1. NGS panel - Genetic testing for non-syndromic sensorineural deafness

Non-syndromic sensorineural deafness

April 25, 2017

Clinical features

Hearing loss, also known as deafness, is the inability of affected person to hear. Hearing loss can be caused by a number of different factors, including genetics, environment, birth complications, trauma, certain medications or toxins, and many others. Hereditary hearing loss (“congenital deafness”) is one of the most common birth defects and it affects 1-3 of 1000 newborns worldwide 1, 2.

Hereditary hearing loss can present as syndromic (e.g. associated with abnormalities in other body systems) and nonsyndromic or isolated deafness. Here we focus on the genetic basis and on possible genetic testing for nonsyndromic deafness.

The onset of deafness can be prelingual, e.g. before speech development, and postlingual, e.g. after the development of normal speech. Furthermore, deafness can present in different types, including the following:

  • Conductive deafness that results from abnormalities of the external and/or the middle ear
  • Sensorineural deafness that results from dysfunction of inner ear structures
  • Mixed deafness that is a combination of conductive and sensorineural deafness type
  • Central auditory dysfunction that results from a dysfunction of the eighth cranial nerve, auditory brain stem, or cerebral cortex

Of all nonsyndromic prelingual cases of deafness, 75–80% are inherited by autosomal recessive inheritance, 20–25% are autosomal dominant, 1-1,5% are X-linked, and ~1% are inherited by mitochondrial genes 2.

Hearing is measured in decibels (dB); it is considered normal if a person can hear within 15 dB of normal thresholds. Mild deafness has a hearing threshold of 26-40 dB, while severe deafness has a threshold of 71-90 dB 2.

More than 70% of hereditary deafness is nonsyndromic3 and to date researchers have identified more than 80-90 associated genes4, 5. Mutations in these genes contribute to deafness by interfering with critical steps in processing sound. Different mutations in the same gene can be associated with different types of deafness, and some genes are associated with both syndromic and nonsyndromic forms of deafness.

Nonsyndromic deafness should be suspected in individuals with the following signs or/and symptoms:

  • Congenital non-progressive sensorineural deafness or deficiency that is mild (26-40 dB) to profound (90 dB)
  • Absence of systemic findings identified by clinical/physical examination and medical history
  • Family history of nonsyndromic deafness

Furthermore, nonsyndromic deafness can affect one ear (unilateral) or both ears (bilateral); it can be stable or may be progressive, becoming more severe with age. Particular types of nonsyndromic deafness show distinctive patterns of hearing loss. For example, the loss may be more pronounced at high, middle, or low tones.

The genes associated with nonsyndromic deafness are included in two panels offered by CENTOGENE:

  1. Deafness, non-syndromic sensorineural autosomal dominant panel and
  2. Deafness, non-syndromic sensorineural autosomal recessive panel.

The genes included in panels are listed in in Tables 1 and 2. Among the genes associated with nonsyndromic deafness are those encoding structural, cytoskeletal proteins, transcription factors, transmembrane proteins and many others (Table 1, 2). Mutations in some of these genes can also cause syndromic forms of deafness, such as Usher syndrome (CDH23 and MYO7A, among others), Pendred syndrome (SLC26A4), Wolfram syndrome (WFS1), and Stickler syndrome (COL11A2). It is often unclear how mutations in the same gene can cause isolated deafness in some individuals and hearing loss with additional signs and symptoms in others.

Most cases of nonsyndromic deafness are inherited in an autosomal recessive pattern and approximately 50% of all severe-to-profound autosomal recessive nonsyndromic deafness results from mutations in the GJB2 gene 2. This form of deafness is known as DFNB1 (Table 2). The GJB2 gene encodes the protein connexin 26, which is a member of the connexin protein family that forms gap junctions within the inner ear. Mutations in the GJB2, or in other connexin-related genes, change their respective connexin proteins and may affect the function or survival of cells that are needed for hearing.

