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

Non-syndromic sensorineural deafness

April 27, 2018

Disease summary:

Deafness, as inability of an affected person to hear is one of the most common birth defects and it can be caused by a number of different factors, including genetics, environment, birth complications, trauma, certain medications and/or toxins1, 2.

Deafness can be classified as follows2, 3:

  • 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 dysfunction of the eighth cranial nerve, auditory brain stem, or cerebral cortex

Hereditary hearing loss can present as syndromic (e.g. associated with abnormalities in other body systems) or non-syndromic (isolated) deafness. It can be inherited in an autosomal dominant or recessive pattern.


Infographics deafness

Autosomal dominant, autosomal recessive

1-3/1,000 newborns worldwide 1, 2

Non-syndromic deafness should be suspected in individuals with the following signs or/and symptoms 2, 3:

  • 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 non-syndromic sensorineural deafness.
  • The diagnosis of non-syndromic sensorineural autosomal dominant deafness relies on clinical findings and family history.
  • Diagnosis is confirmed by the identification of pathogenic variant(s) in one of the following genes:
  • Autosomal dominant: 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
  • Autosomal recessive: 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

There is no cure for non-syndromic sensorineural deafness to date, but treatment options are available 2.

  • Hearing aids
  • Vibrotactile devices
  • Cochlear implants and many other assisting aids.
  • Otologic surgery.
  • Landau-Kleffner syndrome Usher syndrome type I caused by pathogenic variant in MYO7A, USH1C, CDH23, PCDH15, USH1G, and CIB2
  • Usher syndrome type II caused by pathogenic variant in USH2A, ADGRV1, DFNB31
  • Usher syndrome type III caused by pathogenic variant in CLRN1
  • Pendred syndrome caused by pathogenic variant in SLC26A4
  • Jervell and Lange-Nielsen syndrome caused by pathogenic variant in KCNQ1 or KCNE1

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for non-syndromic sensorineural autosomal dominant/ autosomal recessive deafness using NGS Panel Genomic:

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

Step 2: If no pathogenic variant is identified in Step1, continue with bioinformatics analysis covering genes that are either implicated or associated with overlapping phenotype or similar pathways.  

  • Individuals with a positive family history of non-syndromic sensorineural deafness.
  • Individuals with most common symptoms of non-syndromic sensorineural deafness (regardless of family history).

Confirmation of a clinical diagnosis through genetic testing of non-syndromic sensorineural deafness can allow for genetic counseling and may direct medical management and treatment options.


Genes associated with non-syndromic sensorineural deafness encode structural proteins, cytoskeletal proteins, transcription factors and transmembrane proteins amongst others (Table 1).

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.


Disease synonyms

Isolated deafness, Isolated hearing loss, Nonsyndromic autosomal dominant deafness, Nonsyndromic autosomal recessive deafness, Nonsyndromic hearing impairment, Nonsyndromic hearing loss and deafness, Nonsyndromic hearing loss