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 toxins^{1, 2}.

Deafness can be classified as follows^{2, 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.

Inheritance pattern:

Autosomal dominant, autosomal recessive

Prevalence/Incidence:

1-3/1,000 newborns worldwide ^{1, 2}

Clinical symptoms:

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.

Diagnostic criteria:

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

Treatment options:

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.

Differential diagnosis:

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

Recommended strategy:

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.

Who should be tested/Referral reasons:

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).

Test utility/Why is this test good for the patient?

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 (++)

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 (++)

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.

Topic

Ear, Nose & Throat

NGS Panel, NGS Panel + CNV, NGS Panel Genomic

CPT code	81479 (x122) 81254 (x1) 81408 (x2) 81407 (x7) 81252 (x1) 81406 (x4) 81280 (x1) 81405 (x3) 81404 (x9) 81325 (x1) 81272 (x1)
Turnaround time (TAT)	< 25
Number of Genes	199

Sample Requirements

NGS Panels + CNV:
- ≥2μg DNA or
- ≥1ml EDTA Blood or
- ≥1 Filter Card (with 10 complete blood spots)

See Sample Requirements Page for detailed information.

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References

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Van Camp et al. Nonsyndromic hearing impairment: unparalleled heterogeneity. Am J Hum Genet. 1997;60:758–64.
Shearer et al. Massively Parallel Sequencing for Genetic Diagnosis of Hearing Loss: The New Standard of Care. Otolaryngol Head Neck Surg. 2015 Aug; 153(2): 175–182.
Van Camp G, Smith, RJH (2015) Hereditary hearing loss homepage. http://hereditaryhearingloss.org. Accessed 15 June 2015
Verloes et al. Baraitser-Winter Cerebrofrontofacial Syndrome. GeneReviews® Pagon RA, Adam MP, Ardinger HH, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2017.
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Lu et al. Molecular screening of patients with nonsyndromic hearing loss from Nanjing city of China. J Biomed Res. 2011 Sep;25(5):309-18.
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