Mutations in GJB2 also cause a number of allelic disorders (Table 1), including the following:

  • DFNA3, characterized by progressive, moderate-to-severe sensorineural impairment
  • Keratitis-ichthyosis-deafness (KID) syndrome, characterized by ectodermal dysplasia with vascularizing keratitis, progressive erythrokeratoderma, and profound sensorineural hearing loss
  • Hystrix-like ichthyosis-deafness (HID) syndrome, characterized by sensorineural hearing loss and hyperkeratosis of the skin
  • Palmoplantar keratoderma with deafness, characterized by diffuse hyperkeratosis of the hands and feet
  • Vohwinkel syndrome, with circumferential hyperkeratosis of the digits and mild-to-moderate sensorineural hearing loss

Most common GJB2 pathogenic variants include:

  • c.35delG, with a carrier rate of 2-4% in individuals of northern European descent 7
  • c.235delC, the most common variant in the Japanese population (carrier rate: 1-2%) 7
  • c.167delT, the most common variant in the Ashkenazi Jewish population (carrier rate: 7.5%) 7
  • p.Val37Ile, the most common variant in Thailand (carrier rate: 11.6%)10 associated with mild hearing loss 7
  • p.Met34Thr, which has a minor allele frequency of 1-2% and is associated with mild hearing loss 7

In addition to genetic changes, deafness can result from environmental factors or a combination of genetic risk and a person's environmental exposures. Environmental causes of deafness include certain medications, specific infections before or after birth, and exposure to loud noise over an extended period. Age is also a major risk factor of hearing loss. Age-related deafness (presbyacusis) is thought to have both genetic and environmental influences.

Hereditary deafness is managed by a group of experts that includes an otolaryngologist, an audiologist, and a clinical geneticist. Hearing aids and vibrotactile devices, cochlear implants, and many other assisting aids are now available. However, early auditory intervention, through amplification, otologic surgery, or cochlear implants, is essential for optimal cognitive development in children with prelingual deafness.

CENTOGENE offers full gene sequencing and deletion/duplication analysis of the two deafness-associated panels:

  1. Deafness, non-syndromic sensorineural autosomal dominant panel that includes genes: ACTG1, CCDC50, COCH, COL11A2, CRYM, DFNA5, DIABLO, DIAPH1, DIAPH3, EYA4, GJB2, GJB3, GJB6, GRHL2, KCNQ4, MIR96, MYH14, MYH9, MYO6, MYO7A, POU3F4, POU4F3, PRPS1, SIX1, SLC17A8, SMPX, TECTA, TJP2, TMC1, WFS1 (Table 1) and
  2. Deafness, non-syndromic sensorineural autosomal recessive panel that includes genes: CDH23, CLDN14, COL11A2, DFNB31, DFNB59, ESPN, ESRRB, FOXI1, GIPC3, GJB2, GJB3, GJB6, GPSM2, GRXCR1, HGF, ILDR1, KCNJ10, LHFPL5, LOXHD1, LRTOMT, MARVELD2, MSRB3, MYO15A, MYO3A, MYO6, MYO7A, OTOA, OTOF, PCDH15, POU3F4, PRPS1, PTPRQ, RDX, SERPINB6, SLC12A1, SLC26A4, SLC26A5, SMPX, STRC, TECTA, TMC1, TMIE, TMPRSS3, TPRN, TRIOBP, USH1C (Table 2).

Table 1: Overview of the genes in CENTOGENE´s non-syndromic sensorineural autosomal dominant deafness panel

