Hearing Loss

Expanded Hearing Loss Panel, Sequencing and Deletion/Duplication 2008803
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
  • Most comprehensive genetic test for NSHL and syndromic hearing loss
  • Recommended test for NSHL if GJB2, GJB6, and mitochondrial variant testing is negative
  • Recommended test for syndromic hearing loss if symptoms are consistent with disorders included on the panel

First-tier genetic test for individuals with NSHL

Connexin 26 (GJB2), Sequencing 0051374
Method: Polymerase Chain Reaction/Sequencing
  • Diagnostic test or carrier screening for GJB2-related NSHL
  • May be used as first-tier genetic test for individuals with NSHL
Hearing Loss, Nonsyndromic, Connexin 30 (GJB6) 2 Deletions 2001956
Method: Polymerase Chain Reaction/Capillary Electrophoresis
  • Diagnostic test for individuals with NSHL and 1 identified GJB2 variant
  • Carrier screening if family history of GJB6 deletion or for reproductive partner of individual with GJB6 or GJB2 variants
Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Useful when a pathogenic familial variant identifiable by sequencing is known.

Hearing loss can be syndromic or nonsyndromic (NSHL) and may be a result of genetic, physiological, or disease factors. Depending on the cause, hearing loss may have a variable age of onset from birth to early childhood, and range in severity from mild to profound. A genetic cause is found in 50% of individuals born with hearing loss.

Disease Overview

Symptoms

  • Hearing loss may be:
    • Prelingual or postlingual onset
    • Syndromic (associated with other findings) or nonsyndromic
    • Sensorineural, conductive, or mixed etiology
    • Variable in presentation based on genetic and environmental cause(s) of the hearing loss

Prevalence and/or Incidence

  • 1/500 born with hearing loss
    • 50% of individuals with hearing loss have a genetic cause.
  • 1/2,600 – NSHL
    • 50% are homozygous for GJB2 variants.
    • 2-4% are compound heterozygous for GJB2 variant and GJB6 deletion.
    • Homozygous GJB6 deletions are rare.
    • 1-2% have causative mitochondrial variants.

Genotype-Phenotype Correlation

  • Hearing loss associated with GJB2 (connexin 26) or GJB6 (connexin 30) variants – bilateral and stable with prelingual onset
  • Hearing loss and other manifestations associated with mitochondrial (mtDNA) variants vary in severity and age of onset
    • m.1555A>G – stable, severe to profound hearing loss with variable age of onset, predisposition to aminoglycoside ototoxicity
    • m.7445A>G – palmoplantar keratoderma and progressive, mild to severe hearing loss of childhood onset

Test Description

See Genes Tested table for genes included in the panel.

Clinical Sensitivity

  • Hearing Loss, Nonsyndromic Panel (GJB2) Sequencing, (GJB6) 2 Deletions and Mitochondrial DNA 2 Mutations  
    • 50-55% for Caucasians with NSHL; unknown in other ethnicities
  • Connexin 26 (GJB2) Sequencing 
    • 95% of GJB2 pathogenic variants are detected 

Limitations

  • A negative result does not exclude a heritable form of hearing loss.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the targeted genes
    • Regulatory region variants and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Deletions/duplications in ESPN, GIPC3, ILDR1, LOXHD1, LRTOMT, MT-RNR1, OTOA, PDZD7, SIX1
    • Noncoding transcripts
    • The following exons are not sequenced due to technical limitations of the assay:
      • COCH (NM_001347720) 2
      • DNMT1 (NM_001130823) 5
      • OTOA (NM_144672) 20, 21, 22, 23, 24, 25, 26, 27, 28
      • MT-RNR1: targeted sequencing is performed for m.1555A>G only. Other variants in this gene will not be detected.
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Deletions/duplications less than 1kb in the targeted genes by array
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
    • Variants in MT-RNR1 other than the targeted m.1555A>G variant
    • Heteroplasmy present at less than 25% for the MT-RNR1 m.1555A>G variant
    • Single exon deletions/duplications in the following exons:
    • Gene Exon(s)
      CCDC50 (NM_178335) 1, 12
      CDH23 (NM_022124) 28, 63
      CLRN1 (NM_001195794) 3
      CLRN1 (NM_001256819) 2
      CLRN1 (NM_052995) 1, 4
      COL11A2 (NM_080680) 62
      DIAPH1 (NM_001314007) 29
      DIAPH1 (NM_005219) 18, 28
      DNMT1 (NM_001130823) 1, 5, 41
      HARS2 (NM_012208) 1
      HSD17B4 (NM_000414) 24
      HSD17B4 (NM_001199291) 1
      KCNQ4 (NM_004700) 9
      MASP1 (NM_139125) 1
      MYH14 (NM_024729) 3, 13, 17, 24, 25, 30, 34
      MYH9 (NM_002473) 13, 23, 29, 30, 39
      MYO15A (NM_016239) 25, 26, 33, 49, 62
      MYO7A (NM_000260) 17, 26, 29
      OTOF (NM_194248) 26
      PCDH15 (NM_001142769) 13
      RDX (NM_001260495) 3
      RDX (NM_001260496) 5
      RDX (NM_002906) 6, 10
      SLC26A4 (NM_000441) 21
      SLC26A5 (NM_001321787) 19
      SLC26A5 (NM_206884) 15
      TMC1 (NM_138691) 6, 24
      TMIE (NM_147196) 1
      TMPRSS3 (NM_024022) 4
      TRIOBP (NM_001039141) 14, 21
      TRIOBP (NM_138632) 8
      USH1C (NM_005709) 1
      USH1C (NM_153676) 26

