Nonsyndromic deafness

Nonsyndromic deafness is hearing loss that is not associated with other signs and symptoms. In contrast, syndromic deafness involves hearing loss that occurs with abnormalities in other parts of the body.Genetic changes are related to the following types of nonsyndromic deafness.

DFNA: nonsyndromic deafness, autosomal dominant
DFNB: nonsyndromic deafness, autosomal recessive
DFNX: nonsyndromic deafness, X-linked
nonsyndromic deafness, mitochondrial

Each type is numbered in the order in which it was described. For example, DFNA1 was the first described autosomal dominant type of nonsyndromic deafness. Mitochondrial nonsyndromic deafness involves changes to the small amount of DNA found in mitochondria, the energy-producing centers within cells.

Most forms of nonsyndromic deafness are associated with permanent hearing loss caused by damage to structures in the inner ear. The inner ear consists of three parts: a snail-shaped structure called the cochlea that helps process sound, nerves that send information from the cochlea to the brain, and structures involved with balance. Loss of hearing caused by changes in the inner ear is called sensorineural deafness. Hearing loss that results from changes in the middle ear is called conductive hearing loss. The middle ear contains three tiny bones that help transfer sound from the eardrum to the inner ear. Some forms of nonsyndromic deafness involve changes in both the inner ear and the middle ear; this combination is called mixed hearing loss.

The severity of hearing loss varies and can change over time. It can affect one ear (unilateral) or both ears (bilateral). Degrees of hearing loss range from mild (difficulty understanding soft speech) to profound (inability to hear even very loud noises). The loss may be stable, or it may progress as a person gets older. Particular types of nonsyndromic deafness often show distinctive patterns of hearing loss. For example, the loss may be more pronounced at high, middle, or low tones.

Nonsyndromic deafness can occur at any age. Hearing loss that is present before a child learns to speak is classified as prelingual or congenital. Hearing loss that occurs after the development of speech is classified as postlingual.

Genes related to nonsyndromic deafness

Mutations in the ACTG1, CDH23, CLDN14, COCH, COL11A2, DFNA5, ESPN, EYA4, GJB2, GJB6, KCNQ4, MYO15A, MYO6, MYO7A, OTOF, PCDH15, POU3F4, SLC26A4, STRC, TECTA, TMC1, TMIE, TMPRSS3, USH1C, and WFS1 genes cause nonsyndromic deafness, with weaker evidence currently implicating genes CCDC50, DIAPH1, DSPP, ESRRB, GJB3, GRHL2, GRXCR1, HGF, LHFPL5, LOXHD1, LRTOMT, MARVELD2, MIR96, MYH14, MYH9, MYO1A, MYO3A, OTOA, PJVK, POU4F3, PRPS1, PTPRQ, RDX, SERPINB6, SIX1, SLC17A8, TPRN, TRIOBP, and WHRN.

The causes of nonsyndromic deafness can be complex. Researchers have identified more than 30 genes that, when mutated, may cause nonsyndromic deafness; however, some of these genes have not been fully characterized. Many genes related to deafness are involved in the development and function of the inner ear. Gene mutations interfere with critical steps in processing sound, resulting in hearing loss. Different mutations in the same gene can cause different types of hearing loss, and some genes are associated with both syndromic and nonsyndromic deafness. In many families, the gene(s) involved have yet to be identified.

Deafness can also result from environmental factors or a combination of genetic and environmental factors, including certain medications, peri-natal infections (infections occurring before or after birth), and exposure to loud noise over an extended period.

Types include:

