Non-syndromic sensorineural deafness
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
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 genes in Non-syndromic sensorineural autosomal dominant deafness panel
| Gene | OMIM (Gene) | Associated diseases (OMIM) | Inheritance | CentoMD® exclusive variant numbers (++) |
|---|---|---|---|---|
| ACTG1 | 102560 | Deafness, autosomal dominant 20/26; Baraitser-Winter syndrome 2 | AD | 8 |
| CCDC50 | 611051 | ?Deafness, autosomal dominant 44 | AD | 0 |
| COCH | 603196 | Deafness, autosomal dominant 9 | AD | 0 |
| COL11A2 | 120290 | Otospondylomegaepiphyseal dysplasia, autosomal dominant; Otospondylomegaepiphyseal dysplasia, autosomal recessive; Deafness, autosomal dominant 13; Deafness, autosomal recessive 53; Fibrochondrogenesis 2 | AD, AR | 49 |
| CRYM | 123740 | Deafness, autosomal dominant 40 | AD | 0 |
| DFNA5 | 608798 | Deafness, autosomal dominant 5 | AD | 5 |
| DIABLO | 605219 | Deafness, autosomal dominant 64 | AD | 1 |
| DIAPH1 | 602121 | Deafness, autosomal dominant 1; Seizures, cortical blindness, microcephaly syndrome | AD, AR | 4 |
| DIAPH3 | 614567 | Auditory neuropathy, autosomal dominant, 1 | AD | 2 |
| EYA4 | 603550 | Deafness, autosomal dominant 10; ?Cardiomyopathy, dilated, 1J | AD | 10 |
| GJB2 | 121011 | Vohwinkel syndrome; Keratitis-ichthyosis-deafness syndrome; Keratoderma, palmoplantar, with deafness; Bart-Pumphrey syndrome; Deafness, autosomal recessive 1A; Deafness, autosomal dominant 3A; Hystrix-like ichthyosis with deafness | AD, AR | 3 |
| GJB3 | 603324 | Erythrokeratodermia variabilis et progressiva 1; Deafness, digenic, GJB2/GJB3; Deafness, autosomal dominant 2B | AD, AR | 1 |
| GJB6 | 604418 | Ectodermal dysplasia 2, Clouston type; Deafness, digenic GJB2/GJB6; Deafness, autosomal dominant 3B; Deafness, autosomal recessive 1B | AD, AR | 8 |
| GRHL2 | 608576 | Deafness, autosomal dominant 28; Ectodermal dysplasia/short stature syndrome | AD, AR | 2 |
| KCNQ4 | 603537 | Deafness, autosomal dominant 2A | AD | 4 |
| MIR96 | 611606 | Deafness, autosomal dominant 50 | AD | 0 |
| MYH14 | 608568 | Deafness, autosomal dominant 4A; ?Peripheral neuropathy, myopathy, hoarseness, and hearing loss | AD | 19 |
| MYH9 | 160775 | Fechtner syndrome; Epstein syndrome; May-Hegglin anomaly; Macrothrombocytopenia and progressive sensorineural deafness; Deafness, autosomal dominant 17; Sebastian syndrome | AD | 9 |
| MYO6 | 600970 | Deafness, autosomal dominant 22; Deafness, autosomal dominant 22, with hypertrophic cardiomyopathy; Deafness, autosomal recessive 37 | AD, AR | 16 |
| MYO7A | 276903 | Usher syndrome, type 1B; Deafness, autosomal recessive 2; Deafness, autosomal dominant 11 | AD, AR | 41 |
| POU3F4 | 300039 | Deafness, X-linked 2 | XL R | 1 |
| POU4F3 | 602460 | Deafness, autosomal dominant 15 | AD | 3 |
| PRPS1 | 311850 | Gout, PRPS-related; Phosphoribosylpyrophosphate synthetase superactivity; Arts syndrome; Deafness, X-linked 1; Charcot-Marie-Tooth disease, X-linked recessive, 5 | XL, XL R | 5 |
| SIX1 | 601205 | Deafness, autosomal dominant 23; Branchiootic syndrome 3 | AD | 0 |
| SLC17A8 | 607557 | Deafness, autosomal dominant 25 | AD | 3 |
| SMPX | 300226 | Deafness, X-linked 4 | XL D | 0 |
| TECTA | 602574 | Deafness, autosomal dominant 8/12; Deafness, autosomal recessive 21 | AD, AR | 24 |
| TJP2 | 607709 | Hypercholanemia, familial; Cholestasis, progressive familial intrahepatic 4 | AR | 9 |
| TMC1 | 606706 | Deafness, autosomal recessive 7; Deafness, autosomal dominant 36 | AD, AR | 24 |
| WFS1 | 606201 | ?Cataract 41; Diabetes mellitus, noninsulin-dependent, association with; Wolfram syndrome 1; Deafness, autosomal dominant 6/14/38; Wolfram-like syndrome, autosomal dominant | AD, AR | 16 |
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 genes in Non-syndromic sensorineural autosomal recessive deafness panel
| Gene | OMIM (Gene) | Associated diseases (OMIM) | Inheritance | CentoMD® exclusive variant numbers (++) |
|---|---|---|---|---|
| CDH23 | 605516 | Usher syndrome, type 1D; Usher syndrome, type 1D/F digenic; Deafness, autosomal recessive 12; Pituitary adenoma 5, multiple types | AD, AR, Digenic R | 47 |