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

100

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

100

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Genes Tested

Gene MIM Number Disorder Inheritance

ACTG1

102560

Progressive sensorineural NSHL

AD

ADGRV1

602851

Usher syndrome type 1

AR

CCDC50

611051

Progressive sensorineural NSHL

AD

CDH23

605516

Stable NSHL

Usher syndrome type 1

AR

CEACAM16

614591

Progressive sensorineural NSHL

AD

CLDN14

605608

Stable sensorineural NSHL

AR

CLRN1

606397

Retinitis pigmentosa

Usher syndrome type 3

AR

COCH

603196

Postlingual, progressive sensorineural NSHL, with or without vestibular involvement

AD

COL11A2

120290

Sensorineural NSHL

Otospondylomegaepiphyseal dysplasia (OSMED syndrome)

AR

Sensorineural NSHL

AD

CRYM

123740

Sensorineural NSHL

AD

DIAPH1

602121

Progressive sensorineural NSHL

AD

DNMT1

126375

Cerebellar ataxia, deafness, and Narcolepsy, autosomal dominant

Neuropathy, hereditary sensory, type IE

AD

DSPP

125485

Progressive sensorineural hearing loss with dentinogenesis

AD

ESPN

606351

Sensorineural NSHL with or without vestibular involvement

AR or AD

ESRRB

602167

Sensorineural NSHL

AR

EYA4

603550

Progressive sensorineural NSHL

AD

GIPC3

608792

Stable NSHL

AR

GJB2 (connexin 26)

121011

Stable sensorineural NSHL

AR

Progressive sensorineural NSHL

Keratitis-ichthyosis-deafness (KID) syndrome

Hystrix-like ichthyosis-deafness (HID) syndrome

Vohwinkel syndrome

Bart-Pumphrey syndrome

AD

GJB3

603324

Progressive sensorineural NSHL

Erythrokeratodermia variabilis

AD

GJB6 (connexin 30)

604418

Stable sensorineural NSHL

AR

Progressive sensorineural NSHL

Hidrotic ectodermal dysplasia type 2/Clouston syndrome

KID syndrome

AD

GPSM2

609245

Chudley-McCullough syndrome

AR

GRHL2

608576

Progressive, postlingual sensorineural hearing loss

AD

GSDME

608798

Progressive sensorineural NSHL

AD

HARS2

600783

Perrault syndrome 2

AR

HSD17B4

601860

Perrault syndrome 1

D-bifunctional protein deficiency

AR

ILDR1

609739

Stable sensorineural NSHL

AR

KCNQ4

603537

Progressive sensorineural NSHL

AD

LHFPL5

609427

Stable NSHL

AR

LOXHD1

613072

Progressive sensorineural NSHL

AR

LRTOMT

612414

Sensorineural NSHL

AR

MARVELD2

610572

Stable NSHL

AR

MASP1

600521

3MC syndrome 1

AR

MYH14

608568

Progressive sensorineural NSHL

Peripheral neuropathy, myopathy, hoarseness, and hearing loss

AD

MYH9

160775

Progressive sensorineural NSHL

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

AD

MYO15A

602666

Sensorineural NSHL

AR

MYO3A

606808

Progressive NSHL

AR

MYO6

600970

Progressive sensorineural NSHL

AD

NSHL

AR

MYO7A

276903

Progressive sensorineural NSHL

AD

Sensorineural NSHL

Usher syndrome type 1

AR

OTOA

607038

Stable sensorineural NSHL

AR

OTOF

603681

Stable sensorineural NSHL

Nonsyndromic auditory neuropathy (NSAN)

AR

PCDH15

605514

Stable sensorineural NSHLS

Usher syndrome type 1

AR

PDZD7

612971

Usher syndrome, type 2

Sensorinerual NSHL

AR

PJVK

610219

Sensorineural NSHL

AR

POU3F4

300039

NSHL

XL

POU4F3

602460

Progressive sensorineural NSHL

AD

RDX

179410

Stable sensorineural NSHL

AR

SIX1

601205

NSHL

Branchiootic syndrome 3

AD

SLC26A4

605646

Stable or progressive NSHL with enlarged vestibular aqueduct

Pendred syndrome

AR

SLC26A5

604943

Stable sensorineural NSHL

AR

SMPX

300226

Progressive sensorineural hearing loss

XL

TECTA

602574

Sensorineural NSHL

AR or AD

TMC1

606706

Progressive sensorinerual NSHL

AD

Stable sensorineural NSHL

AR

TMIE

607237

Stable sensorineural NSHL

AR

TMPRSS3

605511

Sensorineural NSHL

AR

TPRN

613354

Progressive sensorineural NSHL

AR

TRIOBP

609761

Stable sensorineural NSHL

AR

USH1C

605242

Stable sensorineural NSHL; Usher syndrome type 1

AR

USH1G

607696

Usher syndrome type 1

AR

USH2A

608400

Usher syndrome type 2; Retinitis pigmentosa

AR

WFS1

606201

Progressive sensorineural NSHL, Wolfram-like syndrome

AD

Wolfram syndrome

AR

WHRN

607928

Sensorineural NSHL

Usher syndrome type 2

AR

AD, autosomal dominant; AR, autosomal recessive; XL, X-linked

References 
  1. Smith R, Jones M. Nonsyndromic Hearing Loss and Deafness, DFNB1. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, editors. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Last Update: Aug 2016; Accessed: Jul 2019]
  2. Usami S, Nishio S. Nonsyndromic Hearing Loss and Deafness, Mitochondrial. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, editors. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Last Update: Jun 2018; Accessed: Jul 2019]
  3. Shearer A, Hildebrand M, Smith R. Hereditary Hearing Loss and Deafness Overview. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, eds. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Last Update: Jul 2017; Accessed: Jul 2019]

Last Update: June 2019