OMIM	Gene	Type
124900	DIAPH1	DFNA1
600101	KCNQ4	DFNA2A
612644	GJB3	DFNA2B
601544	GJB2	DFNA3A
612643	GJB6	DFNA3B
600652	MYH14	DFNA4
600994	DFNA5	DFNA5
601543	TECTA	DFNA8/12
601369	COCH	DFNA9
601316	EYA4	DFNA10
601317	MYO7A	DFNA11, neurosensory
601868	COL11A2	DFNA13
602459	POU4F3	DFNA15
603622	MYH9	DFNA17
604717	ACTG1	DFNA20/26
606346	MYO6	DFNA22
605192	SIX1	DFNA23
605583	SLC17A8	DFNA25
608641	GRHL2	DFNA28
606705	TMC1	DFNA36
605594	DSPP	DFNA36, with dentinogenesis
607453	CCDC50	DFNA44
607841	MYO1A	DFNA48
613074	MIR96	DFNA50
220290	GJB2	DFNB1A
612645	GJB6	DFNB1B
600060	MYO7A	DFNB2, neurosensory (see also Usher syndrome)
600316	MYO15A	DFNB3
600971	TMIE	DFNB6
600974	TMC1	DFNB7
601072	TMPRSS3	DFNB8, childhood onset
601071	OTOF	DFNB9
605316	TMPRSS3	DFNB10, congenital
601386	CDH23	DFNB12
603720	STRC	DFNB16
602092	USH1C	DFNB18
603629	TECTA	DFNB21
607039	OTOA	DFNB22
609533	PCDH15	DFNB23
611022	RDX	DFNB24
613285	GRXCR1	DFNB25
609823	TRIOBP	DFNB28
607101	MYO3A	DFNB30
607084	WHRN	DFNB31
608565	ESRRB	DFNB35
609006	ESPN	DFNB36
607821	MYO6	DFNB37
608265	HGF	DFNB39
610153	MARVELD2	DFNB49
609706	COL11A2	DFNB53
610220	PJVK	DFNB59
611451	LRTOMT	DFNB63
610265	LHFPL5	DFNB67
613079	LOXHD1	DFNB77
613307	TPRN	DFNB79
613391	PTPRQ	DFNB84
613453	SERPINB6	DFNB91
304500	PRPS1	DFNX1
304400	POU3F4	DFNX2

Genetics

Nonsyndromic deafness can have different patterns of inheritance. Between 75% and 80% of cases are inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Usually, each parent of an individual with autosomal recessive deafness is a carrier of one copy of the altered gene. These carriers do not have hearing loss.

Another 20% to 25% of nonsyndromic deafness cases are autosomal dominant, which means one copy of the altered gene in each cell is sufficient to result in hearing loss. People with autosomal dominant deafness most often inherit an altered copy of the gene from a parent who has hearing loss.

Between 1% and 2% of cases show an X-linked pattern of inheritance, which means the mutated gene responsible for the condition is located on the X chromosome. Males with X-linked nonsyndromic deafness tend to develop more severe hearing loss earlier in life than females who inherit a copy of the same gene mutation. Fathers will not pass X-linked traits to their sons since they do not pass on the X chromosome to their male offspring.

Mitochondrial nonsyndromic deafness, which results from changes to the DNA in mitochondria, occurs in fewer than 1% of cases in the United States. The altered mitochondrial DNA is passed from a mother to her sons and daughters. This type of deafness is not inherited from fathers.

Late onset progressive deafness is the most common neurological disability of the elderly. Although hearing loss of greater than 25 decibels is present in only 1% of young adults between the ages of 18–24 years of age, this increases to 10% in persons between 55–64 years of age and approximately 50% in octogenarians.

The relative contribution of heredity to age-related hearing impairment is not known, however the majority of inherited late-onset deafness is autosomal dominant and non-syndromic (Van Camp et al., 1997). Over forty genes associated with autosomal dominant non-syndromic hearing loss have been localized and of these fifteen have been cloned.

Epidemiology

About 1 in 1,000 children in the United States is born with profound deafness. By age 9, about 3 in 1,000 children have hearing loss that affects the activities of daily living. More than half of these cases are caused by genetic factors. Most cases of genetic deafness (70% to 80%) are nonsyndromic; the remaining cases are caused by specific genetic syndromes. In adults, the chance of developing hearing loss increases with age; hearing loss affects half of all people older than 80 years.

External links

Pandya, Arti (21 April 2011). Nonsyndromic Hearing Loss and Deafness, Mitochondrial. PMID 20301595. NBK1422. In Pagon RA, Bird TD, Dolan CR, et al., eds. (1993–). GeneReviews™ [Internet]. Seattle WA: University of Washington, Seattle. Check date values in: |date= (help)
Smith, Richard JH; Sheffield, Abraham M; Camp, Guy Van (19 April 2012). Nonsyndromic Hearing Loss and Deafness, DFNA3. PMID 20301708. NBK1536. In GeneReviews
Smith, Richard JH; Camp, Guy Van (2 January 2014). Nonsyndromic Hearing Loss and Deafness, DFNB1. PMID 20301449. NBK1272. In GeneReviews
Huijun Yuan; Xue Z Liu (4 August 2011). DFNX1 Nonsyndromic Hearing Loss and Deafness. PMID 21834172. NBK57098. In GeneReviews
Smith, Richard JH; Gurrola, II, Jose G; Kelley, Philip M (14 June 2011). OTOF-Related Deafness. PMID 20301429. NBK1251. In GeneReviews

Diseases of the ear and mastoid process (H60–H99, 380–389)