| CLDN14 | 605608 | Deafness, autosomal recessive 29 | AR | 2 |
| COL11A2 | 120290 | Otospondylomegaepiphyseal dysplasia, autosomal dominant; Otospondylomegaepiphyseal dysplasia, autosomal recessive; Deafness, autosomal dominant 13; Deafness, autosomal recessive 53; Fibrochondrogenesis 2 | AD, AR | 49 |
| ESPN | 606351 | Deafness, autosomal recessive 36 | AR | 16 |
| ESRRB | 602167 | Deafness, autosomal recessive 35 | AR | 11 |
| FOXI1 | 601093 | Enlarged vestibular aqueduct | AR | 0 |
| GIPC3 | 608792 | Deafness, autosomal recessive 15 | AR | 8 |
| GJB2 | 121011 | Vohwinkel syndrome; Keratitis-ichthyosis-deafness syndrome; Keratoderma, palmoplantar, with deafness; Bart-Pumphrey syndrome; Deafness, autosomal recessive 1A; Deafness, autosomal dominant 3A; Hystrix-like ichthyosis with deafness | AD, AR | 3 |
| GJB3 | 603324 | Erythrokeratodermia variabilis et progressiva 1; Deafness, digenic, GJB2/GJB3; Deafness, autosomal dominant 2B | AD, AR | 1 |
| GJB6 | 604418 | Ectodermal dysplasia 2, Clouston type; Deafness, digenic GJB2/GJB6; Deafness, autosomal dominant 3B; Deafness, autosomal recessive 1B | AD, AR | 8 |
| GPSM2 | 609245 | Chudley-McCullough syndrome | AR | 10 |
| GRXCR1 | 613283 | Deafness, autosomal recessive 25 | AR | 2 |
| HGF | 142409 | Deafness, autosomal recessive 39 | AR | 13 |
| ILDR1 | 609739 | Deafness, autosomal recessive 42 | AR | 6 |
| KCNJ10 | 602208 | Enlarged vestibular aqueduct, digenic; SESAME syndrome | AR | 3 |
| LHFPL5 | 609427 | Deafness, autosomal recessive 67 | AR | 2 |
| LOXHD1 | 613072 | Deafness, autosomal recessive 77 | AR | 14 |
| LRTOMT | 612414 | Deafness, autosomal recessive 63 | AR | 7 |
| MARVELD2 | 610572 | Deafness, autosomal recessive 49 | AR | 2 |
| MSRB3 | 613719 | Deafness, autosomal recessive 74 | AR | 1 |
| MYO15A | 602666 | Deafness, autosomal recessive 3 | AR | 44 |
| MYO3A | 606808 | Deafness, autosomal recessive 30 | AR | 38 |
| MYO6 | 600970 | Deafness, autosomal dominant 22; Deafness, autosomal dominant 22, with hypertrophic cardiomyopathy; Deafness, autosomal recessive 37 | AD, AR | 16 |
| MYO7A | 276903 | Usher syndrome, type 1B; Deafness, autosomal recessive 2; Deafness, autosomal dominant 11 | AD, AR | 41 |
| OTOA | 607038 | Deafness, autosomal recessive 22 | AR | 31 |
| OTOF | 603681 | Auditory neuropathy, autosomal recessive, 1; Deafness, autosomal recessive 9 | AR | 35 |
| PCDH15 | 605514 | Usher syndrome, type 1D/F digenic; Usher syndrome, type 1F; Deafness, autosomal recessive 23 | AR, Digenic R | 39 |
| PJVK | 610219 | Deafness, autosomal recessive 59 | AR | 1 |
| POU3F4 | 300039 | Deafness, X-linked 2 | XL R | 1 |
| PRPS1 | 311850 | Gout, PRPS-related; Phosphoribosylpyrophosphate synthetase superactivity; Arts syndrome; Deafness, X-linked 1; Charcot-Marie-Tooth disease, X-linked recessive, 5 | XL, XL R | 5 |
| PTPRQ | 603317 | Deafness, autosomal recessive 84A; Deafness, autosomal dominant 73 | AD, AR | 53 |
| RDX | 179410 | Deafness, autosomal recessive 24 | AR | 8 |
| SERPINB6 | 173321 | ?Deafness, autosomal recessive 91 | AR | 12 |
| SLC12A1 | 600839 | Bartter syndrome, type 1 | AR | 33 |
| SLC26A4 | 605646 | Pendred syndrome; Deafness, autosomal recessive 4, with enlarged vestibular aqueduct | AR | 12 |
| SLC26A5 | 604943 | ?Deafness, autosomal recessive 61 | AR | 7 |
| SMPX | 300226 | Deafness, X-linked 4 | XL D | 0 |
| STRC | 606440 | Deafness, autosomal recessive 16 | AR | 32 |
| TECTA | 602574 | Deafness, autosomal dominant 8/12; Deafness, autosomal recessive 21 | AD, AR | 24 |
| TMC1 | 606706 | Deafness, autosomal recessive 7; Deafness, autosomal dominant 36 | AD, AR | 24 |
| TMIE | 607237 | Deafness, autosomal recessive 6 | AR | 3 |
| TMPRSS3 | 605511 | Deafness, autosomal recessive 8/10 | AR | 9 |
| TPRN | 613354 | Deafness, autosomal recessive 79 | AR | 4 |
| TRIOBP | 609761 | Deafness, autosomal recessive 28 | AR | 23 |
| USH1C | 605242 | Usher syndrome, type 1C; Deafness, autosomal recessive 18A | AR | 25 |
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.