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  3. NGS Panel – Genetic Testing for Non-Syndromic Sensorineural Deafness

Non-Syndromic Sensorineural Deafness

April 27, 2018

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.

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).

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ABHD12 613599 Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract AR 0
ACTB 102630 Baraitser-Winter syndrome 1; Dystonia, juvenile-onset AD 11
ACTG1 102560 Deafness, Autosomal Dominant 20; Baraitser-Winter syndrome 2 AD 7
ADCY1 103072 autosomal recessive deafness, 44 AR 1
ADGRV1 602851 Febrile seizures, familial, 4; Usher syndrome type 2C AD, AR, DiD 26
AIFM1 300169 Deafness, X-linked 5; Combined oxidative phosphorylation deficiency 6; Cowchock syndrome XLR 6
ANKH 605145 Chondrocalcinosis 2; Craniometaphyseal dysplasia AD 3
ATP2B2 108733 deafness type 12 AR 0
ATP6V1B1 192132 Renal tubular acidosis with deafness AR 9
ATP6V1B2 606939 Congenital deafness with onychodystrophy; Zimmermann-Laband syndrome type 2 AD 3
BCS1L 603647 Mitochondrial complex III deficiency, nuclear type 1; Leigh syndrome; Bjornstad syndrome; GRACILE syndrome AR, M 6
BDP1 607012 AR 0
BSND 606412 Bartter Syndrome type 4A AR 5
BTD 609019 biotinidase deficiency AR 17
CABP2 607314 deafness type 93 AR 0
CACNA1D 114206 Sinoatrial node dysfunction and deafness; Primary aldosteronism, seizures, and neurologic abnormalities AD, AR 6
CCDC50 611051 DEAFNESS, AUTOSOMAL DOMINANT 44 AD 1
CD151 602243 0
CD164 603356 AD 0
CDC14A 603504 Autosomal recessive deafness with or without immotile sperm type 32 AR 0
CDH23 605516 Usher syndrome type 1D; deafness type 12; susceptibility to pituitary adenomas AD, AR, DiR 41
CDKN1C 600856 Beckwith-Wiedemann syndrome; IMAGE syndrome AD 14
CEACAM16 614591 deafness type 4B AD, AR 2
CEP78 617110 AR 0
CHD7 608892 CHARGE syndrome; hypogonadotropic hypogonadism-5 with or without anosmia AD 103
CHSY1 608183 AR 0
CIB2 605564 deafness type 48; Usher syndrome type 1J AR 5
CISD2 611507 Wolfram syndrome 2 AR 14
CLDN14 605608 deafness type 29 AR 2
CLIC5 607293 AR 0
CLPP 601119 Perrault syndrome 3 AR 3
CLRN1 606397 Usher Syndrome type 3A; retinitis pigmentosa type 61 AR 1
COCH 603196 Deafness, autosomal dominant 9 AD, AR 1
COL11A1 120280 Marshall syndrome; Fibrochondrogenesis 1; Stickler syndrome 2 AD, AR 48
COL11A2 120290 Stickler syndrome, type III; Otospondylomegaepiphyseal dysplasia; Deafness, autosomal dominant 13; Deafness, autosomal recessive 53; Fibrochondrogenesis 2 AD, AR 38
COL2A1 120140 Epiphyseal dysplasia, multiple, with myopia and deafness; Legg-Calve-Perthes disease; Platyspondylic skeletal dysplasia, Torrance type; Kniest dysplasia; congenital spondyloepiphyseal dysplasia; SMED Strudwick type; Achondrogenesis, type II or hypochondrogenesis; Spondyloperipheral dysplasia; Osteoarthritis with mild chondrodysplasia; Avascular necrosis of the femoral head; Czech dysplasia; Stickler syndrome type 1; Stanescu type spondyloepiphyseal dysplasia AD 38
