Genetics of Hearing Loss: ACMG Practice Guidelines for Diagnosis

About 3 to 4 per 1,000 live births in the United States are affected by profound deafness or partial hearing loss.1,2  Genetic factors explain more than half of these cases.  Hereditary hearing loss is genetically heterogeneous and is clinically categorized either as syndromic or nonsyndromic.  The nonsyndromal types account for 70% while the remaining 30% is syndromic in nature.  Autosomal recessive inheritance is common in the nonsyndromal forms (75% to 80%), followed by autosomal dominant (15% to 24%) and X-linked transmission (1% to 2%).3,4

Recent guidelines published by the American College of Medical Genetics (ACMG) and the American Medical Association (AMA) Current Procedural Terminology (CPT) suggest that comprehensive genetic testing using next generation sequencing technology (NGS) is a good strategy for evaluating both syndromal and nonsyndromal types of hearing loss.4,5  The AMA CPT code 81430 describes a laboratory procedure using NGS to test at least 60 genes, including CDH23, CLRN1, GJB2, GPR98, MTRNR1, MYO7A, MYO15A, PCDH15, OTOF, SLC26A4, TMC1, TMPRSS3, USH1C, USH1G, USH2A, and WFS1. Another CPT code, 81431, describes a separate procedure to analyze GJB2 and GJB6 for deletions and duplications.5

Mutations at the DFNB1 locus account for an estimated 50% of all autosomal recessive nonsyndromic hearing loss, and affect an estimated 15% to 40% of all individuals in a variety of deaf populations.4 The locus contains genes GJB2 and GJB6 which, respectively, encode the gap junction proteins connexin 26 and connexin 30.6,7  Deafness-causing variants have been identified in the GJB2 gene.6 Within the DFNB1 locus, compound heterozygotes consisting of a GJB2 variant on one allele in association with a GJB6 gene deletion, and biallelic deletions of the GJB6 gene also associate with deafness.7-9 Hearing loss associated with mutations at the DFNB1 locus is sensorineural in nature, resulting in damage to neural receptors of the inner ear, nerve pathways to the brain, or the area of the brain that receives sound information.10 Together with GJB2 and GJB6, to date variants in over 80 genes have been linked to nonsyndromic hearing loss. Details of these genes with links to Online Mendelian Inheritance in Man (OMIM) website ( can be found on the Hereditary Hearing Loss Homepage (Van Camp G, Smith RJH, These genes encode protein products having a variety of functions associated with auditory system development and function, and include transcription factors, structural proteins, gap junction proteins, and ion channel proteins.4

Syndromal types of hearing loss occur with high variability in terms of age of onset, phenotypic expression and inheritance. Variability can occur between families and even within members of the same family. Identification of a hearing loss phenotype may occur secondary to primary clinical features or, in some syndromes, hearing loss is the key presenting finding.4 Some of the more common forms of syndromic hearing loss include Usher, Pendred, Refsum, Waardenburg, Branchiootorenal, Stickler and Alports syndromes. While phenotypic variability between syndromes is high, all have sensorineural hearing loss as a common component.4,10,11 To date, over 40 genes have been linked to syndromic hearing loss (see Van Camp G, Smith RJH, Hereditary Hearing Loss Homepage, and links therein to the OMIM website (


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2. Morton CC, Nance WE. Newborn hearing screening–a silent revolution. The New England journal of medicine 2006;354:2151-64.

3. Smith RJH, Shearer AE, Hildebrand MS, Van Camp G. Deafness and Hereditary Hearing Loss Overview. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA); 1993.

4. Alford RL, Arnos KS, Fox M, et al. American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. Genetics in medicine : official journal of the American College of Medical Genetics 2014;16:347-55.

5. American Medical Association. Current Procedural Terminology CPT 2015 Professional Edition. Chicago, IL: AMA, 2014.

6. Kenneson A, Van Naarden Braun K, Boyle C. GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. Genetics in medicine : official journal of the American College of Medical Genetics 2002;4:258-74.

7. del Castillo I, Villamar M, Moreno-Pelayo MA, et al. A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. The New England journal of medicine 2002;346:243-9.

8. del Castillo FJ, Rodriguez-Ballesteros M, Alvarez A, et al. A novel deletion involving the connexin-30 gene, del(GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment. Journal of medical genetics 2005;42:588-94.

9. Del Castillo I, Moreno-Pelayo MA, Del Castillo FJ, et al. Prevalence and evolutionary origins of the del(GJB6-D13S1830) mutation in the DFNB1 locus in hearing-impaired subjects: a multicenter study. American journal of human genetics 2003;73:1452-8.

10. Smith RJ, Bale JF, Jr., White KR. Sensorineural hearing loss in children. Lancet 2005;365:879-90.

11. Kashtan CE. Alport Syndrome and Thin Basement Membrane Nephropathy. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA); 1993.

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