Outer ear

Middle ear
and mastoid

Inner ear and
central pathways

Equilibrioception

Hearing

Hearing impairment	Conductive hearing loss Otosclerosis Superior canal dehiscence Sensorineural hearing loss Presbycusis Cortical deafness Nonsyndromic deafness

Excessive response	Tinnitus Hyperacusis/Phonophobia

Deafblindness	Wolfram syndrome Usher syndrome

Other	Auditory processing disorder Spatial hearing loss

Cytoskeletal defects

Microfilaments

Myofilament

Actin	Hypertrophic cardiomyopathy 11 Dilated cardiomyopathy 1AA DFNA20 Nemaline myopathy 3

Myosin	Elejalde syndrome Hypertrophic cardiomyopathy 1, 8, 10 Usher syndrome 1B Freeman–Sheldon syndrome DFN A3, 4, 11, 17, 22; B2, 30, 37, 48 May-Hegglin anomaly

Troponin	Hypertrophic cardiomyopathy 7, 2 Nemaline myopathy 4, 5

Tropomyosin	Hypertrophic cardiomyopathy 3 Nemaline myopathy 1

Titin	Hypertrophic cardiomyopathy 9

Other

1/2	Keratinopathy (keratosis, keratoderma, hyperkeratosis): KRT1 Striate palmoplantar keratoderma 3 Epidermolytic hyperkeratosis IHCM KRT2E (Ichthyosis bullosa of Siemens) KRT3 (Meesmann juvenile epithelial corneal dystrophy) KRT4 (White sponge nevus) KRT5 (Epidermolysis bullosa simplex) KRT8 (Familial cirrhosis) KRT10 (Epidermolytic hyperkeratosis) KRT12 (Meesmann juvenile epithelial corneal dystrophy) KRT13 (White sponge nevus) KRT14 (Epidermolysis bullosa simplex) KRT17 (Steatocystoma multiplex) KRT18 (Familial cirrhosis) KRT81/KRT83/KRT86 (Monilethrix) Naegeli–Franceschetti–Jadassohn syndrome Reticular pigmented anomaly of the flexures

3	Desmin: Desmin-related myofibrillar myopathy Dilated cardiomyopathy 1I GFAP: Alexander disease Peripherin: Amyotrophic lateral sclerosis

4	Neurofilament: Parkinson's disease Charcot–Marie–Tooth disease 1F, 2E Amyotrophic lateral sclerosis

5	Laminopathy: LMNA Mandibuloacral dysplasia Dunnigan Familial partial lipodystrophy Emery-Dreifuss muscular dystrophy 2 Limb-girdle muscular dystrophy 1B Charcot–Marie–Tooth disease 2B1 LMNB Barraquer–Simons syndrome LEMD3 Buschke–Ollendorff syndrome Osteopoikilosis LBR Pelger-Huet anomaly Hydrops-ectopic calcification-moth-eaten skeletal dysplasia

Microtubules

Kinesin	Charcot–Marie–Tooth disease 2A Hereditary spastic paraplegia 10

Dynein	Primary ciliary dyskinesia Short rib-polydactyly syndrome 3 Asphyxiating thoracic dysplasia 3

Other	Tauopathy Cavernous venous malformation

Membrane

Ankyrin: Long QT syndrome 4

Hereditary spherocytosis 1

Catenin

APC
- Gardner's syndrome
- Familial adenomatous polyposis
plakoglobin (Naxos syndrome)
GAN (Giant axonal neuropathy)

Other

centrosome: PCNT (Microcephalic osteodysplastic primordial dwarfism type II)

See also: cytoskeletal proteins

Genetic disorder, protein biosynthesis: Transcription factor/coregulator deficiencies

(1) Basic domains

1.2	Feingold syndrome Saethre–Chotzen syndrome

1.3	Tietz syndrome

(2) Zinc finger
DNA-binding domains

2.1	(Intracellular receptor): Thyroid hormone resistance Androgen insensitivity syndrome PAIS MAIS CAIS Kennedy's disease PHA1AD pseudohypoaldosteronism Estrogen insensitivity syndrome X-linked adrenal hypoplasia congenita MODY 1 Familial partial lipodystrophy 3 SF1 XY gonadal dysgenesis

2.2	Barakat syndrome Tricho–rhino–phalangeal syndrome

2.3	Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome Denys–Drash syndrome Duane-radial ray syndrome MODY 7 MRX 89 Townes–Brocks syndrome Acrocallosal syndrome Myotonic dystrophy 2