COL4A3 120070 Alport syndrome 3, AD; benign familial hematuria benign familial; Alport syndrome, AR AD, AR 74
COL4A4 120131 benign familial hematuria benign familial; Alport syndrome, AR AD, AR 41
COL4A5 303630 Alport syndrome XLD 82
COL4A6 303631 deafness type 6 XLR 2
COL9A1 120210 Stickler syndrome, type IV; Epiphyseal dysplasia, multiple, 6 AD 17
COL9A2 120260 Stickler syndrome, type V AD, AR 12
COL9A3 120270 multiple epiphyseal dysplasia type 3 AD 6
CRYM 123740 Deafness, autosomal dominant 40 AD 0
DCAF17 612515 Woodhouse-Sakati syndrome AR 6
DCDC2 605755 nephronophthisis 19; neonatal sclerosing cholangitis AR 10
DIABLO 605219 Deafness, autosomal dominant 64 AD 1
DIAPH1 602121 Deafness, autosomal dominant 1; Seizures, cortical blindness, microcephaly syndrome AD, AR 5
DIAPH3 614567 Auditory neuropathy, autosomal dominant, 1 AD 4
DLX5 600028 Split-hand/foot malformation 1 with sensorineural hearing loss, autosomal recessive AD, AR 0
DMXL2 612186 Polyendocrine-polyneuropathy syndrome; ?Deafness, autosomal dominant 71 AD, AR 3
DNMT1 126375 cerebellar ataxia, deafness and narcolepsy; Neuropathy, hereditary sensory, type IE AD 40
DSPP 125485 Dentin dysplasia type II; Dentinogenesis imperfecta, Shields type II; Dentinogenesis imperfecta, Shields type III AD 5
EDN3 131242 congenital central hypoventilation syndrome; Waardenburg syndrome type 4B; Hirschsprung disease 4 AD, AR 8
EDNRB 131244 Waardenburg syndrome type 4A; Hirschsprung disease, susceptibility to, 2; ABCD syndrome AD, AR 6
ELMOD3 615427 AR 0
EPS8 600206 AR 0
EPS8L2 614988 AR 0
ESPN 606351 deafness type 36 AR 10
ESRP1 612959 AR 0
ESRRB 602167 deafness type 35 AR 10
EYA1 601653 Branchiootorenal Syndrome 1; Otofaciocervical Syndrome 1; Branchiootic syndrome 1 AD 2
EYA4 603550 Deafness, autosomal dominant 10; dilated cardiomyopathy-1J AD 10
FDXR 103270 auditory neuropathy and optic atrophy AR 1
FGF3 164950 Deafness, congenital with inner ear agenesis, microtia, and microdontia AR 1
FGFR1 136350 Craniofacial-skeletal-dermatologic dysplasia; Jackson-Weiss syndrome; hypogonadotropic hypogonadism-2 with or without anosmia; Osteoglophonic dysplasia; Hartsfield syndrome AD 24
FGFR2 176943 Apert syndrome; Saethre-Chotzen Syndrome; Craniofacial-skeletal-dermatologic dysplasia; Jackson-Weiss syndrome; Crouzon syndrome; Beare-Stevenson cutis gyrata syndrome; Lacrimoauriculodentodigital Syndrome; Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis; Scaphocephaly, maxillary retrusion, and mental retardation; Gastric Cancer; Bent bone dysplasia syndrome AD 11
FGFR3 134934 Achondroplasia; Bladder Cancer; colorectal cancer; Hypochondroplasia; Lacrimoauriculodentodigital Syndrome; Nevus, Epidermal; Thanatophoric dysplasia, type I; Thanatophoric dysplasia, type II; Spermatocytic seminoma, somatic; Muenke syndrome; Cervical cancer, somatic; CATSHL syndrome; Crouzon syndrome with acanthosis nigricans AD, AR 19
