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; Baraitser-Winter syndrome 2 | AD | 7 |
| CCDC50 | 611051 | DEAFNESS, AUTOSOMAL DOMINANT 44 | AD | 1 |
| COCH | 603196 | Deafness, autosomal dominant 9 | AD, AR | 0 |
| COL11A2 | 120290 | Stickler syndrome, type III; Otospondylomegaepiphyseal dysplasia; Deafness, autosomal dominant 13; Deafness, autosomal recessive 53; Fibrochondrogenesis 2 | AD, AR | 51 |
| 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 | 3 |
| EYA4 | 603550 | Deafness, autosomal dominant 10; dilated cardiomyopathy-1J | AD | 10 |
| GJB2 | 121011 | Vohwinkel syndrome; keratitis-ichthyosis-deafness syndrome; palmoplantar keratoderma with deafness; Bart-Pumphrey syndrome; nonsyndromic hearing loss; autosomal dominant deafness type 3A; Hystrix-like ichthyosis with deafness | AD, AR | 3 |
| GJB3 | 603324 | erythrokeratoderma variabilis progressive; nonsyndromic hearing loss | AD, AR | 2 |
| GJB6 | 604418 | Clouston Syndrome; nonsyndromic hearing loss; autosomal dominant deafness type 3B; deafness type 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 type 4A; Peripheral neuropathy, myopathy, hoarseness, and hearing loss | AD | 19 |
| MYH9 | 160775 | May-Hegglin anomaly; deafness type 17 | AD | 9 |
| MYO6 | 600970 | deafness type 37 | AD, AR | 16 |
| MYO7A | 276903 | Usher syndrome type 1B; deafness type 2; autosomal dominant deafness type 11 | AD, AR | 41 |
| POU3F4 | 300039 | Deafness, X-linked 2 | XLR | 1 |
| POU4F3 | 602460 | Deafness, autosomal dominant 15 | AD | 3 |
| PRPS1 | 311850 | Phosphoribosylpyrophosphate synthetase superactivity; Arts syndrome; deafness type 1; type X5 Charcot-Marie-Tooth | XL, XLR | 5 |
| SIX1 | 601205 | Deafness, autosomal dominant 23; Brachiootic syndrome 3 | AD | 0 |
| SLC17A8 | 607557 | Deafness, autosomal dominant 25 | AD | 3 |
| SMPX | 300226 | Deafness, X-linked 4 | XLD | 0 |
| TECTA | 602574 | Deafness, autosomal dominant 8/12; deafness type 21 | AD, AR | 24 |
| TJP2 | 607709 | Hypercholanemia, familial; Cholestasis, progressive familial intrahepatic 4 | AR | 9 |
| TMC1 | 606706 | deafness type 7 | AD, AR | 24 |
| WFS1 | 606201 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Wolfram syndrome; Deafness, autosomal dominant 6/14/38; Wolfram-like syndrome | AD, AR | 17 |
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; deafness type 12; susceptibility to pituitary adenomas | AD, AR, DiR | 47 |
| CLDN14 | 605608 | deafness type 29 | AR | 2 |
| COL11A2 | 120290 | Stickler syndrome, type III; Otospondylomegaepiphyseal dysplasia; Deafness, autosomal dominant 13; Deafness, autosomal recessive 53; Fibrochondrogenesis 2 | AD, AR | 51 |
| ESPN | 606351 | deafness type 36 | AR | 16 |
| ESRRB | 602167 | deafness type 35 | AR | 11 |
| FOXI1 | 601093 | autosomal recessive deafness type 4 with enlarged vestibular aqueduct | AR | 0 |
| GIPC3 | 608792 | deafness type 15 | AR | 8 |
| GJB2 | 121011 | Vohwinkel syndrome; keratitis-ichthyosis-deafness syndrome; palmoplantar keratoderma with deafness; Bart-Pumphrey syndrome; nonsyndromic hearing loss; autosomal dominant deafness type 3A; Hystrix-like ichthyosis with deafness | AD, AR | 3 |
| GJB3 | 603324 | erythrokeratoderma variabilis progressive; nonsyndromic hearing loss | AD, AR | 2 |
| GJB6 | 604418 | Clouston Syndrome; nonsyndromic hearing loss; autosomal dominant deafness type 3B; deafness type 1B | AD, AR | 8 |
| GPSM2 | 609245 | Chudley-McCullough syndrome | AR | 10 |
| GRXCR1 | 613283 | Deafness, autosomal recessive 25 | AR | 2 |
| HGF | 142409 | deafness type 39 | AR | 13 |
| ILDR1 | 609739 | deafness type 42 | AR | 5 |
| KCNJ10 | 602208 | autosomal recessive deafness type 4 with enlarged vestibular aqueduct; Seizures, Sensorineural Deafness, Ataxia, Mental Retardation, And Electrolyte Imbalance | AR | 3 |
| LHFPL5 | 609427 | deafness type 67 | AR | 2 |
| LOXHD1 | 613072 | deafness type type 77 | AR | 16 |
| LRTOMT | 612414 | deafness type 63 | AR | 7 |
| MARVELD2 | 610572 | deafness type 49 | AR | 2 |
| MSRB3 | 613719 | Deafness, autosomal recessive 74 | AR | 1 |
| MYO15A | 602666 | deafness type 3 | AR | 44 |
| MYO3A | 606808 | deafness type 30 | AR | 41 |
| MYO6 | 600970 | deafness type 37 | AD, AR | 16 |
| MYO7A | 276903 | Usher syndrome type 1B; deafness type 2; autosomal dominant deafness type 11 | AD, AR | 41 |
| OTOA | 607038 | deafness type 22 | AR | 33 |
| OTOF | 603681 | deafness type 9 | AR | 36 |
| PCDH15 | 605514 | Usher syndrome type 1D; Usher syndrome type 1F; deafness type 23 | AR, DiR | 39 |
| PJVK | 610219 | Deafness, autosomal recessive 59 | AR | 1 |
| POU3F4 | 300039 | Deafness, X-linked 2 | XLR | 1 |
| PRPS1 | 311850 | Phosphoribosylpyrophosphate synthetase superactivity; Arts syndrome; deafness type 1; type X5 Charcot-Marie-Tooth | XL, XLR | 5 |
| PTPRQ | 603317 | deafness type 84A | AD, AR | 54 |
| 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; autosomal recessive deafness type 4 with enlarged vestibular aqueduct | AR | 12 |
| SLC26A5 | 604943 | Deafness, autosomal recessive 61 | AR | 8 |
| SMPX | 300226 | Deafness, X-linked 4 | XLD | 0 |
| STRC | 606440 | deafness type 16 | AR | 33 |
| TECTA | 602574 | Deafness, autosomal dominant 8/12; deafness type 21 | AD, AR | 24 |
| TMC1 | 606706 | deafness type 7 | AD, AR | 24 |
| TMIE | 607237 | Deafness, autosomal recessive 6 | AR | 3 |
| TMPRSS3 | 605511 | deafness type 8 | AR | 9 |
| TPRN | 613354 | deafness type 79 | AR | 4 |
| TRIOBP | 609761 | deafness type 28 | AR | 23 |
| USH1C | 605242 | Usher syndrome type IC; deafness type 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.