Non-syndromic sensorineural deafness
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.
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