FOXI1 601093 autosomal recessive deafness type 4 with enlarged vestibular aqueduct AR 0
GAB1 604439 AR 0
GATA3 131320 Hypoparathyroidism, sensorineural deafness, and renal dysplasia AD 1
GIPC3 608792 deafness type 15 AR 8
GJA1 121014 Oculodentodigital dysplasia AD, AR 3
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, DiD 3
GJB3 603324 erythrokeratoderma variabilis progressive type 1; nonsyndromic hearing loss; Deafness, autosomal dominant 2B AD, AR, DiD 2
GJB6 604418 Clouston Syndrome; nonsyndromic hearing loss; autosomal dominant deafness type 3B; deafness type 1B AD, AR, DiD 8
GPRASP2 300969 XLR 0
GPSM2 609245 Chudley-McCullough syndrome AR 8
GRHL2 608576 Deafness, autosomal dominant 28; Ectodermal dysplasia/short stature syndrome AD, AR 2
GRXCR1 613283 Deafness, autosomal recessive 25 AR 2
GRXCR2 615762 AR 0
GSDME 608798 Deafness, autosomal dominant 5 AD 6
HARS1 142810 axonal Charcot-Marie-tooth disease type 2W AD, AR 3
HARS2 600783 AR 0
HGF 142409 deafness type 39 AR 12
HOMER2 604799 AD 0
HOXB1 142968 Facial paresis, hereditary congenital, 3 AR 5
HSD17B4 601860 Perrault syndrome type 1; D-bifunctional protein deficiency AR 27
ILDR1 609739 deafness type 42 AR 5
KARS1 601421 CHARCOT-MARIE-TOOTH, RECESSIVE INTERMEDIATE TYPE B; Deafness, autosomal recessive 89 AR 1
KCNE1 176261 Jervell and Lange-Nielsen syndrome 2; long QT syndrome 5 AD, AR 6
KCNJ10 602208 autosomal recessive deafness type 4 with enlarged vestibular aqueduct; Seizures, Sensorineural Deafness, Ataxia, Mental Retardation, And Electrolyte Imbalance AR 7
KCNQ1 607542 long QT syndrome-1; Jervell and Lange-Nielsen syndrome; Atrial fibrillation, familial, 3; Short QT syndrome-2 AD, AR 21
KCNQ4 603537 Deafness, autosomal dominant 2A AD 3
KIT 164920 Mast cell disease; Piebaldism; Spermatocytic seminoma, somatic; acute myeloid leukemia; gastrointestinal stromal tumor AD 14
KITLG 184745 AD 0
LARS2 604544 Perrault syndrome 4; Hydrops, lactic acidosis, and sideroblastic anemia AR 1
LHFPL5 609427 deafness type 67 AR 2
LOXHD1 613072 deafness type type 77 AR 15
LRP2 600073 Donnai-Barrow syndrome AR 10
LRTOMT 612414 deafness type 63 AR 6
MAN2B1 609458 alpha-mannosidosis AR 31
MANBA 609489 Mannosidosis, Beta A, Lysosomal AR 18
MARVELD2 610572 deafness type 49 AR 2
MCM2 116945 AD 0
MET 164860 Hepatocellular Carcinoma; Renal cell carcinoma, papillary; deafness type 97 AD, AR 3
MGP 154870 Keutel syndrome AR 0
MITF 156845 Albinism, Ocular, With Sensorineural Deafness; Tietz Syndrome; Waardenburg syndrome type 2A; Melanoma, Cutaneous Malignant, Susceptibility To, 8 AD, AR 11
MPZL2 604873 AR 0
MSRB3 613719 Deafness, autosomal recessive 74 AR 1
MYH14 608568 deafness type 4A; Peripheral neuropathy, myopathy, hoarseness, and hearing loss AD 24
MYH9 160775 Fechtner syndrome; Macrothrombocytopenia and progressive sensorineural deafness; May-Hegglin anomaly; Sebastian syndrome; deafness type 17 AD 8