Gene OMIM
chr. locus
Protein % of mutations Allelic disorders
ACTG1 102560
17q25.3
Gamma actin 1 Rare for DFNA 6
>20% for BWCFF
DFNA20, BRWS2, BWCFF
CCDC50 611051
3q28
Coiled-coil domain containing 50 Rare DFNA44
COCH 603196
14q12
Cochlin Rare DFNA9
COL11A2 120290
6p21.32
Collagen-11A2 Rare DFNA13, DFNB53, FBCG2, STL3, WZS
CRYM 123740
16p12.2
Crystallin Mu Rare DFNA40
DFNA5 608798
7p15.3
DFNA5 gene Rare DFNA5
DIABLO 605219
12q24.31
Direct IAP-binding protein Rare DFNA64
DIAPH1 602121
5q31.3
Cytoskeletal organizator protien DIA1 Rare DFNA1, SCBMS
DIAPH3 614567
13q21.2
Cytoskeletal organizator protien DIA2 Rare AUNA1
EYA4 603550
6q23.2
Eyes absent protein 4 Rare DFNA10, CMD1J
GJB2 121011
13q12.11
Connexin 26 99% of DFNB 7, 8, 9 DFNA3A, DFNB1A, HIDS, KIDS, Keratoderma, palmoplantar, with deafness, VOWNKL and others
GJB3 603324
1p34.3
Connexin 31 Rare DFNA2B, DFNB1A, EKVP
GJB6 604418
13q12.11
Connexin 30 1% of DFNB 4
Rare for DFNA 2
DFNA3B, DFNB1B, DFNB1A, ECTD2
GRHL2 608576
8q22.3
Transcription factor grainyhead-like protein 2 Rare DFNA28, ECTDS
KCNQ4 603537
1p34.2
Potassium channel voltage gated protein 4 100% for DFNA2 1, 12 DFNA2A
MIR96 611606
7q32.2
Micro RNA 96 Rare DFNA50
MYH14 608568
19q13.33
Myosin heavy chain 14 Rare DFNA4A, PNMHH
MYH9 160775
22q12.3
Myosin heavy chain 9 Rare DFNA17, EPSTNS, FTNS, SBS, MHAMacrothrombocytopenia and progressive sensorineural deafness
MYO6 600970
6q14.1
Myosin VI Rare DFNA22, DFNB37
MYO7A 276903
11q13.5
Myosin VIIA 53%-63% for Usher syndrome I 12 DFNA11, DFNB2, USH1
POU3F4 300039
Xq21.1
Transcritpion factor Pou domain 4 All DFNX2 cases 2 DFNX2
POU4F3 602460
5q32
Transcritpion factor Pou domain 4 Rare DFNA15
PRPS1 311850
Xq22.3
Phosphoribosylpyrophosphate synthetase 1 100% for Arts syndrome and CMTX5 13, 14 DFNX1, ARTS, CMTX5, PRPS1 Superactivity
SIX1 601205
14q23.1
SIX homeobox protein 1 2% for BOS 14 DFNA23, BOS3
SLC17A8 607557
12q23.1
Vesicular glutamatte transporter 8 Rare DFNA25
SMPX 300226
Xp22.12
Small muscle protein X-linked All for DFNX4 2 DFNX4
TECTA 602574
11q23.3
Tectorin alpha Rare DFNA12, DFNB21
TJP2 607709
9q21.11
Tight junction protein 2 Rare DFNA51, PFIC4, FHCA
TMC1 606706
9q21.13
Transmembrane cochlear protein 1 Rare DFNA36, DFNB7
WFS1 606201
4p16.1
Wolframin Rare DFNA6, WFS1, WFSL, CTRCT41

Abbreviations Table 1: DFNA: Deafness, autosomal dominant; DFNB: Deafness, autosomal recessive; DFNX: Deafness, X-linked; BRWS: Baraitser-Winter syndrome; FBCG: Fibrochondrogenesis; OSMED: Otospondylomegaepiphyseal dysplasia; STL: Stickler syndrome, WZS: Weissenbacher-Zweymuller syndrome; AUNA: Auditory neuropathy, autosomal dominant; CMD: Cardiomyopathy dilated: ECTDS: Ectodermal dysplasia/short stature syndrome; HID: Hystrix-like ichthyosis with deafness; KID: Keratitis-ichthyosis-deafness syndrome; PNMHH: Peripheral neuropathy, myopathy, hoarseness, and hearing loss; EPSTNS: Epstein syndrome; VOWNKL: Vohwinkel syndrome; EKVP: Erythrokeratodermia variabilis with erythema gyratum repens; ECTD: Ectodermal dysplasia Clouston type; USH: Usher syndrome; ARTS: Arts syndrome; MHA: May-Hegglin anomaly; SBS: Sebastian syndrome; CMTX: Charcot-Marie-Tooth disease, X-linked recessive; BOS: Branchiootic syndrome: PFIC: Cholestasis, progressive familial intrahepatic; WFS1: Wolfram syndrome; CTRCT: Cataract.