2.5	Autoimmune polyendocrine syndrome type 1

(3) Helix-turn-helix domains

3.1	ARX Ohtahara syndrome Lissencephaly X2 MNX1 Currarino syndrome HOXD13 SPD1 Synpolydactyly PDX1 MODY 4 LMX1B Nail–patella syndrome MSX1 Tooth and nail syndrome OFC5 PITX2 Axenfeld syndrome 1 POU4F3 DFNA15 POU3F4 DFNX2 ZEB1 Posterior polymorphous corneal dystrophy Fuchs' dystrophy 3 ZEB2 Mowat–Wilson syndrome

3.2	PAX2 Papillorenal syndrome PAX3 Waardenburg syndrome 1&3 PAX4 MODY 9 PAX6 Gillespie syndrome Coloboma of optic nerve PAX8 Congenital hypothyroidism 2 PAX9 STHAG3

3.3	FOXC1 Axenfeld syndrome 3 Iridogoniodysgenesis, dominant type FOXC2 Lymphedema–distichiasis syndrome FOXE1 Bamforth–Lazarus syndrome FOXE3 Anterior segment mesenchymal dysgenesis FOXF1 ACD/MPV FOXI1 Enlarged vestibular aqueduct FOXL2 Premature ovarian failure 3 FOXP3 IPEX

3.5	IRF6 Van der Woude syndrome Popliteal pterygium syndrome

(4) β-Scaffold factors
with minor groove contacts

4.2	Hyperimmunoglobulin E syndrome

4.3	Holt–Oram syndrome Li–Fraumeni syndrome Ulnar–mammary syndrome

4.7	Campomelic dysplasia MODY 3 MODY 5 SF1 SRY XY gonadal dysgenesis Premature ovarian failure 7 SOX10 Waardenburg syndrome 4c Yemenite deaf-blind hypopigmentation syndrome

4.11	Cleidocranial dysostosis

(0) Other transcription factors

0.6	Kabuki syndrome

Ungrouped

Transcription coregulators

Coactivator:	CREBBP Rubinstein–Taybi syndrome

Corepressor:	HR (Atrichia with papular lesions)

Diseases of collagen, laminin and other scleroproteins

Collagen disease

COL1:	Osteogenesis imperfecta Ehlers–Danlos syndrome, types 1, 2, 7

COL2:	Hypochondrogenesis Achondrogenesis type 2 Stickler syndrome Marshall syndrome Spondyloepiphyseal dysplasia congenita Spondyloepimetaphyseal dysplasia, Strudwick type Kniest dysplasia (see also C2/11)

COL3:	Ehlers–Danlos syndrome, types 3 & 4 Sack–Barabas syndrome

COL4:	Alport syndrome

COL5:	Ehlers–Danlos syndrome, types 1 & 2

COL6:	Bethlem myopathy Ullrich congenital muscular dystrophy

COL7:	Epidermolysis bullosa dystrophica Recessive dystrophic epidermolysis bullosa Bart syndrome Transient bullous dermolysis of the newborn

COL8:	Fuchs' dystrophy 1

COL9:	Multiple epiphyseal dysplasia 2, 3, 6

COL10:	Schmid metaphyseal chondrodysplasia

COL11:	Weissenbacher–Zweymüller syndrome Otospondylomegaepiphyseal dysplasia (see also C2/11)

COL17:	Bullous pemphigoid

Laminin

Other

see also fibrous proteins

Genetic disorder, membrane: Solute carrier disorders

1-10	SLC1A3 Episodic ataxia 6 SLC2A1 De Vivo disease SLC2A5 Fructose malabsorption SLC2A10 Arterial tortuosity syndrome SLC3A1 Cystinuria SLC4A1 Hereditary spherocytosis 4/Hereditary elliptocytosis 4 SLC4A11 Congenital endothelial dystrophy type 2 Fuchs' dystrophy 4 SLC5A1 Glucose-galactose malabsorption SLC5A2 Renal glycosuria SLC5A5 Thyroid dyshormonogenesis type 1 SLC6A19 Hartnup disease SLC7A7 Lysinuric protein intolerance SLC7A9 Cystinuria

11-20	SLC11A1 Crohn's disease SLC12A3 Gitelman syndrome SLC16A1 HHF7 SLC16A2 Allan–Herndon–Dudley syndrome SLC17A5 Salla disease SLC17A8 DFNA25

21-40	SLC26A2 Multiple epiphyseal dysplasia 4 Achondrogenesis type 1B Recessive multiple epiphyseal dysplasia Atelosteogenesis, type II Diastrophic dysplasia SLC26A4 Pendred syndrome SLC35C1 CDOG 2C SLC39A4 Acrodermatitis enteropathica SLC40A1 African iron overload

see also solute carrier family

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