MYO15A 602666 deafness type 3 AR 41
MYO3A 606808 deafness type 30 AR 41
MYO6 600970 deafness type 37 AD, AR 15
MYO7A 276903 Usher syndrome type 1B; deafness type 2; autosomal dominant deafness type 11 AD, AR 31
NARS2 612803 Combined oxidative phosphorylation deficiency 24 AR 4
NDP 300658 Exudative Vitreoretinopathy 2, X-Linked; Norrie disease XLD, XLR 8
NLRP3 606416 Familial Cold Autoinflammatory Syndrome 1; Muckle-Wells syndrome; CINCA syndrome AD 8
OPA1 605290 Optic atrophy plus syndrome; optic atrophy type 1; Behr syndrome; Glaucoma, normal tension, susceptibility to; Mitochondrial DNA depletion syndrome 14 AD, AR 46
OSBPL2 606731 AD 0
OTOA 607038 deafness type 22 AR 34
OTOF 603681 deafness type 9 AR 38
OTOG 604487 AR 0
OTOGL 614925 deafness type 84B AR 5
P2RX2 600844 autosomal dominant deafness type 41 AD 1
PAX3 606597 Waardenburg syndrome, type 3; Waardenburg syndrome type 1 AD, AR 13
PCDH15 605514 Usher syndrome type 1D; Usher syndrome type 1F; deafness type 23 AR, DiR 30
PDZD7 612971 Usher syndrome type 2A; Usher syndrome type 2C; Deafness, autosomal recessive 57 AR, DiD 6
PEX1 602136 Peroxisome biogenesis disorder type 1A (Zellweger); Heimler syndrome type 1; peroxisome biogenesis disorder type 1B AR 42
PEX26 608666 peroxisome biogenesis disorder type 7A (Zellweger); peroxisome biogenesis disorder 7B AR 5
PEX6 601498 peroxisome biogenesis disorder type 4A (Zellweger); peroxisome biogenesis disorder type 4B; Heimler syndrome type 2 AD, AR 35
PJVK 610219 Deafness, autosomal recessive 59 AR 2
PMP22 601097 type 1A Charcot-Marie-Tooth disease; Dejerine-Sottas syndrom; Neuropathy, recurrent, with pressure palsies ?AD, AD, AR 12
PNPT1 610316 Combined oxidative phosphorylation deficiency 13; Deafness, autosomal recessive 70 AR 5
POLR1C 610060 Treacher collins syndrome 3; hypomyelinating leukodystrophy-11 AR 1
POLR1D 613715 Treacher collins syndrome 2 AD, AR 4
POU3F4 300039 Deafness, X-linked 2 XLR 2
POU4F3 602460 Deafness, autosomal dominant 15 AD 4
PRPS1 311850 Phosphoribosylpyrophosphate synthetase superactivity; Arts syndrome; deafness type 1; type X5 Charcot-Marie-Tooth XL, XLR 6
RDX 179410 Deafness, autosomal recessive 24 AR 7
RMND1 614917 Combined oxidative phosphorylation deficiency 11 AR 2
ROR1 602336 AR 0
RPS6KA3 300075 MENTAL RETARDATION, X-LINKED 19; Coffin-Lowry syndrome XLD 17
S1PR2 605111 Deafness, autosomal recessive type 68 AR 1
SALL1 602218 Townes-Brocks syndrome AD 30
SALL4 607343 Okihiro syndrome AD 15
SEMA3E 608166 CHARGE syndrome AD 0
SERPINB6 173321 Deafness, autosomal recessive 91 AR 13
SIX1 601205 Deafness, autosomal dominant 23; Brachiootic syndrome 3 AD 1
SIX5 600963 Branchiootorenal syndrome 2 1
SLC12A1 600839 Bartter syndrome type 1 AR 37
SLC17A8 607557 Deafness, autosomal dominant 25 AD 4
SLC19A2 603941 Thiamine-responsive megaloblastic anemia syndrome AR 1
SLC26A4 605646 Pendred syndrome; autosomal recessive deafness type 4 with enlarged vestibular aqueduct AR 15