Table 2: Overview of the genes in CENTOGENE´s non-syndromic sensorineural autosomal recessive deafness panel

Gene OMIM
chr. locus
Protein % of mutations Allelic disorders
CDH23 605516
10q22.1
Cadherin 23 7-20% of USH1 11 DFNB12, USH1D, USH1D/F
CLDN14 605608
21q22.13
Claudin 14 Rare DFNB29
COL11A2 120290
6p21.32
Collagen-11A2 Rare DFNA13; DFNB53; FBCG2; STL3; WZS
DFNB31/WHRN 607928
9q32
Whirlin >9.5% for USH2D 15 DFNB31, USH2D
DFNB59 610219
2q31.2
Pejvakin Rare DFNB59
ESPN 606351
1p36.31
Espin Rare DFNB36
ESRRB 602167
14q24.3
Estrogen related receptor beta Rare DFNB35
FOXI1 601093
5q35.1
Forkhead box I1 <1% for PDS or DFNB4 16, 17 DFNB4 , PDS
GIPC3 608792
19p13.3
GIPC PDZ domain containing protein Rare DFNB15
GJB2 121011
13q12.11
Connexin 26 99% of DFNB 3, 4, 5 DFNA3A, DFNB1A , HID SYNDROME, KID SYNDROME, Keratoderma, palmoplantar, with deafness, VOWNKL , KNUCKLE PADS, LEUKONYCHIA, AND SENSORINEURAL DEAFNESS
GJB3 603324
1p34.3
Connexin 31 Rare DFNA2B, DFNB1A, EKVP
GJB6 604418
13q12.11
Connexin 30 1% of DFNB 4, Rare for DFNA 1, 2 DFNA3B, DFNB1B DFNB1A ECTD2
GPSM2 609245
1p13.3
G protein signaling protein 2 Rare CMCS (DFNB82)
GRXCR1 613283
4p13
Glutaredoxin Rare DDFNB25
HGF 142409
7q21.11
Hepatocyte growth factor Rare DFNB39
ILDR1 609739
3q13.33
Immunoglobin-like receptor 1 Rare DFNB42
KCNJ10 602208
1q23.2
Potassium channel inwardly rectifying J10 <1% for PDS or DFNB4 16, 17 DFNB4, SESAMES
LHFPL5 609427
6p21.31
LHFP-like protein 5 Rare DFNB67
LOXHD1 613072
18q21.1
Lipoxygenase protein 1 Rare DFNB77
LRTOMT 612414
11q13.4
Leucin-rich transmembrane protein Rare DFNB63
MARVELD2 610572
5q13.2
Marvel protein 2 Rare DFNB49
MSRB3 613719
12q14.3
Methionine sulfoxide reductase B3 Rare DFNB74
MYO15A 602666
17p11.2
Myosin XV 5.71% in Iranian cohort 18 DFNB3
MYO3A 606808
10p12.1
Myosin IIIA Rare DFNB30
MYO6 600970
6q14.1
Myosin VI Rare DFNA22, DFNB37
MYO7A 276903
11q13.5
Myosin VIIA 53%-63% for Usher syndrome I 6 DFNA11, DFNB2, USH1
OTOA 607038
16p12.2
Otoancorin Rare DFNB22
OTOF 603681
2p23.3
Otoferlin 99% for DFNB9 19 DFNB9, AUNB1
PCDH15 605514
10q21.1
Protocadherin 15 7%-12% 5, 11 DFNB23, USH1D, USH1F
POU3F4 300039
Xq21.1
Transcritpion factor Pou domain 4 All DFNX2 cases 1 DFNX2
PRPS1 311850
Xq22.3
Phosphoribosylpyrophosphate synthetase 1 100% for Arts syndrome and CMTX5 7, 8 DFNX1 , ARTS, CMTX5 , PRPS1 SUPERACTIVITY
PTPRQ 603317
12q21.31
Protein-tyrosine phosphatase receptor Q Rare DFNB84A
RDX 179410
11q22.3
Radixin Rare DFNB24
SERPINB6 173321
6p25.2
Serpin protease inhibitor 6 Rare DFNB91
SLC12A1 600839
15q21.1
Na-K-Cl-transporter 2 Rare BARTS1
SLC26A4 605646
7q22.3
Pendrin 50% for PDS or DFNB4 16, 17, 20 DFNB4, PDS
SLC26A5 604943
7q22.1
Prestin 15.56% in Chinese population 21 DFNB61
SMPX 300226
Xp22.12
Small muscle protein All for DFNX4 3 DFNX4
STRC 606440
15q15.3
Stereocilin 100% for DIS (CATSPER2 and STRC deletion) 22 DFNB16, DIS
TECTA 602574
11q23.3
Tectorin alpha Rare DFNA12, DFNB21
TMC1 606706
9q21.13
Transmembrane cochlear protein 1 Rare DFNA36, DFNB7
TMIE 607237
3p21.31
Transmembrane inner ear expressed protein Rare DFNB6
TMPRSS3 605511
21q22.3
Transmembrane serine protease 3 <1 % of autosomal recessive nonsyndromic hearing loss (ARNSHL) in Caucasians. 23 DFNB8/DFNB10, ARNSHL
TPRN 613354
9q34.3
Taperin Rare DFNB79
TRIOBP 609761
22q13.1
Trio-actin binding protein 2/6,527 ARHI cases 24 DFNB28
USH1C 605242
11p15.1
Harmonin 1-15% for USH1C 11
All (c.216G>A) in individuals of Acadian ancestry 11
DFNB18A, USH1C

