Discovery. 2015: 1–20.