SLC26A5 604943 Deafness, autosomal recessive 61 AR 8
SLC29A3 612373 Histiocytosis-lymphadenopathy plus syndrome AR 0
SLC33A1 603690 spastic paraplegia 42; Congenital cataracts, hearing loss, and neurodegeneration AD, AR 7
SLC44A4 606107 AD 0
SLC52A2 607882 Brown-Vialetto-Van Laere syndrome 2 AR 2
SLC52A3 613350 Fazio-Londe disease; Brown-Vialetto-Van Laere syndrome 1 AR 5
SLITRK6 609681 Deafness and myopia AR 0
SMAD4 600993 Myhre syndrome; Juvenile polyposis syndrome, infantile form; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Pancreatic Cancer AD 3
SMPX 300226 Deafness, X-linked 4 XLD 0
SNAI2 602150 Piebaldism; Waardenburg syndrome type 2d AD, AR 0
SOX10 602229 PCWH syndrome; Waardenburg syndrome type 2E; Waardenburg syndrome, type 4C AD 20
SOX2 184429 Microphthalmia, Syndromic 3 AD 8
SPATA5 613940 Epilepsy, hearing loss, and mental retardation syndrome AR 3
STRC 606440 deafness type 16 AR 32
SUCLA2 603921 mitochondrial DNA depletion syndrome 5 AR 15
SUCLG1 611224 mitochondrial DNA depletion syndrome 9 AR 8
SYNE4 615535 deafness, autosomal recessive 76 AR 1
TBC1D24 613577 DOOR syndrome; Myoclonic epilepsy, infantile, familial; Rolandic epilepsy with proxysmal exercise-induced dystonia and writer's cramp; deafness type 86; Epileptic encephalopathy, early infantile, 16; deafness type 65 AD, AR 7
TBX1 602054 Tetralogy of Fallot; DiGeorge syndrome; Velocardiofacial syndrome; Conotruncal Heart Malformations AD 11
TCOF1 606847 Treacher Collins syndrome type 1 AD 11
TECTA 602574 Deafness, autosomal dominant 8/12; deafness type 21 AD, AR 21
TFAP2A 107580 Branchiooculofacial syndrome AD 5
TIMM8A 300356 Mohr-Tranebjaerg syndrome XLR 3
TJP2 607709 Hypercholanemia, familial; Cholestasis, progressive familial intrahepatic 4 AR 14
TMC1 606706 deafness type 7 AD, AR 23
TMIE 607237 Deafness, autosomal recessive 6 AR 4
TMPRSS3 605511 deafness type 8 AR 9
TNC 187380 Deafness, autosomal dominant 56 AD 5
TPRN 613354 deafness type 79 AR 4
TRIOBP 609761 deafness type 28 AR 27
TRMU 610230 Deafness, Aminoglycoside-Induced; Liver Failure, Infantile, Transient AR, M 8
TSPEAR 612920 Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis AR 2
TWNK 606075 Mitochondrial DNA depletion syndrome 7 (hepatocerebral type); Progressive external ophthalmoplegia, autosomal dominant, 3 AD, AR 4
TYR 606933 Albinism, Ocular, With Sensorineural Deafness; oculocutaneous albinism type 1A; Skin/hair/eye pigmentation 3; Albinism, oculocutaneous, type IB AD, AR 21
USH1C 605242 Usher syndrome type IC; deafness type 18A AR 15
USH1G 607696 Usher syndrome type 1G AR 0
USH2A 608400 Usher syndrome type 2A; retinitis pigmentosa type 39 AR 48
VCAN 118661 Wagner syndrome 1 AD 9
WBP2 606962 AR 0
WFS1 606201 congenital nuclear cataract type 41; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Wolfram syndrome; Deafness, autosomal dominant 6/14/38; Wolfram-like syndrome AD, AR 22
WHRN 607928 deafness type 31; Usher syndrome type 2D AR 5