Abbreviations Table 2: DFNA: Deafness, autosomal dominant; DFNB: Deafness, autosomal recessive; DFNX: Deafness, X-linked; USH: Usher syndrome; BARTS: Bartter syndrome; PDS: Pendred syndrome (Deafness with goiter); DIS: Deafness infertility syndrome; ARNSHL: autosomal recessive nonsyndromic hearing loss; BRWS: Baraitser-Winter syndrome; FBCG: Fibrochondrogenesis;; AUNA: Auditory neuropathy, autosomal dominant; CMCS: Chudley-McCullough syndrome; CMD: Cardiomyopathy dilated: ECTDS: Ectodermal dysplasia/short stature syndrome; HID: Hystrix-like ichthyosis with deafness; KID: Keratitis-ichthyosis-deafness syndrome; PNMHH: Peripheral neuropathy, myopathy, hoarseness, and hearing loss; EPSTNS: Epstein syndrome; VOWNKL: Vohwinkel syndrome; EKVP: Erythrokeratodermia variabilis with erythema; ECTD: Ectodermal dysplasia Clouston type; ARTS: Arts syndrome; MHA: May-Hegglin anomaly; SBS: Sebastian syndrome; CMTX: Charcot-Marie-Tooth disease, X-linked recessive; BOS: Branchiootic syndrome: PFIC: Cholestasis, progressive familial intrahepatic; WFS1: Wolfram syndrome; CTRCT: Cataract.


Differential diagnosis

The differential diagnosis of deafness, non-syndromic sensorineural autosomal dominant-related disorders – depending on the major symptoms in the initial case – includes the following diseases2:

  • Landau-Kleffner syndrome Usher syndrome type I caused by mutation in MYO7A, USH1C, CDH23, PCDH15, USH1G, and CIB2
  • Usher syndrome type II caused by mutatation in USH2A, ADGRV1, DFNB31
  • Usher syndrome type III caused by mutation in CLRN1
  • Pendred syndrome caused by mutation in SLC26A4
  • Jervell and Lange-Nielsen syndrome caused by mutation in KCNQ1 or KCNE1

Testing strategy

CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free Whole Genome Sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for non-syndromic sensorineural deafness using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Deafness, non-syndromic sensorineural autosomal dominant/autosomal recessive panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Deafness, non-syndromic sensorineural autosomal dominant/autosomal recessive panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.


Referral reasons

The following individuals are candidates for non-syndromic sensorineural deafness gene testing:

  • Individuals with a family history of non-syndromic sensorineural deafness and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling non-syndromic sensorineural deafness
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected for this particular phenotype. In parallel, other genes reported to be related with non-syndromic sensorineural deafness should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes. Confirmation of a clinical diagnosis of autosomal dominant non-syndromic sensorineural deafness through genetic testing can allow for genetic counseling and may direct medical management.

Genetic counseling can provide a patient and/or family with the natural history of the non-syndromic sensorineural deafness, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.


More information on CENTOGENE´s non-syndromic sensorineural autosomal dominant deafness panel can be found in our genetic test catalogue.